NEW YORK – A UK-led team has profiled somatic mutation patterns in normal gastric epithelium samples from sites along the gastrointestinal tract, tallying somatic mutation rates and uncovering recurrent alterations and mutations falling in cancer driver genes in individuals with or without gastric cancer..

纽约——一个英国领导的团队对沿胃肠道位点的正常胃上皮样本中的体细胞突变模式进行了分析，统计了体细胞突变率，并揭示了在有或没有胃癌的个体中发生在癌症驱动基因中的反复变异和突变。

The work

工作

appeared in

出现在

Nature

自然

on Wednesday

星期三

.

。

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This study is the first to take a detailed look at the gastric epithelium to see the patterns of somatic mutations that are acquired in normal gastric cells,'

这项研究首次对胃上皮进行了详细观察，以查看正常胃细胞中获得的体细胞突变模式。

first and co-corresponding author Tim Coorens, a researcher with the Wellcome Sanger Institute, who is now based at the Broad Institute, said in an email.

第一作者和共同通讯作者蒂姆·科伦斯在一封电子邮件中说，他是威康桑格研究所的研究员，目前就职于布罗德研究所。

For their analyses, Coorens and colleagues in the UK and China used laser capture microdissection and whole-genome sequencing to assess 238 microdissected tissue samples from

为了进行分析，Coorens 和他在英国和中国的同事使用了激光捕获显微切割和全基因组测序技术，对 238 个显微切割组织样本进行了评估。

four sites along the gastrointestinal tract

沿胃肠道的四个部位

in 30 donor individuals, including 18 participants diagnosed with gastric cancer. They also performed targeted sequencing on cancer driver genes in 829 samples from individual or clustered sets of gastric glands from stomach samples.

在30名捐赠者个体中，包括18名被诊断为胃癌的参与者。他们还对来自胃样本的单个或成簇胃腺体的829个样本中的癌症驱动基因进行了靶向测序。

The results offered a look at mutation rates in tissues from the

结果提供了组织中突变率的观察

esophagus, stomach, small intestine, and colon. The sequence data also provided a glimpse at potential mutagenic contributors

食道、胃、小肠和结肠。该序列数据还提供了潜在诱变因素的一些线索。

impacting the gastrointestinal tract — from infection or chronic inflammation to lifestyle exposures.

影响胃肠道——从感染或慢性炎症到生活方式的暴露。

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Over the years, we have come to realize that cancer precursor clones are exceedingly common in normal tissues, but overt cancers are relatively rare,' Coorens explained. 'Precisely understanding the pathway a normal cell needs to take to becoming a cancer — through mutations, environmental pressures, or other mechanisms — enables us to detect cancers early, identify risk factors, and perhaps even prevent cancer.'.

“多年以来，我们已经意识到癌前克隆在正常组织中非常常见，但明显的癌症相对罕见，”库伦斯解释道。“精确理解正常细胞通过突变、环境压力或其他机制转变为癌症的路径，可以让我们早期检测癌症、识别风险因素，甚至可能预防癌症。”

The work builds on prior efforts to characterize somatic mutation patterns found in other organ and tissue types, including the bladder, colorectal epithelium, and endometrial epithelial tissue, he noted, adding that the stomach 'is

这项工作建立在先前对其他器官和组织类型中发现的体细胞突变模式进行表征的努力之上，他指出，其中包括膀胱、结直肠上皮和子宫内膜上皮组织，并补充说胃部是

unique in its function and exposures, and consequently has a different mutation landscape than other epithelial tissues.'

在其功能和暴露方面是独特的，因此其突变景观与其他上皮组织不同。

In gastric gland samples from the stomachs of cancer-free individuals, the team identified monoclonal cell populations that appeared to reflect endogenous mutational processes. In normal esophageal and stomach samples, the genome sequence data pointed to an average accrual of around 30 somatic single-nucleotide changes annually, while small or large intestine samples appeared to accumulate around 50 single-nucleotide changes each year..

在无癌症个体的胃腺样本中，研究团队发现了似乎反映内源性突变过程的单克隆细胞群。在正常的食管和胃样本中，基因组序列数据显示每年平均积累约30个体细胞单核苷酸变异，而小肠或大肠样本则似乎每年积累约50个单核苷酸变异。

In contrast, stomach gastric gland samples from individuals with gastric cancer contained sequences stemming from oxidative damage- and proliferation-related mutational processes and higher mutation levels overall, the researchers reported.

研究人员报告说，相比之下，胃癌患者的胃腺样本包含来自氧化损伤和增殖相关突变过程的序列，总体上也具有更高的突变水平。

By digging into sequence data from stomach tissue sites marked by precancerous metaplastic features and/or chronic inflammation, meanwhile, the team saw signs of selection for cell clones containing mutations in ARID1A, CTNNB1, KDM6A, and other cancer driver genes.

同时，通过深入研究具有癌前化生特征和/或慢性炎症的胃组织位点的序列数据，研究团队观察到含有ARID1A、CTNNB1、KDM6A及其他癌症驱动基因突变的细胞克隆的选择迹象。

'While chronic inflammation may be selecting for clones with cancer-driver mutations, it also promotes glands to undergo intestinal metaplasia, which massively increases their mutation burden and renders them more prone to acquire cancer driver mutations,' Coorens explained. 'This in turn heavily increases the risk of metaplastic glands to become tumors.'.

“虽然慢性炎症可能会选择具有癌症驱动突变的克隆，但它同时也促使腺体发生肠上皮化生，这会大大增加它们的突变负担，并使它们更容易获得癌症驱动突变，”库伦斯解释说。“这反过来又大大增加了化生腺体变成肿瘤的风险。”

Even so, unusual alterations were not limited to cancerous or precancerous cells. Cell clones containing driver gene alterations appeared to increase with chronic inflammation and with age, making up some 8 percent of gastric epithelial lining cells in samples from participants who reached the age of 60 years old..

即使如此，非正常的变化并不局限于癌细胞或癌前细胞。含有驱动基因变化的细胞克隆似乎随着慢性炎症和年龄的增长而增加，在达到60岁的参与者样本中，约占胃上皮细胞的8%左右。

And in a subset of seemingly normal gastric epithelium samples, investigators identified recurrent trisomies, often involving chromosome 13 or chromosome 20 — changes suspected of arising in response to early infection events or other exposures.

在一部分看似正常的胃上皮样本中，研究人员发现了反复出现的三体性，通常涉及13号或20号染色体——这些变化被认为是由早期感染事件或其他暴露因素引发的。

'We've not seen this in any other tissue, and it hints towards an unknown, external mutagen that only some of these people may have been exposed to,' co-senior and co-corresponding author Suet Yi Leung, a pathology, oncology, and immunology researcher affiliated with the University of Hong Kong and the Hong Kong Science Park, said in a statement..

“我们从未在其他任何组织中见过这种情况，这暗示着一种未知的外部诱变因素，而只有其中一部分人可能接触过，”资深作者兼通讯作者之一、香港大学和香港科学园病理学、肿瘤学及免疫学研究员梁雪怡在一份声明中表示。

While additional research will be needed to understand the roots and roles of these trisomies and to untangle the specific somatic mutational events that prompt gastric cancer development, the new research highlights the somatic mutation patterns that can be unearthed with large-scale sequencing efforts..

虽然还需要更多的研究来理解这些三体的根源和作用，并理清促使胃癌发展的特定体细胞突变事件，但这项新研究强调了通过大规模测序工作可以揭示的体细胞突变模式。

To that end, Coorens noted that he is currently participating in a National Institutes of Health-funded effort known as 'Somatic mosaicism across human tissues' (SMaHT) that is profiling the somatic mutation landscape in normal tissue samples from a large cohort of diverse donor participants.

为此，科伦斯指出，他目前正参与一个名为“跨人体组织的体细胞嵌合性”（SMaHT）的项目，该项目由美国国立卫生研究院资助，旨在分析来自大量多样化捐赠者的大样本正常组织中的体细胞突变情况。

'In the last few years, studying somatic mutations in normal tissues has gained traction because we finally have experimental sequencing technologies that are scalable, accessible, and precise enough to enable this research across many donors and tissues,' he noted.

“在过去的几年里，研究正常组织中的体细胞突变逐渐受到关注，因为我们终于有了可扩展、易获取且足够精确的实验测序技术，能够支持跨多捐赠者和组织的研究，”他指出。