BRCA1、BRCA2和NOD2在胰腺炎和胰腺癌症风险评估中的已知遗传变异-动脉网

The known genetic variants of BRCA1, BRCA2 and NOD2 in pancreatitis and pancreatic cancer risk assessment

Nature 等信源发布 2025-01-13 18:39



可切换为仅中文







Abstract

摘要

The single nucleotide polymorphism in

单核苷酸多态性

NOD2

节点2

(rs2066847) is associated with conditions that may predispose to the development of gastrointestinal disorders, as well as the known

（rs2066847）与可能导致胃肠道疾病发展的疾病以及已知的疾病有关

BRCA1

and

和

BRCA2

brca

variants classified as risk factors in many cancers. In our study, we analyzed these variants in a group of patients with pancreatitis and pancreatic cancer to clarify their role in pancreatic disease development. The DNA was isolated from whole blood samples of 553 patients with pancreatitis, 83 patients with pancreatic cancer, 44 cases of other pancreatic diseases, and 116 healthy volunteers.

在许多癌症中被归类为危险因素的变体。在我们的研究中，我们分析了一组胰腺炎和胰腺癌患者的这些变异，以阐明它们在胰腺疾病发展中的作用。从553例胰腺炎患者，83例胰腺癌患者，44例其他胰腺疾病患者和116名健康志愿者的全血样本中分离出DNA。

The .

的。

NOD2

节点2

(rs2066847),

（rs2066847），

BRCA1

(rs80357914) and

（rs80357914）和

BRCA2

brca

(rs276174813) were genotyped. The statistically significant 3-fold increased risk of pancreatic cancer was detected among the patients with rs2066847 polymorphism (OR = 2.77,

（rs276174813）进行了基因分型。rs2066847多态性（OR）患者患胰腺癌的风险增加了3倍 = 2.77,

-value = 0.019). We did not find the studied polymorphisms in

-值=0.019）。我们没有发现研究的多态性

BRCA1

(rs80357914) and

（rs80357914）和

BRCA2

brca

(rs276174813). However, the adjacent polymorphisms have been detected only in patients with pancreatic diseases. The studied variant in

（rs276174813）。然而，仅在胰腺疾病患者中检测到相邻的多态性。

NOD2

节点2

occurs more frequently in pancreatic patients and significantly increases the risk of pancreatic cancer. It can be considered as a genetic risk factor that predisposes to cancer development. The analyzed regions in

。它可以被认为是易患癌症的遗传风险因素。中的分析区域

BRCA1

and

和

BRCA2

brca

may be a potential target in further search for a genetic marker of pancreatic diseases.

可能是进一步寻找胰腺疾病遗传标记的潜在目标。

Introduction

简介

Pancreatitis, regardless of whether it is acute or chronic, always carries the risk of malignant transformation leading to the development of one of the most dangerous and most difficult to treat and diagnose cancers: pancreatic cancer

胰腺炎，无论是急性还是慢性，总是有恶性转化的风险，导致发展为最危险、最难治疗和诊断的癌症之一：胰腺癌

. Genetic background plays an important role here, but as is widely known, many genes are involved in the metabolic pathways of the pancreas. The search for genetic markers differentiating patients with pancreatic cancer or pancreatitis would be a huge achievement in advancing the development of personalized therapies and prevention regimens against the development of these diseases.

遗传背景在这里起着重要作用，但众所周知，许多基因参与胰腺的代谢途径。寻找区分胰腺癌或胰腺炎患者的遗传标记将是推动针对这些疾病发展的个性化治疗和预防方案发展的巨大成就。

. Significant progress in oncological treatment was made after the development of modern diagnostics and the introduction of molecular drugs acting specifically against the molecular change in the cancer cell

现代诊断学的发展和专门针对癌细胞分子变化的分子药物的引入，在肿瘤治疗方面取得了重大进展

. The recent development of precision medicine is crucial because, based on extensive data on epidemiology, clinical parameters, family history, and genetic analyses, it can propose various strategic models for a given pancreatic disease

. An association between germline single nucleotide variants (SNV) of many genes and an increased risk of pancreatic cancer or pancreatitis has already been proven

许多基因的种系单核苷酸变异（SNV）与胰腺癌或胰腺炎风险增加之间的关联已被证明

. However, no clear differences have yet been identified because the same variants are often involved in different pathomechanisms of pancreatic diseases. Additionally, the influence of hereditary susceptibility to pancreatic cancer is enhanced by environmental factors such as smoking or alcohol consumption, which favors the formation of pathogenic somatic mutations leading to the development of cancer.

但是，尚未发现明显的差异，因为相同的变体通常涉及胰腺疾病的不同病理机制。此外，吸烟或饮酒等环境因素增强了遗传易感性对胰腺癌的影响，这有利于形成导致癌症发展的致病性体细胞突变。

. The literature often identifies germline mutations of many genes that increase the risk of pancreatitis or pancreatic cancer

文献通常确定了许多基因的种系突变，这些突变会增加胰腺炎或胰腺癌的风险

. This entails an increased risk of loss of heterozygosity or loss of function in somatic cells (mostly in the

。这会增加体细胞杂合性丧失或功能丧失的风险（主要是在

KRAS

克拉斯

CDKN2A

TP53

TP53型

and

和

SMAD4

/DPC4) often identified at different stages of the pancreatic cancer development

/DPC4）通常在胰腺癌发展的不同阶段被发现

. Germline

.种系

BRCA1

mutations occur in 4–7% of pancreatic cancers and they are the most common mutated genes in familial pancreatic cancer, however, mutations in

突变发生在4-7%的胰腺癌中，它们是家族性胰腺癌中最常见的突变基因，然而

BRCA2

brca

are more common (5–17% of pancreatic cancer) and increase the risk of disease by 3.5–10 times

更常见（占胰腺癌的5-17%），患病风险增加3.5-10倍

. Currently, the NCCN guidelines recommend testing all patients with pancreatic cancer for the presence of germline

目前，NCCN指南建议测试所有胰腺癌患者是否存在种系

BRCA1

BRCA2

brca

mutations. This is related to attempts at early detection of pancreatic cancer in patients’ relatives by recommending screening. Other high-risk factors include, among others: having a first-degree relative with pancreatic cancer, diagnosis of Peutz-Jeghers syndrome or Lynch syndrome, detection of a .

突变。这与通过推荐筛查在患者亲属中早期发现胰腺癌的尝试有关。。

CDKN2A

mutation

突变

. Recently, the role of other genes has been reported, e.g. according to The Cancer Genome Atlas,

.最近，已经报道了其他基因的作用，例如根据癌症基因组图谱，

CHEK2

支票2

gene mutations are observed in 0.7% of pancreatic cancer cases and it probably interacts with the

在0.7%的胰腺癌病例中观察到基因突变，它可能与

BRCA

gene, deepening DNA repair disorders and contributing to cancer development

基因，加深DNA修复障碍并促进癌症发展

. Another gene that is recently attracting increasing attention of clinical geneticists is

.最近引起临床遗传学家越来越多关注的另一个基因是

NOD2

节点2

. This gene is associated with inflammatory bowel disease and pancreatitis. Recurrent pancreatitis can lead to cancer development by stimulating cell proliferation, inducing DNA damage, and stimulating angiogenesis. The conducted analyses for the

该基因与炎症性肠病和胰腺炎有关。复发性胰腺炎可通过刺激细胞增殖，诱导DNA损伤和刺激血管生成而导致癌症发展。对

NOD2

节点2

mutations among the patients with pancreatic cancer have not revealed any significant correlations yet, but only served as the preliminary studies

胰腺癌患者的突变尚未发现任何显着相关性，但仅作为初步研究

. This well-founded hypothesis needs to be further verified and explored on a bigger study group.

。这个有充分依据的假设需要在更大的研究小组中进一步验证和探索。

The aim of the study was to analyze the occurrence of three single nucleotide polymorphisms (SNP) in

这项研究的目的是分析三种单核苷酸多态性（SNP）在

NOD2

节点2

and

和

BRCA1

BRCA2

brca

genes among patients with acute pancreatitis and pancreatic cancer, in comparison to healthy volunteers. The results are an important scientific contribution to the knowledge on pathomechanisms of pancreatic diseases and may have influence on the development of predictive schemes.

与健康志愿者相比，急性胰腺炎和胰腺癌患者的基因。这些结果是对胰腺疾病发病机制知识的重要科学贡献，并可能对预测方案的发展产生影响。

Results

结果

A total of 796 DNA samples was used for the analysis of the selected single nucleotide variants in the 11th exon of

共有796个DNA样本用于分析

NOD2

节点2

(rs2066847), 2nd exon of

（rs2066847），第二外显子

BRCA1

(rs80357914), and 10th exon of

（rs80357914）和

BRCA2

brca

(rs276174813). Research material was isolated from 680 clinical patients and 116 healthy volunteers. The patients were distinguished based on the type of the diseases: acute and chronic pancreatitis, pancreatic cancer, and other pancreatic diseases. In further differentiation, the etiological factor of pancreatitis was considered, however in some cases it could not be identified.

（rs276174813）。从680名临床患者和116名健康志愿者中分离出研究材料。根据疾病类型对患者进行区分：急性和慢性胰腺炎，胰腺癌和其他胰腺疾病。在进一步的鉴别中，考虑了胰腺炎的病因，但在某些情况下无法确定。

The analyses were not performed for all samples due to technical problems (lack of research material or PCR product, lack of HRM analysis/Sanger sequencing of sufficient quality). The final number of samples for which genetic analysis was performed is shown in Table .

由于技术问题（缺乏研究材料或PCR产物，缺乏足够质量的HRM分析/桑格测序），未对所有样品进行分析。表中显示了进行遗传分析的最终样本数。

. Due to the small number of cases in some factors of acute pancreatitis and chronic pancreatitis, the following groups were finally distinguished for statistical analysis: idiopathic, biliary, alcoholic, other (postpartum, hyperlipidemia, drug-related, cancer-related, autoimmunological) and the group not diagnosed with an etiological factor..

由于急性胰腺炎和慢性胰腺炎某些因素的病例数较少，因此最终将以下几组进行了统计分析：特发性，胆汁性，酒精性，其他（产后，高脂血症，药物相关，癌症相关，自身免疫性）和未诊断出病因的组。。

Table 1 The total number of participants included in the study and the number of samples with genetic analysis in particular genes (

表1研究中包括的参与者总数以及对特定基因进行遗传分析的样本数量(

NOD2

节点2

BRCA1

BRCA2

brca

美联社

acute pancreatitis,

急性胰腺炎，

CP公司

chronic pancreatitis,

慢性胰腺炎，

C级

pancreatic cancer,

胰腺癌，

other

其他

other diseases; etiological factor of pancreatitis:

其他疾病；胰腺炎的病因：

我

idiopathic,

特发性，

b类

biliary,

胆汁，

Alc

Alcoholic,

酒精，

postpartum,

产后，

小时

hyperlipidemia,

高脂血症，

博士

drug-related,

与毒品有关，

CR公司

cancer-related,

癌症相关，

一

autoimmunological,

自身免疫，

ND公司

not diagnosed.

未诊断。

Full size table

全尺寸表

The allele frequencies in the studied group were determined, alongside the analysis of the frequencies of the investigated genetic variants in both global and European populations, based on the ALFA Allele Frequency Database (NCBI) and shown in Table

根据ALFA等位基因频率数据库（NCBI），确定了研究组中的等位基因频率，并分析了全球和欧洲人群中研究的遗传变异的频率，如表所示

(

https://www.ncbi.nlm.nih.gov

). For the

)。对于

NOD2

节点2

gene variant (rs2066847), the global allele frequency of the duplication variant is reported as 0.08544, with a notably higher prevalence in European populations, where the frequency is 0.09429. In the studied population, the allele frequency was lower and amounted to 0,0516 (Table

基因变异（rs2066847），据报道重复变异的全球等位基因频率为0.08544，在欧洲人群中的患病率明显更高，频率为0.09429。在研究人群中，等位基因频率较低，为00516（表

). Regarding the

)。关于

BRCA1

gene variant (rs80357914), the global allele frequency of the CT variant is 0.00065, whereas in European populations, it is slightly lower at 0.00051. For the

基因变异（rs80357914），CT变异的全球等位基因频率为0.00065，而在欧洲人群中，该频率略低，为0.00051。对于

BRCA2

brca

gene variant (rs276174813), data from the gnomAD Study were utilized. According to the database, the global allele frequency for the delCTTAT variant is 0.000004, while in European populations, the frequency is slightly higher at 0.000008. In our study, there were no cases of both variants. Further statistical analysis included the assessment of variant frequencies in individual study groups, as well as for the etiological factor contributing to the disease occurrence.

基因变异（rs276174813），来自gnomAD研究的数据被利用。根据数据库，delCTTAT变体的全球等位基因频率为0.000004，而在欧洲人群中，该频率略高，为0.000008。在我们的研究中，没有两种变体的情况。。

It should be mentioned that the frequency of alleles in specific populations is often lower than the global average due to differences in genetic diversity and allele distribution across regions. An interesting result was revealed for rs2066847 of .

应该提到的是，由于不同地区的遗传多样性和等位基因分布的差异，特定人群中等位基因的频率通常低于全球平均水平。的rs2066847显示了一个有趣的结果。

NOD2

节点2

gene (Table

基因（表

). This polymorphism occurred least frequently among the control group and patients with “other diseases” (6% of participants). Considering the type of pancreatitis, the participants with the rs2066847 polymorphism seem to be more predisposed to chronic pancreatitis (CP), the prevalence of the polymorphism was 4% higher in this group compared to acute pancreatitis (AP) (10% of AP patients), but the difference was not statistically significant (Fisher’s exact two sided), probably due to due to the small size of the CP group (.

)。。考虑到胰腺炎的类型，rs2066847多态性的参与者似乎更容易患慢性胰腺炎（CP），与急性胰腺炎（AP）相比，该组多态性的患病率高4%（AP患者的10%），但差异无统计学意义（Fisher的精确双侧），可能是由于CP组的规模较小（。

= 21). In the AP group of patients, the polymorphism occurred least frequently in the case of an idiopathic factor (7% of patients), and most frequently in the case of alcoholic acute pancreatitis (12.76% of AP-Alc). This prevalence was not statistically significant compared to any other group of patients (chi-square or Fisher’s exact two sided).

在AP组患者中，多态性在特发性因素（7%的患者）中发生频率最低，在酒精性急性胰腺炎（12.76%的AP Alc）中发生频率最高。与任何其他患者组（卡方或Fisher精确双侧）相比，这种患病率在统计学上并不显着。

In the AP-Alc group, polymorphism was detected in 18 patients: 17/132 males with AP-Alc and only one female among 12 females with AP-Alc. However, this difference was also not statistically significant (Fisher’s exact two sided). The highest prevalence of the tested polymorphism was revealed in the group of patients with pancreatic cancer (16.86% of patients).

在AP Alc组中，在18例患者中检测到多态性：AP Alc男性17/132，AP Alc女性12例中只有1例女性。然而，这种差异也没有统计学意义（费舍尔的精确双面）。在胰腺癌患者组中，测试多态性的患病率最高（占患者的16.86%）。

In general, there is a tendency for the number of patients with the polymorphism to increase as the severity of pancreatic disease increases (Fig. .

一般来说，随着胰腺疾病严重程度的增加，多态性患者的数量有增加的趋势（图）。

). The statistically significant three-fold increased risk of pancreatic cancer was detected among the patients with rs2066847 polymorphism (OR 2.77, 95% CI 1.20–6.42; RR = 3.13, 95% CI 1.23–7.94;

)。在rs2066847多态性（OR）患者中，发现胰腺癌风险增加了三倍 2.77, 95%可信区间1.20-6.42；RR=3.13，95%可信区间1.23-7.94；

-value = 0.019, Fisher’s exact test, two-sided). When comparing the occurrence of the tested genetic polymorphism between the remaining groups, no correlation was found (Tables

-值=0.019，费舍尔的精确测试，双面）。当比较其余组之间测试的遗传多态性的发生率时，未发现相关性（表

and

和

Table 2 The allele frequency in study group and global and European population according to NCBI database. [

表2根据NCBI数据库，研究组以及全球和欧洲人群的等位基因频率。（笑声）[

https://www.ncbi.nlm.nih.gov

, Access date: 07.Dec. 2024].

，访问日期：2024年12月7日]。

Full size table

全尺寸表

Table 3 Occurrence of c.2938dup in

表3中c.2938dup的出现

NOD2

节点2

(rs2066847) among studied participants,

（rs2066847）在研究参与者中，

n (%)

氮（%）

number (percent) of participants with positive or negative results for the occurrence of rs2066847,

rs2066847阳性或阴性结果的参与者人数（百分比），

美联社

acute pancreatitis,

急性胰腺炎，

CP公司

chronic pancreatitis;

慢性胰腺炎；

C级

pancreatic cancer,

胰腺癌，

other

其他

other diseases; etiological factor of pancreatitis:

其他疾病；胰腺炎的病因：

我

idiopathic,

特发性，

b类

biliary,

胆汁，

Alc

Alcoholic,

酒精，

CR公司

cancer-related,

癌症相关，

一

autoimmunological,

自身免疫，

ND公司

not diagnosed.

未诊断。

Full size table

全尺寸表

Fig. 1

图1

The occurrence of

发生

NOD2

节点2

polymorphism (rs2066847) in particular groups of participants:

特定参与者群体的多态性（rs2066847）：

control

控制

healthy volunteers,

健康志愿者，

AP and CP

AP和CP

patients with acute or chronic pancreatitis,

急性或慢性胰腺炎患者，

个人电脑

pancreatic cancer,

胰腺癌，

PD公司

pancreatic diseases (AP, CP, PC),

胰腺疾病（AP，CP，PC），

外径

other disease,

其他疾病，

positive

积极的

percentage of patients with rs2066847,

rs2066847患者的百分比，

negative

消极的

percentage of patients without rs2066847.

没有rs2066847的患者百分比。

Full size image

全尺寸图像

Table 4 Odds ratio (OR) and relative risk (RR) of

表4优势比（OR）和相对风险（RR）

NOD2

节点2

polymorphism (rs2066847) in the studied groups of participants, p-value was estimated by Fisher’s exact or chi-square test*, two-sided.

多态性（rs2066847）在研究的参与者组中，通过Fisher精确或卡方检验*估计p值，双面。

Full size table

全尺寸表

The analysis of the genetic polymorphism was also performed considering the sex of the studied participants (Table

考虑到研究参与者的性别，还对遗传多态性进行了分析（表

). The polymorphism was observed in 2% more males than females, as well as in the case of pancreatic cancer—the polymorphism occurred almost twice as often in men. However, the difference was not statistically significant, probably due to the size of the groups.

)。在男性中观察到的多态性比女性多2%，在胰腺癌的情况下，男性发生多态性的频率几乎是男性的两倍。然而，差异在统计学上并不显着，可能是由于群体的规模。

In the case of

在以下情况下

BRCA1

and

和

BRCA2

brca

, we did not identify the studied single nucleotide polymorphisms in any sample. However, all samples that showed a different curve in the HRM-PCR reaction (

，我们没有在任何样品中鉴定出所研究的单核苷酸多态性。然而，所有在HRM-PCR反应中显示不同曲线的样品(

= 13) revealed different single nucleotide variants after sequencing (Table

13）测序后发现不同的单核苷酸变异（表

S2级

). All these samples belonged to patients with pancreatic disease—84.6% of the patients had acute pancreatitis, one patient had pancreatic cancer, and one had another pancreatic disease. Within these polymorphisms, 3 different ones have been identified for

)。所有这些样本均属于胰腺疾病患者-84.6%的患者患有急性胰腺炎，一名患者患有胰腺癌，另一名患者患有另一种胰腺疾病。在这些多态性中，已经鉴定出3种不同的多态性

BRCA1

(rs80357031, rs766004110, rs80356839), and 4 different for

（rs80357031，rs766004110，rs80356839），以及4个不同的

BRCA2

brca

(rs80358475, rs28897710, rs56328701, rs2137474144). Only one of these samples had the studied

（rs80358475，rs28897710，rs56328701，rs2137474144）。

NOD2

节点2

polymorphism. These genetic variants are classified as nonpathogenic. In order to assess the sensitivity of the method, we randomly sequenced PCR products without changes in the HRM curve. For

多态性。这些遗传变异被归类为非致病性。为了评估该方法的灵敏度，我们对PCR产物进行了随机测序，而HRM曲线没有变化。对于

BRCA1

and

和

BRCA2

brca

, 11 and 15 samples, respectively. Most samples did not show polymorphic changes, but it should be emphasized that these methods are not intended to identify any change but have been optimized for the detection of rs80357914 and rs276174813.

，分别为11和15个样本。大多数样品没有显示多态性变化，但应该强调的是，这些方法并非旨在识别任何变化，而是已针对rs80357914和rs276174813的检测进行了优化。

Discussion

讨论

Pancreatic diseases are a serious health, social and economic problem worldwide, due to their often-severe course, complications, and high risk of recurrence

胰腺疾病是世界范围内严重的健康、社会和经济问题，因为它们的病程通常很严重，并发症多，复发风险高

. Globally, the incidence of acute pancreatitis ranges from 30 to 40 cases per 100,000 individuals annually, with some regions in Europe reporting rates as high as 100 cases per 100,000 individuals

。在全球范围内，急性胰腺炎的发病率每年为每10万人30至40例，欧洲一些地区的报告率高达每10万人100例

. In contrast, the average global incidence of pancreatic cancer is 4.9 cases per 100,000 individuals, while in Europe, the rates are higher, reaching 8–12 cases per 100,000 individuals

相比之下，全球胰腺癌的平均发病率为每10万人4.9例，而在欧洲，发病率更高，达到每10万人8-12例

. Considering the relatively high incidence of pancreatitis, which is also etiological factors of pancreatic cancer, multifactorial etiology of pancreatic diseases and the difficulties in prevention and treatment, the problem is undeniably important and requires further research. They affect not only the organ itself, but the whole organism, limiting the efficient functioning of a person in society, thus increasing the cost of maintaining the individual and reducing the productivity of society.

考虑到胰腺炎的发病率相对较高，胰腺炎也是胰腺癌的病因，胰腺疾病的多因素病因以及预防和治疗的困难，这个问题无疑很重要，需要进一步研究。。

The most important are acute and chronic pancreatitis and malignant and non-malignant pancreatic tumours.

最重要的是急性和慢性胰腺炎以及恶性和非恶性胰腺肿瘤。

. Pancreatic diseases pose difficulties not only for efficient diagnosis but also for the development of effective methods of prevention and prediction. The reason for this is the multifactorial and polygenic nature of these diseases

胰腺疾病不仅对有效诊断构成困难，而且对开发有效的预防和预测方法也构成困难。原因是这些疾病的多因素和多基因性质

. The specific and crucial genes for the pancreas show activity that is not remarkably tissue-specific, but also highly inducible. This is why it is so difficult to find clear pathways leading to a given pancreatic disease, especially when it comes to inflammation and cancer

胰腺的特异性和关键基因显示出的活性不具有明显的组织特异性，但也具有高度诱导性。这就是为什么很难找到导致特定胰腺疾病的明确途径，尤其是在炎症和癌症方面

. Many genetic polymorphisms correlated with pancreatitis or pancreatic cancer have already been detected, and new ones are still being revealed

. Progress in genetic research and the increase in interest in this area provide a great opportunity to develop predictive schemes for the development of pancreatic disease and to propose new therapeutic methods

.基因研究的进展和对该领域兴趣的增加为开发胰腺疾病发展的预测方案和提出新的治疗方法提供了极好的机会

. The presented results of our work constitute an important contribution of an additional polymorphism that significantly increases the risk of pancreatic cancer. We paid attention to the three genes already mentioned and well known in the development of cancers and other related diseases, but we focused particular attention on selected clinically important genetic polymorphisms: rs2066847 of .

。我们的工作结果构成了另一种多态性的重要贡献，该多态性显着增加了胰腺癌的风险。我们注意到了在癌症和其他相关疾病的发展中已经提到并众所周知的三个基因，但我们特别关注了选定的临床重要遗传多态性：rs2066847。

NOD2

节点2

, rs80357914 of

，rs80357914

BRCA1

, and rs276174813 of

，以及rs276174813

BRCA2

brca

. Recent studies suggest that

.最近的研究表明

BRCA1

and

和

BRCA2

brca

mutations affect cellular responses not only through DNA repair defects but also by altering immune signaling pathways. For instance,

突变不仅通过DNA修复缺陷影响细胞反应，还通过改变免疫信号通路影响细胞反应。例如，

BRCA1

mutations can dysregulate NF-κB signaling, a pathway also influenced by

突变可以失调NF-κB信号传导，这一途径也受到

NOD2

节点2

activity. NF-κB is critical in immune responses and inflammation, which are processes where

活动。NF-κB在免疫反应和炎症中至关重要，这是一个

NOD2

节点2

plays a key role. Dysregulated NF-κB activity has been linked to cancer development and progression in

起着关键作用。NF-κB活性失调与癌症的发展和进展有关

BRCA

-mutated cells. This overlapping impact on NF-κB suggests a possible indirect connection between

-突变的细胞。这种对NF-κB的重叠影响表明两者之间可能存在间接联系

BRCA1

BRCA2

brca

and

和

NOD2

节点2

through immune regulation and inflammatory signaling pathways

通过免疫调节和炎症信号通路

. Additionally,

.此外，

NOD2’s

role in autophagy and cellular stress responses, mechanisms also implicated in BRCA-related tumor suppression, provides another avenue for potential interaction. Aberrations in these shared pathways might contribute to a more comprehensive understanding of cancer etiology, particularly in inflammation-driven cancers.

在自噬和细胞应激反应中的作用，也与BRCA相关的肿瘤抑制有关的机制，为潜在的相互作用提供了另一种途径。这些共享途径中的畸变可能有助于更全面地了解癌症病因，特别是在炎症驱动的癌症中。

NOD2

节点2

(nucleotide-binding oligomerization domain containing 2) known also as the

（包含2的核苷酸结合寡聚化结构域）也称为

CARD15

卡片15

gene is located on chromosome 16q12.1 in humans and it encodes a pattern recognition receptor, which recognizes the conserved motifs in bacterial peptidoglycan and is involved in apoptosis by activating the NF-κB protein

该基因位于人类16q12.1染色体上，编码一种模式识别受体，该受体识别细菌肽聚糖中的保守基序，并通过激活NF-κB蛋白参与细胞凋亡

. Mutations in this gene have been associated with many inflammatory diseases, for example, Crohn’s disease, Blau syndrome, severe pulmonary sarcoidosis

该基因的突变与许多炎症性疾病有关，例如克罗恩病、布劳综合征、严重肺结节病

. as well as cancers in the colon, ovary, breast, lung, larynx, Non-Hodgkin lymphoma, melanoma and many others

以及结肠癌、卵巢癌、乳腺癌、肺癌、喉癌、非霍奇金淋巴瘤、黑色素瘤等多种癌症

. Three

.三

NOD2

节点2

polymorphisms are of particular importance:

NOD2

节点2

(NM_001370466.1): c.2023 C > T p.(Arg675Trp) (rs2066844),

（NM_001370466.1）：c.2023×cτ>T p.（Arg675Trp）（rs2066844），

NOD2

节点2

(NM_001370466.1): c.2641G > C p.(Gly881Arg) (rs2066845) and NM_022162.3(NOD2): c.3019dup p.(Leu1007fs) (rs2066847) due to their association with increased risk of gastrointestinal cancers, but not with pancreatic cancer

（NM 001370466.1）：c.2641G> c p。（Gly881Arg）（rs2066845）和NM 022162.3（NOD2）：c.3019dup p。（Leu1007fs）（rs2066847）与胃肠道癌风险增加有关，但与胰腺癌无关

. The last one is frameshift mutation

最后一个是移码突变

NOD2

节点2

(NM_022162.3): c.3019dup p.(Leu1007fs) (rs2066847) in exon 11 and results in a prematurely truncated protein predicted to reduce its functional efficiency. This polymorphism was strongly correlated with Crohn’s Disease

（NM\U 022162.3）：外显子11中的c.3019dup p。（Leu1007fs）（rs2066847），并导致蛋白质过早截短，预计会降低其功能效率。这种多态性与克罗恩病密切相关

. There is evidence that the pathophysiology of the pancreas is associated with inflammatory bowel diseases, in particular Crohn’s disease

有证据表明，胰腺的病理生理学与炎症性肠病，特别是克罗恩病有关

, therefore, the role of

因此

NOD2

节点2

and rs2066847 polymorphism seems particularly interesting at this point. Contrary to previous reports, we have shown for the first time this polymorphism clearly correlates with an increased risk of pancreatic cancer − 3 times higher risk (Table

rs2066847多态性在这一点上似乎特别有趣。与以前的报道相反，我们首次表明这种多态性与胰腺癌风险增加明显相关，风险增加了3倍（表

) and shows a trend of increasing cases of pancreatic disease with an increasing number of mutations in the studied groups of participants (Fig.

)并且在研究的参与者组中显示出胰腺疾病病例增加的趋势，突变数量增加（图）。

). Congruent studies were conducted by Nej et al.

)。Nej等人进行了一致的研究。

; they showed a similar frequency of this polymorphism occurrence in healthy individuals (7%) and families with a history of pancreatic cancer (14%), but they did not confirm the association with an increased risk of familial pancreatic cancer, probably due to the small size of the study groups. We would like to mention that in our research we noticed the highest prevalence of polymorphism in the AP-Alc group compared to idiopathic AP cases, which can suggest a potential interaction between genetic predisposition and environmental factors, such as alcohol consumption.

；他们在健康个体（7%）和有胰腺癌病史的家庭（14%）中显示出类似的多态性发生频率，但他们没有证实与家族性胰腺癌风险增加有关，这可能是由于研究组规模较小。我们要提到的是，在我们的研究中，我们注意到与特发性AP病例相比，AP Alc组的多态性患病率最高，这可能表明遗传易感性与环境因素（如饮酒）之间存在潜在的相互作用。

These results are consistent with previous studies indicating that .

这些结果与之前的研究结果一致。

NOD2

节点2

mutations may modulate the response to alcohol-induced injury

突变可能调节对酒精引起的损伤的反应

NOD2

节点2

and the aforementioned rs2066847 should be investigated further because of their reasonable association with inflammatory bowel and pancreatic diseases.

由于上述rs2066847与炎症性肠病和胰腺疾病的合理关联，因此应进一步研究。

Initially, in the case of the

最初，在

BRCA1

and

和

BRCA2

brca

genes, the analysis was aimed at detecting two polymorphisms: rs80357914 and rs276174813, which have clinical importance (pathogenic) for breast and ovarian cancers

基因，该分析旨在检测两个多态性：rs80357914和rs276174813，它们对乳腺癌和卵巢癌具有临床重要性（致病性）

BRCA1

and

和

BRCA2

brca

genes are tumor suppressor genes that are primarily involved in cell cycle control, DNA repair pathways, and regulation of apoptosis. They are expressed in various cells, therefore mutations in these genes may predispose to multi-organ cancers, mostly including breast and ovary but also others such as colon, and prostate.

基因是主要参与细胞周期控制，DNA修复途径和细胞凋亡调节的肿瘤抑制基因。它们在各种细胞中表达，因此这些基因的突变可能易患多器官癌，主要包括乳腺癌和卵巢癌，也包括其他癌症，如结肠癌和前列腺癌。

There is evidence that mutations in these genes may also increase the risk of pancreatic cancer.

有证据表明，这些基因的突变也可能增加患胰腺癌的风险。

. The primary research including homogenic populations indicated the germline mutation rates in pancreatic cancer cases ranged from 1 to 11% for

。包括同基因人群在内的初步研究表明，胰腺癌病例的种系突变率为1%至11%

BRCA1

and 0–17% for

0-17%

BRCA2

brca

. More recent studies that used panel testing confirm the presence of pathogenic or likely pathogenic variants up to 3% for

。最近使用面板测试的研究证实，对于

BRCA1

and up to 6% for

高达6%

BRCA2

brca

among patients with pancreatic cancers

在胰腺癌患者中

. Nevertheless, single nucleotide polymorphisms in these genes are common and they are often associated with a founder effect

然而，这些基因中的单核苷酸多态性很常见，它们通常与创始人效应有关

. The rs80357914 of

.的rs80357914

BRCA1

represents c.68_69delAG frameshift mutation in codon 23 of exon 2 and creates the STOP codon in position 39, which leads to premature termination of translation and significant truncation of the protein. This mutation was described for the first time in the Ashkenazi Jews as founder mutation

代表外显子2密码子23中的c.68Å69delAG移码突变，并在39位产生终止密码子，这导致翻译的过早终止和蛋白质的显着截短。这种突变在德系犹太人中首次被描述为创始人突变

and now it is present in 1–16% of the patients with a family history of breast or ovarium cancer, depending on the region of the Polish population

现在，它存在于1-16%有乳腺癌或卵巢癌家族史的患者中，具体取决于波兰人口的地区

. This aggressive mutation was not detected in any of our studied samples., nor was the second polymorphism studied - rs276174813 of

。在我们研究的任何样本中均未检测到这种侵袭性突变。，也没有研究第二个多态性-rs276174813

BRCA2

brca

. The population frequency of the analyzed mutations is very low, as indicated by the data presented in Table

。如表中所示，所分析突变的种群频率非常低

, that is probably why no positive case could be found in the study group. Doraczyńska-Kowalik et al. revealed in the Polish population of patients with breast or ovarian cancer, approximately 0.69% had the tested mutations (rs276174813 and rs80357914)

，这可能就是为什么在研究组中找不到阳性病例的原因。Doraczyńska-Kowalik等人在波兰乳腺癌或卵巢癌患者中发现，大约0.69%的患者有测试突变（rs276174813和rs80357914）

. There are no data regarding the involvement of these polymorphisms in pancreatic cancer or pancreatitis. However, other adjacent polymorphisms were detected based on the changed HRM-PCR curve in the samples (Table

。没有关于这些多态性与胰腺癌或胰腺炎有关的数据。然而，根据样品中HRM-PCR曲线的变化，检测到其他相邻的多态性（表

S2级

). In

)。在

BRCA1

, three polymorphisms were detected, in

，在

BRCA2

brca

—four polymorphisms. They have uncleared clinical significance, but it is worth emphasizing that they were present only in patients, mostly with acute pancreatitis. It is worth examining this on a larger group of patients. Perhaps screening in this region could be used to determine the risk of patients with pancreatic disease or to select a genetic panel for this purpose..

-四个多态性。它们的临床意义尚不明确，但值得强调的是，它们仅存在于患者中，主要是急性胰腺炎。值得对更多患者进行研究。也许可以使用该区域的筛查来确定胰腺疾病患者的风险，或者为此目的选择一个基因组。。

To sum up our research, the group of patients with pancreatic cancer stands out. The statistically significant three-fold increased risk of pancreatic cancer in the case of rs2066847 carriers (OR 2.77,

总结我们的研究，这组胰腺癌患者脱颖而出。rs2066847携带者患胰腺癌的风险增加了三倍（或 2.77,

= 0.019) is the most significant result of this study. This may suggest that

=0.019）是这项研究最重要的结果。这可能表明

NOD2

节点2

influences the mechanisms of pancreatic carcinogenesis. Literature indicates that

影响胰腺癌发生的机制。文献表明

NOD2

节点2

mutations may lead to immune response dysfunction, which promotes chronic inflammation and neoplastic progression

突变可能导致免疫反应功能障碍，从而促进慢性炎症和肿瘤进展

However, we would like to point out some limitations of the work. The lack of correlation of genetic determinants with pancreatitis may be due to many other etiological factors. Population studies on large numbers of highly homogeneous groups and experimental studies examining the biochemical pathways of the studied polymorphism may be the key to solving this issue.

然而，我们想指出这项工作的一些局限性。遗传决定因素与胰腺炎缺乏相关性可能是由于许多其他病因。对大量高度同质群体的群体研究和检查所研究多态性的生化途径的实验研究可能是解决这个问题的关键。

We would like to underline that the prevalence of rs2066847 was higher in patients with chronic pancreatitis (CP) compared with acute pancreatitis (AP). These differences were not statistically significant, but the small size of the CP group may have contributed to the lack of significance, emphasizing the need for larger cohort studies.

我们要强调的是，与急性胰腺炎（AP）相比，慢性胰腺炎（CP）患者rs2066847的患病率更高。这些差异在统计学上并不显着，但CP组的规模较小可能导致缺乏意义，强调需要进行更大规模的队列研究。

In the literature, polymorphisms in the .

在文献中，多态性。

NOD2

节点2

gene have been associated with various inflammatory conditions, including Crohn’s disease, suggesting a potential molecular mechanism related to the regulation of the immune response and susceptibility to chronic inflammation in the pancreas

该基因与包括克罗恩病在内的各种炎症状态有关，提示潜在的分子机制与胰腺免疫反应的调节和慢性炎症的易感性有关

. It is worth adding that the literature on the research topic is poor and most of the articles are of an experimental nature, the limited literature on this topic determines the lack of a full discussion of the obtained results. Nevertheless, our results indicate a stronger link between pancreatic cancer and a genetic basis than in other cases examined.

。然而，我们的结果表明，与其他检查的病例相比，胰腺癌与遗传基础之间的联系更强。

As already mentioned at the beginning of this work—pancreatic cancer is one of the most devastating diseases with extremely high mortality associated with late diagnosis, limitations of surgical treatment, and resistance to systemic therapy.

正如在这项工作开始时已经提到的那样，胰腺癌是最具破坏性的疾病之一，死亡率极高，与晚期诊断，手术治疗的局限性和对全身治疗的抵抗有关。

. It is one of the worst prognosis cancers with a 5-year survival rate of 5–8%. According to the National Cancer Registry, in 2021, in Poland, pancreatic cancer cases accounted for 2.2% of cancers in men and 2.2% of cancers in women, while deaths accounted for 4.6% and 5.5% of all cancer-related deaths, respectively.

。它是预后最差的癌症之一，5年生存率为5-8%。根据国家癌症登记处的数据，2021年，在波兰，胰腺癌病例分别占男性癌症的2.2%和女性癌症的2.2%，而死亡分别占所有癌症相关死亡的4.6%和5.5%。

Current statistics from the Global Burden of Disease Study 2019 confirm initial predictions, with an estimated incidence of + 0.6% in 2004–2019. As the incidence increased, the mortality rate also increased, although at a slower rate of + 0.3% per year.

2019年全球疾病负担研究的最新统计数据证实了初步预测，2004-2019年估计发病率为+0.6%。随着发病率的增加，死亡率也在增加，尽管每年的速度较慢，为+0.3%。

. Healthcare expenditures showed a positive correlation with morbidity and an inverse correlation with mortality, which was especially true for expenditures on medical care and hospital care. Pancreatic cancer is projected to become the second leading cause of cancer-related deaths in the United States in the next decade.

。预计在未来十年，胰腺癌将成为美国癌症相关死亡的第二大原因。

While advances in the treatment of other types of cancer have increased lifespan, mortality from pancreatic cancer has not changed significantly.

虽然其他类型癌症治疗的进展延长了寿命，但胰腺癌的死亡率没有显着变化。

. Most patients are diagnosed at an advanced stage of the disease and are treated mainly with chemotherapy regimens such as Fofirinox and gemcitabine with nab-paclitaxel

。大多数患者被诊断为疾病的晚期，主要接受化疗方案治疗，如Fofirinox和吉西他滨联合nab-紫杉醇

. The overall survival for patients with metastatic pancreatic cancer is less than one year. Significant progress in oncological treatment was made after the introduction of molecularly targeted drugs. This is related to modern diagnostics of changes in the genome of cancer cells

转移性胰腺癌患者的总生存期不到一年。引入分子靶向药物后，肿瘤治疗取得了重大进展。这与癌细胞基因组变化的现代诊断有关

. Detection of various genetic disorders in pancreatic cancer cells may become a diagnostic and therapeutic goal

检测胰腺癌细胞中的各种遗传疾病可能成为诊断和治疗的目标

. Gene mutations detected in pancreatic cancer cells are germline and somatic mutations. The influence of hereditary pancreatic cancer susceptibility genes is enhanced by environmental factors such as smoking or alcohol consumption, which favors the formation of pathogenic somatic mutations leading to the development of cancer.

在胰腺癌细胞中检测到的基因突变是种系和体细胞突变。吸烟或饮酒等环境因素增强了遗传性胰腺癌易感基因的影响，这有利于形成导致癌症发展的致病性体细胞突变。

Conclusions

结论

Single nucleotide polymorphism rs2066847 in

单核苷酸多态性rs2066847

NOD2

节点2

occurs more frequently in pancreatic patients and may predispose to cancer development, it increases the risk of cancer threefold. There was no correlation of

在胰腺患者中发生频率更高，并且可能易患癌症，这会使患癌症的风险增加三倍。没有相关性

NOD2

节点2

variant with acute pancreatitis and chronic pancreatitis. We did not find significant mutations in

急性胰腺炎和慢性胰腺炎的变异。我们没有发现明显的突变

BRCA1

and

和

BRCA2

brca

, however, the studied regions may be a potential target for further analysis in pancreatic patients.

但是，所研究的区域可能是胰腺患者进一步分析的潜在目标。

Materials and methods

材料和方法

Study group

研究小组

The study included 553 patients with a history of pancreatitis, 83 patients with pancreatic cancer, 44 patients with other pancreatic diseases (e.g. pancreatic cysts, pancreatic tumors, ampullary carcinoma), and 116 healthy volunteers (control group) recruited in the Świętokrzyskie voivodeship from 2013 to 2024.

这项研究包括553名有胰腺炎病史的患者，83名胰腺癌患者，44名其他胰腺疾病患者（如胰腺囊肿，胰腺肿瘤，壶腹癌）和116名健康志愿者（对照组），这些志愿者是2013年至2024年在托克尔兹基斯基voivodeship招募的。

The whole peripheral blood was obtained from the healthy volunteers and patients of Provincial Hospital in Kielce, Holy Cross Cancer Center, and St Alexander Hospital in Kielce, then stored at − 80 °C in the Department of Interventional Medicine with the Laboratory of Medical Genetics, Collegium Medicum of The Jan Kochanowski University in Kielce, Poland.

整个外周血是从基尔塞省立医院，圣十字癌症中心和基尔塞圣亚历山大医院的健康志愿者和患者那里获得的，然后保存在-80°C的介入医学系，由波兰基尔塞扬·科查诺夫斯基大学医学院医学遗传学实验室提供。

The characteristics of the study group with the inclusion and exclusion criteria are presented in Table .

表中列出了具有纳入和排除标准的研究组的特征。

. The study group size was determined based on the average incidence rates of the respective diseases. Specifically, an incidence rate of 35 cases per 100,000 individuals was utilized for acute pancreatitis, while for pancreatic cancer, the corresponding rate was established at 4.9 cases per 100,000 individuals, ensuring an evidence-based and statistically robust approach.

研究组的规模是根据各自疾病的平均发病率确定的。具体而言，急性胰腺炎的发病率为每10万人35例，而胰腺癌的发病率为每10万人4.9例，确保了循证和统计学上的稳健方法。

. The participants in the control group were not younger than 56 years old, so age is not a differentiating factor between groups and minimizes the impact of young age on reducing the risk of developing a given disease. The remaining study groups were not differentiated by age, because we wanted to verify every case of the disease, regardless of age, in relation to the genetic factor.

对照组的参与者不低于56岁，因此年龄不是组间的区别因素，并将年龄对降低患特定疾病风险的影响降至最低。其余的研究组没有按年龄区分，因为我们想验证每一个病例，无论年龄大小，都与遗传因素有关。

The etiology of acute (AP, .

急性（AP）的病因。

= 532) and chronic pancreatitis (CP,

532）和慢性胰腺炎（CP，

= 21) was divided into seven categories: idiopathic, biliary, alcoholic, postpartum, hyperlipidemia, drug-related, cancer-related, autoimmunological. However, due to the small number of cases with chronic pancreatitis, the etiological agent was reported only in supplements (Table

= 21）分为七类：特发性，胆汁性，酒精性，产后，高脂血症，药物相关，癌症相关，自身免疫。然而，由于慢性胰腺炎病例较少，病因仅在补充剂中报告（表

S1级

). In 92 cases of pancreatitis, the etiological factor could not be determined based on the interview and was classified as ND (not diagnosed). The pancreatic cancer stage TNM was classified according to the American Joint Committee of Cancer (AJCC) 8th edition. The tumor grade and type of the cancer were classified based on histological examination (64, 65).

)。在92例胰腺炎患者中，无法根据访谈确定病因，被归类为ND（未诊断）。胰腺癌分期TNM根据美国癌症联合委员会（AJCC）第8版进行分类。根据组织学检查对肿瘤分级和癌症类型进行分类（64,65）。

Detailed clinical data of patients including the type and etiology of disease, family history, sex, and age of patients are presented in Table .

表中列出了患者的详细临床数据，包括疾病的类型和病因，家族史，性别和年龄。

S1级

. Data collected in the family history concerned the incidence of pancreatic diseases in general (diabetes, pancreatitis, pancreatic cancer). The data were categorized according to the level of relationship and coded according to the following scheme: no diseases in the family, illness in the mother or father, sick siblings, grandfather or grandmother’s illness, a sick son or daughter, extended family..

。家族史中收集的数据涉及一般胰腺疾病（糖尿病，胰腺炎，胰腺癌）的发病率。数据根据关系水平进行分类，并根据以下方案进行编码：家庭中没有疾病，母亲或父亲患病，兄弟姐妹患病，祖父或祖母患病，儿子或女儿患病，大家庭。。

Table 5 The characteristics of the study groups with the inclusion and exclusion criteria.

表5具有纳入和排除标准的研究组的特征。

美联社

acute pancreatitis,

急性胰腺炎，

CP公司

chronic pancreatitis,

慢性胰腺炎，

C级

pancreatic cancer,

胰腺癌，

other

其他

other diseases,

其他疾病，

Control

控制

healthy volunteers,

健康志愿者，

number of participants.

参与者人数。

Full size table

全尺寸表

DNA isolation and quality control

DNA分离和质量控制

DNA isolation was performed using a commercial column kit Genomic Micro AX Blood Gravity (A&A Biotechnology, Gdańsk) according to the manufacturer’s protocol. Before DNA isolation, the blood was thawed, and the tubes were mixed to homogenize the input material. The material was stored at 4 °C. The quality and quantity of isolated DNA were spectrophotometrically analyzed using a droplet measurement device (DeNovix Ds-11, DeNovix Inc., Wilmington, USA).

根据制造商的方案，使用商业柱试剂盒Genomic Micro AX Blood Gravity（a＆a Biotechnology，Gdańsk）进行DNA分离。在分离DNA之前，将血液解冻，并将管混合以使输入材料均质化。将材料储存在4℃。使用液滴测量装置（DeNovix Ds-11，DeNovix Inc.，Wilmington，USA）通过分光光度法分析分离的DNA的质量和数量。

Absorbance was checked for wavelengths of 230 nm, 260 nm, and 280 nm. The minimum DNA concentration required for the research was 10 ng/µl. Samples for which the above criteria were not met were re-isolated..

检查230 nm，260 nm和280 nm波长的吸光度。该研究所需的最低DNA浓度为10 ng/µl。重新分离不符合上述标准的样品。。

PCRs

PCR

NOD2

节点2

For genotyping

用于基因分型

NOD2

节点2

(NM_001370466.1): c.2938dup (rs2066847) mutations TaqMan SNP Genotyping assays (ThermoFischer Scientifics) were used. The amplification and detection procedure were carried out in total reaction volume 10 µl, containing 5 µl TaqPathTM ProAmpTM Master Mix (Applied Biosystems), 0.25 µl TaqMan

（NM\U 001370466.1）：使用c.2938dup（rs2066847）突变TaqMan SNP基因分型测定法（ThermoFischer Scientifics）。扩增和检测程序在总反应体积10l中进行，其中含有5l TaqPathTM-ProAmpTM预混液（Applied Biosystems），0.25l TaqMan

SNP Genotyping Assay (20×) (ThermoFischer Scientifics), 1 µl Genomic DNA (10ng) and 3.75 µ Nuclease-Free Water (ThermoFischer Scientifics). The PCR amplification was conducted using Rotor-Gene Q (Qiagen) with an initial step of 95 °C for 10 min followed by 45 cycles of 95 °C for 15 s and 60 °C for 60 s.

SNP基因分型测定（20x）（ThermoFischer Scientifics），1µl基因组DNA（10ng）和3.75µ无核酸酶水（ThermoFischer Scientifics）。使用Rotor Gene Q（Qiagen）进行PCR扩增，初始步骤为95°C 10分钟，然后进行45个循环，分别为95°C 15 s和60°C 60 s。

Random positive samples were sequenced and compared to reference sequence..

对随机阳性样品进行测序，并与参考序列进行比较。。

BRCA1

and

和

BRCA2

brca

BRCA1

(NM_007294.4): c.68_69delAG (rs80357914) in exon 2 and

（NM\U 007294.4）：外显子2中的c.68\U 69delAG（rs80357914）和

BRCA2

brca

(NM_ 000059.4): c. 1796_1800del (rs276174813) in exon 10 to reference GRCh38 (

（NM\u000059.4）：外显子10中的c.1796\u 1800del（rs276174813）参考GRCh38(

https://www.ncbi.nlm.nih.gov/refseq/

) were genotyped by PCR amplification and high resolution melting (HRM) curve analysis using specific primers (Table

)通过PCR扩增和使用特异性引物的高分辨率熔解（HRM）曲线分析进行基因分型（表

) and Master Mix with DNA binding Dye (RT HS-PCR Mix EvaGreen

)并与DNA结合染料（RT HS-PCR Mix EvaGreen

, A&ABiotechnology, Poland). The following sequences of the primers were kindly provided by the Department of Molecular Diagnostics, Holy Cross Cancer Center, Kielce, Poland.

，A＆ABiotechnology，波兰）。。

Table 6 Amplified regions of

表6扩增区域

BRCA 1

gene, oligonucleotide primers and amplicons size (bp). F – forward, R – reverse, bp – based pairs.

基因，寡核苷酸引物和扩增子大小（bp）。F–正向，R–反向，基于bp的对。

Full size table

全尺寸表

All primers (synthesized by the oligo.pl company) were designed in this study using BLAST software (The National Center for Biotechnology Information—NCBI) and verified by OligoAnalyzer™ Tool (Integrated DNA Technologies, Inc.). The sequences of the primers, the size of PCR products, and the gene regions with accession numbers are presented in Table .

本研究使用BLAST软件（美国国家生物技术信息中心NCBI）设计了所有引物（由oligo.pl公司合成），并通过OligoAnalyzer™工具（Integrated DNA Technologies，Inc.）进行了验证。引物的序列，PCR产物的大小以及具有登录号的基因区域列于表中。

The final volume of PCR reagents for each sample was as follows: 5 µL of EvaGreen MasterMix, 1 µL of each 10 pmol primer (Forward and Reverse), 1 µL (10 ng) of DNA or water in negative control, all filled up with water to 10 µL of total volume. The analysis was conducted in a RotorGene Q 5-plex Thermalcycler (Qiagen, Germany) according to the protocol: Initial denaturation 95 °C for 10 min followed by 40 cycles of 95 °C for 15 s, 67 °C for 30 s (with touchdown 1 °C/10 cycles), 72 °C for 20 s.

每个样品的PCR试剂的最终体积如下：5µL EvaGreen MasterMix，1µL每10 pmol引物（正向和反向），1µL（10 ng）DNA或阴性对照中的水，全部用水填充至总体积的10µL。根据方案，在RotorGene Q 5-plex热循环仪（Qiagen，Germany）中进行分析：初始变性95°C 10分钟，然后进行40个循环，95°C 15 s，67°C 30 s（着陆1°C/10个循环），72°C 20 s。

The fluorescent data were acquired at the end of each extension step during PCR cycles (Excitation on 460 ± 10 nm, detection on 510 ± 5 nm). The HRM analysis was preceded by incubation at 95 °C for 10 s and 40 °C for 20 s (heteroduplex formation). The melting analysis was conducted on the temperature range 73–81 °C.

在PCR循环期间的每个延伸步骤结束时获得荧光数据（在460±10 nm激发，在510±5 nm检测）。HRM分析之前，先在95°C下孵育10 s，在40°C下孵育20 s（异源双链体形成）。熔融分析在73-81°C的温度范围内进行。

The Rotor-Gene Q proprietary software (version 2.3.5) was used to genotype the different genotypes. The negative derivative of fluorescence (F) over temperature (T) (dF/dT) curve primarily displays the temperature of melting (Tm), the normalized raw curve depicting the decreasing fluorescence versus increasing temperature, and difference curves were used.

Rotor Gene Q专有软件（版本2.3.5）用于对不同的基因型进行基因分型。荧光（F）随温度（T）的负导数（dF/dT）曲线主要显示熔化温度（Tm），归一化的原始曲线描绘了荧光随温度升高而降低，并使用了差异曲线。

A sample without genetic variants was used as a negative reaction control. The above testing protocol was optimized and validated using DNA samples with .

没有遗传变异的样品用作阴性反应对照。使用DNA样品对上述测试方案进行了优化和验证。

BRCA1

(NM_007294.4): c.68_69delAG (rs80357914) in exon 2 or

（NM\U 007294.4）：外显子2中的c.68\U 69delAG（rs80357914）或

BRCA2

brca

(NM_ 000059.4): c. 1796_1800del (rs276174813), which were derived from in-house sources. All samples with suspected genetic variants (a different HRM normalization graph and melt curve analysis from the negative reaction control) were verified using reference capillary sequencing using the SeqStudio Genetic Analyzer sequencer (Applied Biosystems by ThermoFisher Scientific).

（NM\u000059.4）：约1796\u 1800del（rs276174813），来自内部来源。使用SeqStudio遗传分析仪测序仪（ThermoFisher Scientific的Applied Biosystems），使用参考毛细管测序对所有具有可疑遗传变异的样品（与阴性反应对照不同的HRM归一化图和熔解曲线分析）进行验证。

The sequences of the PCR products were compared to the reference sequences of .

将PCR产物的序列与的参考序列进行比较。

BRCA1

或

BRCA2

brca

available from GeneBank using the BLAST platform (Table

可使用BLAST平台从GeneBank获得（表

Sequencing

测序

Negative samples for

阴性样品

BRCA1

and

和

BRCA2

brca

mutations were randomly sequenced to confirm negative results, as well as all samples suspected of polymorphism. Sequencing of individual samples consisted of four steps: purification of the PCR products, sequencing reaction, purification of the products resulting from the sequencing reaction, and capillary electrophoresis.

突变被随机测序以确认阴性结果，以及所有疑似多态性的样品。单个样品的测序包括四个步骤：PCR产物的纯化，测序反应，测序反应产物的纯化和毛细管电泳。

ThermoFisher Scientific (MA, USA) reagent was used for this procedure. In the first step, PCR products were visually assessed by agarose gel electrophoresis (band intensity), and the samples were diluted twice if necessary. To 5 µL of the sample solution, 2 µL of ExoSap-IT Express PCR Product Cleanup (cat.

ThermoFisher Scientific（MA，USA）试剂用于该程序。第一步，通过琼脂糖凝胶电泳（条带强度）目视评估PCR产物，必要时将样品稀释两次。。

75001.200.UL) was added. The samples were mixed and centrifuged (5 s at 1000 × g). The samples were incubated in a Master Cycler X50 (Eppendorf, SE Hamburg, Germany) for 4 min at 37 °C and 1 min at 80 °C and then placed on ice. The individual primers (Table .

增加了75001.200微升）。将样品混合并离心（1000×g，5 s）。。单个引物（表）。

) were diluted to 3.2 µM. For each primer, a reaction mixture was prepared consisting 0.5 µL of BigDye Terminator v3.1 Ready Reaction Mix (from BigDye Terminator v3.1 Cycle Sequencing Kit, no cat. 4337458), 1 µL of BigDye Terminator v1.1 and v3.1 5× Sequencing Buffer (cat. 4336697), 6.5 µL of deionized water (RNase/DNase-free), 1 µL of primer (3.2 µM), respectively multiplied by the number of samples.

)稀释至3.2µM。对于每种引物，制备反应混合物，其由0.5μlBigDye Terminator v3.1就绪反应混合物（来自BigDye Terminator v3.1循环测序试剂盒，无目录号4337458），1μlBigDye Terminator v1.1和v3.1 5x测序缓冲液（目录号4336697），6.5μL去离子水（无RNase/DNase），1μL引物（3.2μM）分别乘以样品数量。

The mixture was vortexed and centrifuged (5 s at 1000 × g). Nine microliters of the obtained mixture and 1 µL of the PCR product purified in the previous step were then added to the plate. The plate was sealed, vortexed for 3 s, centrifuged (5 s at 1000 × g), and incubated in a Master Cycler X50 (Eppendorf, SE, Hamburg, Germany) under the following conditions: denaturation at 96 °C for 1 min, followed by amplification for 25 cycles at 96 °C for 10 s, annealing for 5 s at 50 °C, and extension at 60 °C for 4 min, and 4 °C until the samples were ready for purification.

将混合物涡旋并离心（在1000×g下5秒）。然后将9微升获得的混合物和1微升在前一步中纯化的PCR产物添加到平板中。将板密封，涡旋3秒，离心（1000×g下5秒），并在主循环仪X50（Eppendorf，SE，Hamburg，Germany）中在以下条件下孵育：在96℃变性1分钟，然后在96℃扩增25个循环10秒，在50℃退火5秒，在60℃延伸4分钟和4℃直至样品准备好纯化。

A mixture was then prepared per sample: 45 µL of SAM solution (no cat. 4376497), 10 µL of XTerminator solution (cat. 4376493) vortexed, and 55 µL of the solution was added to each well on the plate removed from the thermal cycler to prevent the balls from sinking to the bottom. After resealing with foil, the mixture was vortexed for 20 min at 1800 rpm and centrifuged (2 min at 1000 × g).

然后每个样品制备混合物：45μlSAM溶液（无目录号4376497），10μlXTerminator溶液（目录号4376493）涡旋，并将55μL溶液加入到从热循环仪中取出的板上的每个孔中，以防止球下沉到底部。用箔重新密封后，将混合物以1800 rpm涡旋20分钟并离心（以1000×g离心2分钟）。

After changing the foil to septa and checking the buffer level, the plate was inserted into a SeqStudio Genetic Analyzer sequencer (Applied Biosystems by ThermoFisher Scientific) and sequenced on the Short Seq_BDX run module. After the process was completed, the results were automatically saved on the disk in the ab1 format..

将箔更换为隔膜并检查缓冲液水平后，将板插入SeqStudio遗传分析仪测序仪（ThermoFisher Scientific的Applied Biosystems）中，并在Short Seq\u BDX运行模块上测序。过程完成后，结果会自动以ab1格式保存在磁盘上。。

Statistical analysis

统计分析

Qualitative data distributions were described by frequency and percentages. Frequencies were compared using the chi-square test or Fisher’s exact test (in case the sample number is below

定性数据分布由频率和百分比描述。使用卡方检验或Fisher精确检验比较频率（如果样本数低于

= 10). The normality of the distribution was checked with the Shapiro–Wilk test. Due to the violation of the assumption of normality verified by Shapiro–Wilk test (

。由于违反了Shapiro-Wilk检验验证的正态性假设(

< 0.05), the distributions of quantitative features were compared using the Mann–Whitney U test. All statistical tests were two-sided. The occurrence of specific SNVs between study groups was determined by OR (odds ratio) and RR (relative risk) with confidence interval (95% CI) and it was analyzed statistically using Fisher’s exact or chi-square test, two-sided.

<0.05），使用Mann-Whitney U检验比较了定量特征的分布。所有的统计检验都是双面的。研究组之间特定SNV的发生率由OR（优势比）和RR（相对风险）确定，置信区间（95%CI），并使用Fisher精确或卡方检验进行统计分析。

< 0.05 was considered statistically significant. GraphPad Prism, version 9 (San Diego, CA, USA) was used for the analyses and derivation of figures.

<0.05被认为具有统计学意义。GraphPad Prism版本9（美国加利福尼亚州圣地亚哥）用于分析和推导数字。

Data availability

数据可用性

All data generated or analysed during this study are included in this published article and its supplementary information files (Tables

本研究中生成或分析的所有数据均包含在本文及其补充信息文件（表）中

S1级

and

和

S2级

). Anonymized clinical data and detailed genetic results for the study participants are available in Table

)。

S1级

, and HRM-PCR results are available in Table

，HRM-PCR结果见表

S2级

. Sequencing chromatograms of PCR products for positive and negative control of BRCA1 and BRCA2 gene fragments as well as HRM-PCR reaction curves is available from the corresponding author on reasonable request.

。应合理要求，通讯作者可提供用于BRCA1和BRCA2基因片段阳性和阴性对照的PCR产物测序色谱图以及HRM-PCR反应曲线。

References

参考文献

Le Cosquer, G. et al. Pancreatic cancer in chronic pancreatitis: pathogenesis and diagnostic approach.

Le Cosquer，G。等。慢性胰腺炎中的胰腺癌：发病机制和诊断方法。

Cancers

癌症

, 761.

https://doi.org/10.3390/cancers15030761

(2023).

Kirkegård, J. et al. Acute pancreatitis as an early marker of pancreatic cancer and cancer stage, treatment, and prognosis.

Kirkegård，J.等人。急性胰腺炎作为胰腺癌和癌症分期，治疗和预后的早期标志物。

Cancer Epidemiol.

癌症流行病学。

, 101647.

https://doi.org/10.1016/j.canep.2019.101647

(2020).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Bassi, C. et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after.

Bassi，C。等人。国际研究小组（ISGPS）术后胰瘘定义和分级的2016年更新：11年后。

Surg. (United States)

Surg.（美国）

161

(3), 584–591.

https://doi.org/10.1016/j.surg.2016.11.014

(2017).

Article

文章

Google Scholar

谷歌学者

Umans, D. S. et al. Pancreatitis and pancreatic cancer: a case of the chicken or the egg.

胰腺炎和胰腺癌：鸡或蛋的病例。

World J. Gastroenterol.

世界J.胃肠病学。

, 3148–3157.

https://doi.org/10.3748/wjg.v27.i23.3148

(2021).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Ebert, M., Schandl, L. & Schmid, R. M. Differentiation of chronic pancreatitis from pancreatic Cancer: recent advances in molecular diagnosis.

。

Dig. Dis.

挖掘。。

, 32–36 (2001).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Ryan, D. P., Hong, T. S. & Bardeesy, N. Pancreatic adenocarcinoma.

Ryan，D.P.，Hong，T.S。＆Bardeesy，N。胰腺癌。

N. Engl. J. Med.

N.Engl。医学杂志。

371

, 1039–1049 (2014).

Article

文章

PubMed

Google Scholar

谷歌学者

Klein, A. P. et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

Klein，A.P.等人的全基因组荟萃分析确定了五个新的胰腺癌易感基因座。

Nat. Commun.

Nat.普通。

, 556 (2018).

Article

文章

ADS

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Ansari, D., Torén, W., Zhou, Q., Hu, D. & Andersson, R. Proteomic and genomic profiling of pancreatic cancer.

Ansari，D.，Torén，W.，Zhou，Q.，Hu，D。＆Andersson，R。胰腺癌的蛋白质组学和基因组分析。

Cell Biol. Toxicol.

细胞生物学。有毒。

, 333–343 (2019).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Shelton, C. A. & Whitcomb, D. C. Precision medicine for pancreatic diseases.

Shelton，C.A。和Whitcomb，D.C。胰腺疾病的精准医学。

Curr. Opin. Gastroenterol.

Curr。Opin。胃肠病学。

, 428–436 (2020).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Hayashi, A., Hong, J. & Iacobuzio-Donahue, C. A. The pancreatic cancer genome revisited.

Hayashi，A.，Hong，J。＆Iacobuzio-Donahue，C.A。重新审视了胰腺癌基因组。

Nat. Rev. Gastroenterol. Hepatol.

胃肠病学国家修订版。肝病。

, 469–481 (2021).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Halbrook, C. J., Lyssiotis, C. A., di Pasca, M. & Maitra, A. Pancreatic cancer: advances and challenges.

Halbrook，C.J.，Lyssiotis，C.A.，di Pasca，M。和Maitra，A。胰腺癌：进展和挑战。

Cell

细胞

186

, 1729–1754 (2023).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Guo, K. et al. Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics.

郭，K。等。通过综合生物信息学探索慢性胰腺炎与胰腺导管腺癌之间的关键遗传关联。

Front. Genet.

前面。基因。

, 1115660.

https://doi.org/10.3389/fgene.2023.1115660

(2023).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Oracz, G. et al. Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients.

Oracz，G。等人。非酒精性早发性波兰和德国患者的功能丧失TRPV6变异与慢性胰腺炎有关。

Pancreatology

胰腺科

, 1434–1442 (2021).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Zhan, W., Shelton, C. A., Greer, P. J., Brand, R. E. & Whitcomb, D. C. Germline variants and risk for pancreatic Cancer.

Zhan，W.，Shelton，C.A.，Greer，P.J.，Brand，R.E。＆Whitcomb，D.C。种系变异和胰腺癌风险。

Pancreas

胰腺

, 924–936 (2018).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Thompson, E. D. et al. The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go.

Thompson，E.D.等人，《2020年胰腺导管腺癌的遗传学：巨大进展，但还有很长的路要走。

Mod. Pathol.

勇气。病理。

, 2544–2563.

https://doi.org/10.1038/s41379-020-0629-6

(2020).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Strum, W. B. & Boland, C. R. Advances in acute and chronic pancreatitis.

Strum，W.B。＆Boland，C.R。急性和慢性胰腺炎的进展。

World J. Gastroenterol.

世界J.胃肠病学。

, 1194–1201.

https://doi.org/10.3748/wjg.v29.i7.1194

(2023).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Głuszek, S. & Kozieł, D. Genetic determination of pancreatitis.

Głuszek，S.&Kozieł，D.胰腺炎的遗传决定。

Med. Stud.

中间螺柱。

, 70–77 (2018).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Paniccia, A. et al. Prospective, multi-institutional, real-time next-generation sequencing of pancreatic cyst fluid reveals diverse genomic alterations that improve the clinical management of pancreatic cysts.

Panicia，A。等人。胰腺囊肿液的前瞻性，多机构，实时下一代测序揭示了多种基因组改变，可改善胰腺囊肿的临床管理。

Gastroenterology

胃肠病学

164

, 117–133e7.

，117-133e7。

https://doi.org/10.1053/j.gastro.2022.09.028

(2023).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Ma, Y. et al. Loss of Heterozygosity for Kras

Ma，Y.等人，Kras杂合性的丧失

G12D

G12D级

promotes malignant phenotype of pancreatic ductal adenocarcinoma by activating HIF-2α-c-Myc-regulated glutamine metabolism.

通过激活HIF-2α-c-Myc调节的谷氨酰胺代谢促进胰腺导管腺癌的恶性表型。

Int. J. Mol. Sci.

。

, 6697.

https://doi.org/10.3390/ijms23126697

(2022).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Lizard-Nacol, S. et al. Loss of Heterozygosity at the TP53 gene: independent occurrence from genetic instability events in node-negative breast Cancer.

Lizard Nacol，S。等人。TP53基因杂合性的丧失：与淋巴结阴性乳腺癌的遗传不稳定事件无关。

Int. J. Cancer

国际癌症杂志

, 599–603 (1997).

Article

文章

PubMed

Google Scholar

谷歌学者

Gu, Y. et al. Impact of clonal TP53 mutations with loss of heterozygosity on adjuvant chemotherapy and immunotherapy in gastric cancer.

Gu，Y。等人。克隆性TP53突变与杂合性丧失对胃癌辅助化疗和免疫治疗的影响。

Br. J. Cancer

Br.J.癌症

131

, 1320–1327.

https://doi.org/10.1038/s41416-024-02825-1

(2024).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Hu, H. et al. Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications.

Hu，H.等人。胰腺癌关键驱动基因突变：分子靶向治疗和其他临床意义。

Acta Pharmacol. Sin.

药学会议记录。没有。

, 1725–1741.

https://doi.org/10.1038/s41401-020-00584-2

(2021).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Wong, W., Raufi, A. G., Safyan, R. A., Bates, S. E. & Manji, G. A. BRCA mutations in pancreas cancer: spectrum, current management, challenges and future prospects.

Wong，W.，Raufi，A.G.，Safyan，R.A.，Bates，S.E。和Manji，G.A。胰腺癌中的BRCA突变：频谱，当前管理，挑战和未来前景。

Cancer Manage. Res.

癌症管理。研究。

, 2731–2742 (2020).

Article

文章

Google Scholar

谷歌学者

Vittal, A., Saha, D., Samanta, I. & Kasi, A. CHEK2 mutation in a patient with pancreatic adenocarcinoma—a rare case report.

Vittal，A.，Saha，D.，Samanta，I。＆Kasi，A。胰腺癌患者的CHEK2突变-罕见病例报告。

AME Case Rep.

AME案例代表。

, 5.

https://doi.org/10.21037/acr-20-83

(2021).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Nej, K. et al. The NOD23020insC mutation and the risk of familial pancreatic cancer?

Nej，K。等人。NOD23020insC突变与家族性胰腺癌的风险？

Hered Cancer Clin. Pract.

遗传癌症临床。实践。

(3), 149–150 (2004).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Hernandez, D., Wagner, F., Hernandez-Villafuerte, K. & Schlander, M. Economic burden of pancreatic cancer in Europe: a literature review.

Hernandez，D.，Wagner，F.，Hernandez-Villafuerte，K。＆Schlander，M。欧洲胰腺癌的经济负担：文献综述。

J. Gastrointest. Cancer

J、胃肠学家。癌症

, 391–407.

https://doi.org/10.1007/s12029-022-00821-3

(2023).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Peery, A. F. et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: Update 2021.

Peery，A.F.等人，《美国胃肠道、肝脏和胰腺疾病的负担和成本：2021年更新》。

Gastroenterology

胃肠病学

162

, 621–644 (2022).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Iannuzzi, J. P. et al. Global incidence of acute pancreatitis is increasing over time: a systematic review and meta-analysis.

Iannuzzi，J.P.等人。急性胰腺炎的全球发病率随着时间的推移而增加：系统综述和荟萃分析。

Gastroenterology

胃肠病学

162

, 122–134 (2022).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Kozieł, D. & Głuszek, S. Epidemiology of acute pancreatitis in Poland – selected problems.

Kozieł，D.&Głuszek，S.波兰急性胰腺炎的流行病学——选定问题。

Med. Stud.

中间螺柱。

, 1–3 (2016).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.

Bray，F.等人，《2022年全球癌症统计：GLOBOCAN对185个国家36种癌症的全球发病率和死亡率的估计》。

CA Cancer J. Clin.

CA Cancer J.Clin。

, 229–263 (2024).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Shimizu, K. et al. Evidence-based clinical practice guidelines for chronic pancreatitis 2021.

Shimizu，K.等人，《慢性胰腺炎循证临床实践指南2021》。

J. Gastroenterol.

J、胃肠道。

, 709–724.

https://doi.org/10.1007/s00535-022-01911-6

(2022).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Lilly, A. C., Astsaturov, I. & Golemis, E. A. Intrapancreatic fat, pancreatitis, and pancreatic cancer.

Lilly，A.C.，Astsathov，I。＆Golemis，E.A。胰腺内脂肪，胰腺炎和胰腺癌。

Cell. Mol. Life Sci.

细胞。分子生命科学。

, 206.

https://doi.org/10.1007/s00018-023-04855-z

(2023).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Klein, A. P. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors.

Klein，A.P。胰腺癌流行病学：了解生活方式和遗传风险因素的作用。

Nat. Reviews Gastroenterol. Hepatol.

Nat。评论肠胃病。肝病。

, 493–502.

https://doi.org/10.1038/s41575-021-00457-x

(2021).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Szatmary, P. et al. Acute pancreatitis: diagnosis and treatment.

Szatmary，P。等。急性胰腺炎：诊断和治疗。

Drugs

药物

, 1251–1276.

https://doi.org/10.1007/s40265-022-01766-4

(2022).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Kenner, B. et al. Artificial Intelligence and early detection of pancreatic cancer: 2020 summative review.

Kenner，B.等人，《人工智能与胰腺癌的早期检测：2020年总结性评论》。

Pancreas

胰腺

, 251–279 (2021).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Kandikattu, H. K., Venkateshaiah, S. U. & Mishra, A. Chronic pancreatitis and the development of pancreatic Cancer.

Kandikattu，H.K.，Venkateshaiah，S.U。和Mishra，A。慢性胰腺炎和胰腺癌的发展。

Endocr. Metab. Immune Disord. Drug Targets

内分泌。代谢。免疫紊乱。药物靶标

, 1182–1210 (2020).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhao, Z. Y. & Liu, W. Pancreatic cancer: a review of risk factors, diagnosis, and treatment.

Zhao，Z.Y。＆Liu，W。胰腺癌：危险因素，诊断和治疗的综述。

Technol. Cancer Res. Treat.

技术。癌症研究治疗。

, 1–13.

https://doi.org/10.1177/1533033820962117

(2020).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Kamimura, K., Yokoo, T. & Terai, S. Gene therapy for pancreatic diseases: current status.

Kamimura，K.，Yokoo，T。＆Terai，S。胰腺疾病的基因治疗：现状。

Int. J. Mol. Sci.

。

, 3415.

https://doi.org/10.3390/ijms19113415

(2018).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Huang, X., Zhang, G., Tang, T. Y., Gao, X. & Liang, T. B. Personalized pancreatic cancer therapy: from the perspective of mRNA vaccine.

Huang，X.，Zhang，G.，Tang，T.Y.，Gao，X。＆Liang，T.B。个性化胰腺癌治疗：从mRNA疫苗的角度来看。

Military Med. Res.

军事医学研究。

, 53.

https://doi.org/10.1186/s40779-022-00416-w

(2022).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Kolbeinsson, H. M., Chandana, S., Wright, G. P. & Chung, M. Pancreatic cancer: a review of current treatment and novel therapies.

Kolbeinsson，H.M.，Chandana，S.，Wright，G.P。＆Chung，M。胰腺癌：当前治疗和新疗法的回顾。

J. Invest. Surg.

J、投资。。

, 2129884.

https://doi.org/10.1080/08941939.2022.2129884

(2023).

Article

文章

Google Scholar

谷歌学者

Bhat-Nakshatri, P. et al. Signaling pathway alterations driven by BRCA1 and BRCA2 germline mutations are sufficient to initiate breast tumorigenesis by the PIK3CAH1047R Oncogene.

Bhat-Nakshatri，P。等人。由BRCA1和BRCA2种系突变驱动的信号通路改变足以启动PIK3CAH1047R癌基因的乳腺肿瘤发生。

Cancer Res. Commun.

癌症是常见的。

, 38–54 (2024).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Li, Z. & Shang, D. NOD1 and NOD2: essential monitoring partners in the innate immune system.

Li，Z。＆Shang，D。NOD1和NOD2：先天免疫系统中必不可少的监测伙伴。

Curr. Issues Mol. Biol.

货币。问题分子生物学。

, 9463–9479 (2024).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.

Kobayashi，K.S.等人。肠道先天性和适应性免疫的Nod2依赖性调节。

Science

科学

307

, 731–734 (2005).

Article

文章

ADS

PubMed

MATH

数学

Google Scholar

谷歌学者

Kawai, T. & Akira, S. The roles of TLRs, RLRs and NLRs in pathogen recognition.

Kawai，T。＆Akira，S。TLR，RLR和NLR在病原体识别中的作用。

Int. Immunol.

内部免疫。

, 317–337.

https://doi.org/10.1093/intimm/dxp017

(2009).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Kim, T. H. et al. Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2.

Kim，T.H.等人，《改变宿主：由NOD2的Blau综合征突变赋予的病原体相互作用》。

Rheumatol. Int.

风湿病。内景。

, 257–262 (2007).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Sato, H. et al. CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.

Sato，H。等人，CARD15/NOD2多态性与严重的肺结节病有关。

Eur. Respir. J.

欧，深呼吸。J

, 324–330 (2010).

Article

文章

PubMed

Google Scholar

谷歌学者

Kutikhin, A. G. Role of NOD1/CARD4 and NOD2/CARD15 gene polymorphisms in cancer etiology.

Kutikhin，A.G。NOD1/CARD4和NOD2/CARD15基因多态性在癌症病因学中的作用。

Hum. Immunol.

嗯，免疫。

, 955–968.

https://doi.org/10.1016/j.humimm.2011.06.003

(2011).

Article

文章

PubMed

Google Scholar

谷歌学者

Lener, M. R. et al. Prevalence of the NOD2 3020insC mutation in aggregations of breast and lung cancer.

Lener，M.R.等人。乳腺癌和肺癌聚集中NOD2 3020insC突变的患病率。

Breast Cancer Res. Treat.

乳腺癌研究治疗。

, 141–145 (2006).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Lubiński, J. et al. The 3020insC allele of NOD2 predisposes to cancers of multiple organs.

Lubiński，J。等人。NOD2的3020insC等位基因易患多器官癌。

Hered Cancer Clin. Pract.

遗传癌症临床。实践。

, 59–63 (2005).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Branquinho, D., Freire, P. & Sofia, C. NOD2 mutations and colorectal cancer—where do we stand?

Branquinho，D.，Freire，P。＆Sofia，C。NOD2突变和结直肠癌我们站在哪里？

World J. Gastrointest. Surg.

世界J.Gastrointest。。

(4), 284–293 (2016).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liu, J., He, C., Xu, Q., Xing, C. & Yuan, Y. NOD2 polymorphisms associated with cancer risk: a meta-analysis.

Liu，J.，He，C.，Xu，Q.，Xing，C。＆Yuan，Y。与癌症风险相关的NOD2多态性：荟萃分析。

PLoS One

公共科学图书馆一号

(2), e89340.

（2），e89340。

https://doi.org/10.1371/journal.pone.0089340

(2014).

Article

文章

ADS

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Schnitzler, F. et al. The NOD2 p.Leu1007fsX1008 mutation (rs2066847) is a stronger predictor of the clinical course of Crohns disease than the FOXO3A Intron variant rs12212067.

与FOXO3A内含子变体rs12212067相比，NOD2 p.Leu1007fsX1008突变（rs2066847）是克罗恩病临床过程的更强预测因子。

PLoS One

公共科学图书馆一号

(11), e108503.

（11），e108503。

https://doi.org/10.1371/journal.pone.0108503

(2014).

Article

文章

ADS

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Schnitzler, F. et al. Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn’s disease and active smoking status resulting in ileal stenosis requiring surgery.

Schnitzler，F。等人。在患有克罗恩病和主动吸烟状态的NOD2突变p.Leu1007fsX1008的所有纯合子携带者中发展出统一的，非常侵袭性的疾病表型，导致回肠狭窄需要手术。

PLoS One

公共科学图书馆一号

(7), e0236421.

（7），e0236421。

https://doi.org/10.1371/journal.pone.0236421

(2020).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Antón, M. D. et al. Chronic pancreatitis as the initial presentation of Crohn’s disease.

Antón，M.D.等人。慢性胰腺炎是克罗恩病的最初表现。

Gastroenterol. Hepatol.

胃肠病学。Hepatol。

, 300–302 (2003).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Hartwig, M. et al. Prevalence of the BRCA1 c.6869delAG (BIC: 185delAG) mutation in women with breast cancer from north-central Poland and a review of the literature on other regions of the country.

Hartwig，M.等人。波兰中北部乳腺癌女性中BRCA1 c.6869delAG（BIC:185delAG）突变的患病率以及该国其他地区的文献综述。

Wspolczesna Onkologia

现代肿瘤学

(1), 34–37 (2013).

Article

文章

MathSciNet

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Watanabe, T., Kudo, M. & Strober, W. Immunopathogenesis of pancreatitis.

Watanabe，T.，Kudo，M。＆Strober，W。胰腺炎的免疫发病机制。

Mucosal Immunol.

粘膜免疫。

(2), 283–298.

https://doi.org/10.1038/mi.2016.101

(2017).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Daly, M. B. et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021.

。

JNCCN J. Natl. Compr. Cancer Netw.

JNCCN J.Natl。压缩机。癌症网络。

(1), 77–102.

https://doi.org/10.6004/JNCCN.2021.0001

(2021).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Lal, G. et al. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations.

Lal，G.等人，《胰腺癌的遗传易感性：家族史和种系p16，BRCA1和BRCA2突变的作用》。

Cancer Res.

癌症研究。

(2), 409–416 (2000).

PubMed

MATH

数学

Google Scholar

谷歌学者

Salo-Mullen, E. E. et al. Identification of germline genetic mutations in patients with pancreatic cancer.

Salo Mullen，E.E.等人。胰腺癌患者种系基因突变的鉴定。

Cancer

癌症

121

(24), 4382–4388 (2015).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Lowery, M. A. et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms.

Lowery，M.A.等人。胰腺外分泌肿瘤患者生殖系改变的前瞻性评估。

J. Natl. Cancer Inst.

J、纳特尔。癌症研究所。

110

(10), djy024.

（10），djy024。

https://doi.org/10.1093/jnci/djy024

(2018).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Hu, C. et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer.

Hu，C.等人。癌症易感基因的遗传种系突变与胰腺癌风险之间的关联。

JAMA J. Am. Med. Assoc.

美国医学会杂志。

319

(23), 2401–2409 (2018).

Article

文章

MATH

数学

Google Scholar

谷歌学者

Górski, B. et al. A high proportion of founder BRCA1 mutations in polish breast cancer families.

Górski，B。等人。波兰乳腺癌家族中创始人BRCA1突变的比例很高。

Int. J. Cancer

国际癌症杂志

110

, 683–686 (2004).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Ferla, R. et al. Founder mutations in BRCA1 and BRCA2 genes.

。

Ann. Oncol.

安科。

(Supp. 6), vi93–98.

（补编6），vi93-98。

https://doi.org/10.1093/annonc/mdm234

(2007).

Article

文章

PubMed

MATH

数学

Google Scholar

谷歌学者

Werner, H. BRCA1: an endocrine and metabolic regulator.

Werner，H。BRCA1：内分泌和代谢调节剂。

Front. Endocrinol.

正面。内分泌。

, 844575.

https://doi.org/10.3389/fendo.2022.844575

(2022).

Article

文章

Google Scholar

谷歌学者

Roa, B. B., Boyd, A. A., Volcie, K. & Richards, S. C. Ashkenazi jewish population frequencies for common mutations in BRCA1 and BRCA2.

Roa，B.B.，Boyd，A.A.，Volcie，K。＆Richards，S.C。Ashkenazi犹太人BRCA1和BRCA2常见突变的频率。

Nat. Genet.

纳特，基因。

, 185–187 (1996).

Article

文章

PubMed

Google Scholar

谷歌学者

King, M. C. et al. Breast and ovarian Cancer risks due to inherited mutations in BRCA1 and BRCA2.

King，M.C.等人。BRCA1和BRCA2的遗传突变导致乳腺癌和卵巢癌的风险。

Science

科学

302

, 643 (2003).

Article

文章

ADS

PubMed

Google Scholar

谷歌学者

Doraczynska-Kowalik, A. et al. Detection of BRCA1/2 pathogenic variants in patients with breast and/or ovarian cancer and their families. Analysis of 3,458 cases from Lower Silesia (Poland) according to the diagnostic algorithm of the National Cancer Control Programme.

Doraczynska-Kowalik，A。等人。乳腺癌和/或卵巢癌患者及其家属中BRCA1/2致病变异的检测。根据国家癌症控制计划的诊断算法，对来自下西里西亚（波兰）的3458例病例进行了分析。

Front. Genet.

前面。基因。

, 941375.

https://doi.org/10.3389/fgene.2022.941375

(2022).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Negroni, A., Pierdomenico, M., Cucchiara, S. & Stronati, L. NOD2 and inflammation: current insights.

。

J. Inflamm. Res.

J.英拉姆。我没有。

, 49–60.

https://doi.org/10.2147/JIR.S137606

(2018).

Article

文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease.

Ogura，Y。等人。NOD2的移码突变与克罗恩病的易感性有关。

Nature

自然

411

, 603–606 (2001).

Article

文章

ADS

PubMed

MATH

数学

Google Scholar

谷歌学者

Takaori, K. et al. International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer.

Takaori，K.等。国际胰腺病学会（IAP）/欧洲胰腺俱乐部（EPC）对胰腺癌治疗指南的共识审查。

Pancreatology

胰腺科

, 14–27 (2016).

Article

文章

PubMed

Google Scholar

谷歌学者

Cucchetti, A. et al. European’ health care indicators and pancreatic cancer incidence and mortality: a mediation analysis of Eurostat data and global burden of Disease Study 2019.

Cucchetti，A.等人，《欧洲卫生保健指标与胰腺癌发病率和死亡率：欧盟统计局数据和2019年全球疾病负担研究的中介分析》。

Pancreatology

胰腺科

, 829–835 (2023).

Article

文章

PubMed

Google Scholar

谷歌学者

Okano, K. & Suzuki, Y. Strategies for early detection of resectable pancreatic cancer.

Okano，K。＆Suzuki，Y。早期发现可切除胰腺癌的策略。

World J. Gastroenterol.

世界J.胃肠病学。

(32), 11230–11240 (2014).

Article

文章

PubMed

PubMed Central

公共医学中心

MATH

数学

Google Scholar

谷歌学者

Altimari, M., Wells, A., Abad, J. & Chawla, A. The differential effect of neoadjuvant chemotherapy and chemoradiation on nodal downstaging in pancreatic adenocarcinoma.

Altimari，M.，Wells，A.，Abad，J。＆Chawla，A。新辅助化疗和放化疗对胰腺癌淋巴结分期的不同影响。

Pancreatology

胰腺科

, 805–810 (2023).

Article

文章

PubMed

Google Scholar

谷歌学者

Download references

下载参考资料

Acknowledgements

致谢

This work was supported by project number SUPS.RN.24.015 financed by Jan Kochanowski University, Kielce, Poland. We would like to thank all swab donors and hospital directors who agreed to this scientific collaboration.

这项工作得到了项目编号SUPS的支持。RN.24.015由波兰基尔塞Jan Kochanowski大学资助。我们要感谢所有同意这项科学合作的拭子捐赠者和医院院长。

Author information

作者信息

Authors and Affiliations

作者和隶属关系

Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland

Jarosław Matykiewicz, Wioletta Adamus-Białek, Monika Wawszczak-Kasza, Bartosz Molasy, Magdalena Kołomańska, Rusłan Oblap, Łukasz Madej, Dorota Kozieł & Stanisław Głuszek

Jarosław Matykiewicz、Wioletta Adamus Białek、Monika Wawszczak Kasza、Bartosz Molasy、Magdalena Kołomańska、Rusłan Oblap、Łukasz Madej、Dorota Kozieła

Authors

作者

Jarosław Matykiewicz

雅罗斯瓦夫·马提凯维奇

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Wioletta Adamus-Białek

维奥莱塔·阿达穆斯·比亚维克

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Monika Wawszczak-Kasza

Monika Wawszczak Kasza女士

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Bartosz Molasy

巴托斯·莫拉西

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Magdalena Kołomańska

马格达莱娜·科沃曼斯卡

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Rusłan Oblap

鲁斯兰Oblap

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Łukasz Madej

卢卡什·马德吉

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Dorota Kozieł

多罗塔·科齐耶

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Stanisław Głuszek

斯坦尼斯瓦夫·格乌泽克

View author publications

查看作者出版物

You can also search for this author in

您也可以在中搜索此作者

PubMed

Google Scholar

谷歌学者

Contributions

捐款

J.M.: conceptualization, data curation, resources; W.A.-B.: data curation, statistical analysis of results, tables and figures preparation, writing—original draft, editing, review; M.W.-K.: data curation, methodology, validation, supervision, resources, writing—review, editing; B.M.: data curation, validation, supervision, resources; M.K.: data curation, validation, resources; R.O.: methodology, laboratory work, validation; Ł.M.: methodology, laboratory work, validation; D.K.: data curation, validation, supervision, resources; S.G.: conceptualization, supervision, resources, writing—review and editing.All authors read and approved the final manuscript.

J、 M.：概念化，数据管理，资源；W、 A.-B.：数据管理，结果统计分析，表格和数字准备，撰写原稿，编辑，审查；M、 W.-K.：数据管理，方法论，验证，监督，资源，写作评论，编辑；B、 M.：数据管理，验证，监督，资源；M、 K.：数据管理，验证，资源；R、 O.：方法学，实验室工作，验证；Ł。M、：方法学，实验室工作，验证；D、 K.：数据管理，验证，监督，资源；S、 G.：概念化，监督，资源，写作评论和编辑。。

Each author has made substantial contributions to the conception and approved the submitted version. Each author has agreed to be personally accountable for the author’s own contributions and declares that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature..

每位作者都对这个概念做出了重大贡献，并批准了提交的版本。每位作者都同意对作者自己的贡献承担个人责任，并声明对与作品任何部分的准确性或完整性有关的问题，即使是作者本人没有参与的问题，也会进行适当的调查，解决，并将解决方案记录在文献中。。

Corresponding author

通讯作者

Correspondence to

通信对象

Wioletta Adamus-Białek

维奥莱塔·阿达穆斯·比亚维克

Ethics declarations

道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval and informed consent

道德审批和知情同意

The study complied with the principles of the Declaration of Helsinki. This study was approved by the Bioethics Committee of Collegium Medicum, Jan Kochanowski University of Kielce, Resolution No 1/2012 from 11.04.2012. All participants were informed of the purpose of the project and planned research.

这项研究符合《赫尔辛基宣言》的原则。这项研究得到了基尔切扬·科查诺夫斯基大学医学院生物伦理委员会的批准，2012年4月11日第1/2012号决议。所有参与者都被告知该项目的目的和计划的研究。

All participants provided informed consent to participate in the project. Table .

所有参与者都提供了参与该项目的知情同意书。表。

S1级

presents the anonymized project members with detailed characteristics.

为匿名项目成员提供详细的特征。

Additional information

其他信息

Publisher’s note

出版商注释

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。

Electronic supplementary material

电子补充材料

Below is the link to the electronic supplementary material.

以下是电子补充材料的链接。

Supplementary Material 1

补充材料1

Supplementary Material 2

补充材料2

Rights and permissions

权限和权限

Open Access

开放存取

This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

本文是根据知识共享署名非商业性NoDerivatives 4.0国际许可证授权的，该许可证允许以任何媒介或格式进行任何非商业性使用，共享，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出您是否修改了许可材料。

You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit .

要查看此许可证的副本，请访问。

http://creativecommons.org/licenses/by-nc-nd/4.0/

Reprints and permissions

重印和许可

About this article

关于本文

Cite this article

引用本文

Matykiewicz, J., Adamus-Białek, W., Wawszczak-Kasza, M.

Matykiewicz，J.、Adamus Białek，W.、Wawszczak Kasza，M。

et al.