癌症头颈部一个基因组上不同亚类的标记-动脉网

Hallmarks of a genomically distinct subclass of head and neck cancer

Nature 等信源发布 2024-10-20 00:46

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AbstractCancer is caused by an accumulation of somatic mutations and copy number alterations (CNAs). Besides mutations, these copy number changes are key characteristics of cancer development. Nonetheless, some tumors show hardly any CNAs, a remarkable phenomenon in oncogenesis. Head and neck squamous cell carcinomas (HNSCCs) arise by either exposure to carcinogens, or infection with the human papillomavirus (HPV).

摘要癌症是由体细胞突变和拷贝数改变（CNA）的积累引起的。除突变外，这些拷贝数变化是癌症发展的关键特征。尽管如此，一些肿瘤几乎没有显示任何CNA，这是肿瘤发生中的一个显着现象。头颈部鳞状细胞癌（HNSCC）是由暴露于致癌物或感染人乳头瘤病毒（HPV）引起的。

HPV-negative HNSCCs are generally characterized by many CNAs and frequent mutations in CDKN2A, TP53, FAT1, and NOTCH1. Here, we present the hallmarks of the distinct subgroup of HPV-negative HNSCC with no or few CNAs (CNA-quiet) by genetic profiling of 802 oral cavity squamous cell carcinomas (OCSCCs).

HPV阴性的HNSCC通常以许多CNA和CDKN2A，TP53，FAT1和NOTCH1中的频繁突变为特征。在这里，我们通过对802例口腔鳞状细胞癌（OCSCC）的基因分析，提出了HPV阴性HNSCC的不同亚组的特征，其中没有或很少有CNA（CNA-quiet）。

In total, 73 OCSCC (9.1%) are classified as CNA-quiet and 729 as CNA-other. The CNA-quiet group is characterized by wild-type TP53, frequent CASP8 and HRAS mutations, and a less immunosuppressed tumor immune microenvironment with lower density of regulatory T cells. Patients with CNA-quiet OCSCC are older, more often women, less frequently current smokers, and have a better 5-year overall survival compared to CNA-other OCSCC.

总共有73个OCSCC（9.1%）被归类为CNA quiet，729个被归类为CNA other。CNA安静组的特征是野生型TP53，频繁的CASP8和HRAS突变，以及免疫抑制较少的肿瘤免疫微环境和较低密度的调节性T细胞。与CNA其他OCSCC相比，CNA安静OCSCC患者年龄较大，女性较多，目前吸烟者较少，5年总生存率较高。

This study demonstrates that CNA-quiet OCSCC should be considered as a distinct, clinically relevant subclass. Given the clinical characteristics, the patient group with these tumors will rapidly increase in the aging population..

这项研究表明，CNA安静的OCSCC应被视为一个独特的，临床相关的亚类。鉴于临床特征，患有这些肿瘤的患者群体将随着人口老龄化而迅速增加。。

IntroductionHead and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide and has a mortality rate of approximately 50% with annually 890,000 new cases and 450,000 deaths1. HNSCC arise in the mucosal linings of the upper aerodigestive tract and are most frequently located in the oral cavity, hypopharynx, nasopharynx, larynx, or oropharynx.

。HNSCC出现在上呼吸消化道的粘膜衬里中，最常见于口腔，下咽，鼻咽，喉或口咽。

Among HNSCC, carcinomas of the oral cavity (OCSCC) are most prevalent with an increase in incidence over the years1. Risk factors for nasopharyngeal cancers, most prevalent in East and Southeast Asia, are tobacco smoking and Epstein-Barr virus (EBV) infection2. Tumors of the oral cavity, hypopharynx, and larynx, which are more commonly found in Western countries, are predominantly carcinogen-induced, with smoking and excessive alcohol consumption as classical risk factors.

在HNSCC中，口腔癌（OCSCC）最为普遍，多年来发病率增加1。在东亚和东南亚最普遍的鼻咽癌的危险因素是吸烟和爱泼斯坦-巴尔病毒（EBV）感染2。在西方国家更常见的口腔，下咽和喉部肿瘤主要是致癌物引起的，吸烟和过量饮酒是典型的危险因素。

In contrast, oropharyngeal squamous cell carcinomas (OPSCCs) are increasingly caused by human papillomavirus (HPV) infection. HPV-positive and HPV-negative OPSCC are considered as separate disease entities due to the differences in etiology, molecular characteristics, clinical presentation and prognosis.

相反，口咽鳞状细胞癌（OPSCCs）越来越多地由人乳头瘤病毒（HPV）感染引起。。

HPV-positive OPSCCs have a substantially more favorable prognosis than HPV-negative tumors3,4,5.HPV-negative HNSCC are generally characterized by many copy number alterations (CNAs) as well as frequent mutations in the tumor suppressor gene TP534. TP53 is located at chromosome 17p13 and encodes the tumor suppressor p53 that responds to cellular stress signals such as DNA damage4,6.

HPV阳性的OPSCC比HPV阴性的肿瘤具有更有利的预后3,4,5。HPV阴性的HNSCC通常以许多拷贝数改变（CNA）以及肿瘤抑制基因TP534的频繁突变为特征。TP53位于染色体17p13上，编码肿瘤抑制因子p53，其响应细胞应激信号，例如DNA损伤4,6。

Strikingly, Smeets et al.7 identified an HPV-negative HNSCC subclass of tumors with few or no chromosomal gains and losses. These tumors were characterized by wild-type (wt) TP537. The cancer genome atlas (TCGA) network also reported on the existence of this gr.

引人注目的是，Smeets等[7]发现了一种HPV阴性的HNSCC亚类肿瘤，染色体得失很少或没有。这些肿瘤的特征是野生型（wt）TP537。癌症基因组图谱（TCGA）网络也报道了这种gr的存在。

Data availability

数据可用性

The raw sequencing data generated in this study have been deposited in the European Genome-phenome Archive (EGA) under accession number EGAD50000000790 via [https://ega-archive.org/datasets/EGAD50000000790]. Data will be made available under a data transfer agreement that will only contain statements on acknowledgment to the source publication in manuscripts using the data, commercial use of the data (not allowed), transfer of the data to other parties (not allowed), the aim of the study and the estimated time required for the planned analyzes, in practice 1 to 3 years, but as long as needed.

这项研究中产生的原始测序数据已通过登录号EGAD50000000790保存在欧洲基因组-表型库（EGA）中[https://ega-archive.org/datasets/EGAD50000000790]。数据将根据数据传输协议提供，该协议仅包含使用数据的手稿中对源出版物的确认声明，数据的商业使用（不允许），将数据传输给其他方（不允许），研究目的和计划分析所需的估计时间，在实践中为1至3年，但只要需要。

The mIHC imaging data generated in this study is deposited in the bioimage archive database and available under the accession number S-BIAD1352 via [https://www.ebi.ac.uk/biostudies/BioImages/studies/S-BIAD1352]. Publicly available clinical data of 530 HNSCC samples from TCGA were downloaded from cBioPortal and available via [https://www.cbioportal.org/study/clinicalData?id=hnsc_tcga].

本研究中产生的mIHC成像数据保存在bioimage存档数据库中，可通过登录号S-BIAD1352获得[https://www.ebi.ac.uk/biostudies/BioImages/studies/S-BIAD1352]。来自TCGA的530份HNSCC样本的公开临床数据可从cBioPortal下载，并可通过[https://www.cbioportal.org/study/clinicalData?id=hnsc_tcga]。

Segment data derived from Affymetrix SNP 6.0 array were downloaded from cBioPortal available via [https://www.cbioportal.org/study/summary?id=hnsc_tcga]. MAF files were acquired via the genomic data commons (GDC) portal using GDCquery_Maf of the TCGAbiolinks R package. Purity and ploidy estimates of samples using ABSOLUTE were obtained from supplemental data from the 2018 Pan-Cancer Atlas publications, available through the GDC website via [https://portal.gdc.cancer.gov/projects/TCGA-HNSC]. Source data are provided with this paper..

来自Affymetrix SNP 6.0阵列的片段数据可通过以下途径从cBioPortal下载[https://www.cbioportal.org/study/summary?id=hnsc_tcga]。MAF文件是使用TCGAbiolinks R软件包的GDCquery\u MAF通过基因组数据共享（GDC）门户获取的。使用ABSOLUTE对样品进行纯度和倍性估计是从2018年泛癌图谱出版物的补充数据中获得的，可通过GDC网站获得[https://portal.gdc.cancer.gov/projects/TCGA-HNSC]。本文提供了源数据。。

Code availability

代码可用性

Binned read counts, targeted sequencing depth, filtered somatic variants, summary figures and code is sufficient to reproduce analyzes and is available via figshare [https://figshare.com/projects/Hallmarks_of_Copy_Number_Alteration-Quiet_Oral_Cavity_Tumors/193910]68,69,70. Hallmarks of Copy Number Alteration-Quiet Oral Cavity Tumors (figshare.com)..

装箱读取计数，目标测序深度，过滤的体细胞变异，摘要数字和代码足以重现分析，可通过figshare获得[https://figshare.com/projects/Hallmarks_of_Copy_Number_Alteration-Quiet_Oral_Cavity_Tumors/193910]68,69,70。拷贝数改变的标志安静的口腔肿瘤（figshare.com）。。

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Poell, J. B. & Muijlwijk, T. Sequencing data figshare. Hallmarks of a genomically distinct subclass of head and neck cancer. Available from: Sequencing data (figshare.com) (2024).Poell J. B. & Muijlwijk, T. Sequencing analysis output figshare. In: Hallmarks of a genomically distinct subclass of head and neck cancer.

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Available from: Sequencing analysis output (figshare.com) (2024).Poell, J. B. & Muijlwijk, T. Code figshare. Hallmarks of a genomically distinct subclass of head and neck cancer. Code (figshare.com) (2024).Download referencesAcknowledgementsThe authors wish to thank all patients who participated in this study, Steven M.

可从以下网站获得：Sequencing analysis output（figshare.com）（2024）。Poell，J.B。和Muijlwijk，T。代码figshare。头颈癌基因组不同亚类的标志。代码（figshare.com）（2024）。。

Mes PhD for help with and design of the MLPA assay, Widad Rifi MSc for contribution with probe design and optimization and technical assistance, Dennis N.L.M. Nijenhuis MSc for help with the multiplex immunohistochemistry, Leon Wils MSc for help with the cancer genome atlas mutational analysis, Marijke Stigter-van Walsum for help with targeted sequencing, Microscopy and Cytometry Core Facility, Amsterdam UMC for facilitating the Vectra Polaris (Akoya), clinicians and nurses from the department of Otolaryngology-head and neck surgery from Amsterdam UMC for support with tissue collection, Cancer Center Amsterdam (CCA) for financially support of this work (PV 19/02).Author informationAuthor notesThese authors jointly supervised this work: Jos B.

Mes博士为MLPA分析的帮助和设计，Widad Rifi MSc为探针设计和优化以及技术援助做出贡献，Dennis N.L.M.Nijenhuis MSc为多重免疫组织化学提供帮助，Leon Wils MSc为癌症基因组图谱突变分析提供帮助，Marijke Stigter van Walsum为靶向测序，显微镜和细胞计数核心设施提供帮助，阿姆斯特丹UMC为Vectra Polaris（Akoya）提供便利，阿姆斯特丹UMC耳鼻咽喉头颈外科的临床医生和护士为组织收集提供支持，阿姆斯特丹癌症中心（CCA）为这项工作提供财政支持（PV 19/02））。作者信息作者注意到这些作者共同监督了这项工作：Jos B。

Poell, Ruud H. Brakenhoff.Authors and AffiliationsAmsterdam UMC, location Vrije Universiteit Amsterdam, Otolaryngology / Head and Neck Surgery, Amsterdam, The NetherlandsTara Muijlwijk, Irene H. Nauta, Anabel van der Lee, Kari J. T. Grünewald, Arjen Brink, Sonja H. Ganzevles, Rieneke van de Ven, C. René Leemans, Jos B.

Poell，Ruud H.Brakenhoff。作者和附属机构阿姆斯特丹弗里耶大学UMC，位置，耳鼻咽喉/头颈外科，阿姆斯特丹，荷兰国家标准协会Muijlwijk，Irene H.Nauta，Anabel van der Lee，Kari J.T.Grünewald，Arjen Brink，Sonja H.Ganzevles，Rieneke van de Ven，C。RenéLeemans，Jos B。

Poell & Ruud H. BrakenhoffCancer Center Amsterdam, Cancer Biology and .

Poell＆Ruud H.Brakenhoff癌症中心阿姆斯特丹，癌症生物学和。

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PubMed Google ScholarContributionsData collection: T.M., I.H.N., Avd.L., K.J.T.G., S.H.G. Patient database: I.H.N. Data analyzes: T.M., Avd.L., K.J.T.G., A.B., M.Avd.W., J.B.P. Visualization: T.M. Scoring of tumor and histological parameters: L.A.N.P., E.B. Providing M.L.P.A.

PubMed谷歌学术贡献数据集：T.M.，I.H.N.，Avd。五十、，K.J.T.G.，S.H.G.患者数据库：I.H.N.数据分析：T.M.，Avd。五十、，K.J.T.G.，A.B.，M.Avd。W、，J.B.P.可视化：肿瘤和组织学参数的T.M.评分：L.A.N.P.，E.B.提供M.L.P.A。

probes: S.S., L.A. Supervision: Rvd.V., J.B.P., R.H.B. Funding acquisition: C.R.L., R.H.B., Rvd.V. Writing of the original draft: T.M. Writing review and editing: J.B.P., R.H.B., Rvd.V. Read and approved the final version of the manuscript: T.M., I.H.N., Avd.L., K.J.T.G., A.B., S.H.G., R.J.Bd.J., L.A., S.S., M.Avd.W., L.A.N.P., E.B., Rvd.V., C.R.L., J.B.P., R.H.B.Corresponding authorsCorrespondence to.

探针：S.S.，洛杉矶监督：Rvd。五、，J.B.P.，R.H.B.资金收购：C.R.L.，R.H.B.，Rvd。五、原稿撰写：T.M.写作评论和编辑：J.B.P.，R.H.B.，Rvd。五、阅读并批准了手稿的最终版本：T.M.，I.H.N.，Avd。五十、，K.J.T.G.，A.B.，S.H.G.，R.J.Bd.J.，洛杉矶，S.S.，M.Avd。W、。五、，C.R.L.，J.B.P.，R.H.B。通讯作者通讯。

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