3929例HPV阳性宫颈细胞中的体细胞突变与感染结果和HPV类型有关-动脉网

Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type

Nature 等信源发布 2024-09-12 21:48

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AbstractInvasive cervical cancers (ICC), caused by HPV infections, have a heterogeneous molecular landscape. We investigate the detection, timing, and HPV type specificity of somatic mutations in 3929 HPV-positive exfoliated cervical cell samples from individuals undergoing cervical screening in the U.S.

摘要由HPV感染引起的浸润性宫颈癌（ICC）具有异质性分子景观。我们调查了美国接受宫颈筛查的3929例HPV阳性脱落宫颈细胞样本中体细胞突变的检测，时间和HPV类型特异性。

using deep targeted sequencing in ICC cases, precancers, and HPV-positive controls. We discover a subset of hotspot mutations rare in controls (2.6%) but significantly more prevalent in precancers, particularly glandular precancer lesions (10.2%), and cancers (25.7%), supporting their involvement in ICC carcinogenesis.

在ICC病例，癌前病变和HPV阳性对照中使用深度靶向测序。。

Hotspot mutations differ by HPV type, and HPV18/45-positive ICC are more likely to have multiple hotspot mutations compared to HPV16-positive ICC. The proportion of cells containing hotspot mutations is higher (i.e., higher variant allele fraction) in ICC and mutations are detectable up to 6 years prior to cancer diagnosis.

热点突变因HPV类型而异，与HPV16阳性ICC相比，HPV18/45阳性ICC更可能具有多个热点突变。在ICC中，含有热点突变的细胞比例较高（即变异等位基因分数较高），并且在癌症诊断前长达6年可检测到突变。

Our findings demonstrate the feasibility of using exfoliated cervical cells for detection of somatic mutations as potential diagnostic biomarkers..

我们的发现证明了使用脱落的宫颈细胞检测体细胞突变作为潜在诊断生物标志物的可行性。。

IntroductionInvasive cervical cancer (ICC) is the fourth most common cancer worldwide1 and virtually all cases are caused by an infection with one of the 13 high-risk (HR) human papillomavirus (HPV) types2. The natural history of HPV leading to ICC is well-established, mostly based on HPV16 and squamous cell carcinoma (SCC), and is characterized by a multistage disease model that starts with HPV infection, that is persistently detectable over time when not controlled by the immune system2.

引言浸润性宫颈癌（ICC）是世界上第四大最常见的癌症1，几乎所有病例都是由13种高危（HR）人乳头瘤病毒（HPV）类型之一的感染引起的2。。

These persistent infections often lead to the development of precancerous lesions that grow within the epithelium, often for years, that eventually can invade the surrounding tissue to become ICC2. The natural history of adenocarcinoma (ADC), the second most common histologic subtype, remains poorly understood.The cancer genome atlas (TCGA) project has identified driver mutations that presumably lead to ICC3,4.

这些持续性感染通常会导致癌前病变的发展，这些病变通常会在上皮内生长数年，最终会侵入周围组织成为ICC2。腺癌（ADC）是第二常见的组织学亚型，其自然史仍然知之甚少。癌症基因组图谱（TCGA）项目已经确定了可能导致ICC3,4的驱动突变。

However, ICC is a heterogeneous disease with distinct somatic mutation spectrums related to SCC and ADC histologies4. Recurrent somatic mutations in PIK3CA, FBXW7, MAPK1, PTEN, EP300, NFE2L2, CASP8, STK11, HLA-A, and HLA-B are enriched in SCC, while in ADC, ELF3, CBFB, KRAS and ARID1A are enriched4,5.

然而，ICC是一种异质性疾病，具有与SCC和ADC组织学相关的独特体细胞突变谱4。PIK3CA，FBXW7，MAPK1，PTEN，EP300，NFE2L2，CASP8，STK11，HLA-A和HLA-B中的复发性体细胞突变在SCC中富集，而在ADC，ELF3，CBFB，KRAS和ARID1A中富集4,5。

One study also noted that the epigenomic and transcriptomic landscape of ICC differed by HPV species groups (Alpha 9 vs. Alpha 7)6. ICC is additionally enriched with somatic mutations induced by the off-target activity of APOBEC3 enzymes, responsible for inducing C to T or C to G changes at specific trinucleotide motifs (5’TCW3’ [W is A or T]), in response to the exogenous DNA from HPV infection7,8,9,10.

一项研究还指出，ICC的表观基因组和转录组学景观因HPV物种组而异（α9与α7）6。ICC还富含由APOBEC3酶的脱靶活性诱导的体细胞突变，负责诱导特定三核苷酸基序（5'TCW3'[W是A或T]）的C到T或C到G的变化，以响应来自HPV感染的外源DNA 7,8,9,10。

The two most frequent mutational hotspots in ICC, E542K and E545K in PIK3CA, are linked to APOBEC3 activity4,5,11. If the intended anti-viral activity of APOBEC3 does not lead to .

ICC中两个最常见的突变热点，PIK3CA中的E542K和E545K，与APOBEC3活性相关4,5,11。如果APOBEC3的预期抗病毒活性不导致。

Data availability

数据可用性

The somatic gene sequence data generated in this study have been deposited in dpGAP under accession code phs003691. The de-identified phenotype data are available under this accession. Source data are provided with this paper.

本研究中产生的体细胞基因序列数据已保存在dpGAP中，登录号为phs003691。未鉴定的表型数据可在此登录下获得。本文提供了源数据。

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Pinheiro，M.等人。人乳头瘤病毒31型和宫颈癌发生的系统发育基因组分析：2093个病毒基因组的研究。病毒131948（2021）。下载参考文献致谢本出版物的内容不一定反映卫生与公众服务部的观点或政策，也不提及商品名称，商业产品或组织意味着美国的认可。

Government. This research was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH (HHSN261200800001E), the National Cancer Institute (CA78527 and CA238592).FundingOpen access funding provided by the National Institutes of Health.Author informationAuthor notesThese authors contributed equally: Bin Zhu, Lisa Mirabello.Authors and AffiliationsDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USAMaisa Pinheiro, Nicolas Wentzensen, Michael Dean, Meredith Yeager, Amulya Shastry, Joseph F.

。这项研究由美国国立卫生研究院国家癌症研究所癌症流行病学和遗传学部门的校内研究计划资助。该项目全部或部分由美国国立卫生研究院国家癌症研究所（HHSN261200800001E），国家癌症研究所（CA78527和CA238592）的联邦资金资助。基金由国立卫生研究院提供的开放获取资金。作者信息作者注意到这些作者做出了同样的贡献：朱斌，丽莎·米拉贝洛。作者和附属机构癌症流行病学和遗传学部，国家癌症研究所，国立卫生研究院，罗克维尔，医学博士，USAMaisa Pinheiro，尼古拉斯·温特森，迈克尔·迪恩，梅雷迪斯·耶格，阿穆利亚·沙斯特里，约瑟夫·F。

Boland, Sara Bass, Laurie Burdett, Sambit Mishra, Philip E. Castle, Mark Schiffman, Bin Zhu & Lisa MirabelloCancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD, USAMichael Dean, Meredith Yeager, Amulya Shastry, Joseph F. Boland, Sara Bass, Laurie Burdett & Sambit MishraDepartment of Biology, Hood College, Frederick, MD, USAMeredith YeagerDepartment of Microbiology, The Chinese University of Hong Kong, Hong Kong, ChinaZigui ChenRegional Laboratory and Women’s Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland, CA, USAThomas LoreyDi.

Boland，Sara Bass，Laurie Burdett，Sambit Mishra，Philip E.Castle，Mark Schiffman，Bin Zhu&Lisa MirabelloCancer基因组学研究实验室，Leidos Biomedical Research，Inc.，Frederick，MD，USAMACHAEL Dean，Meredith Yeager，Amulya Shastry，Joseph F.Boland，Sara Bass，Laurie Burdett&Sambit Mishrade Hood生物学系，Hood College，Frederick，MD，USAMeredith Yeager香港中文大学微生物学系，ChinaZigui Chen区域实验室和凯撒永久研究所恩特北加利福尼亚州，奥克兰，加利福尼亚州，USATOMAS LoreyDi。

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PubMed Google ScholarContributionsStudy conceptualization: M.P. and L.M. Data curation: M.P., L.M., A.S., J.F.B., S.B., M.Y., and S.M. Formal analysis: M.P., B.Z., L.M., and Z.C. Funding acquisition: L.M., M.S., N.W. Methodology: B.Z., L.M., L.B., M.Y., and S.M. Resources: L.M., M.S., N.W., P.E.C., R.D.B., and T.L.

PubMed谷歌学术贡献研究概念化：M.P.和L.M.数据管理：M.P.，L.M.，A.S.，J.F.B.，S.B.，M.Y。和S.M.形式分析：M.P.，B.Z.，L.M。和Z.C.资金获取：L.M.，M.S.，N.W.方法：B.Z.，L.M.，L.B.，M.Y。和S.M.资源：L.M.，M.S.，N.W.，P.E.C.，R.D.B。和T.L。

Supervision: L.M. and B.Z. Writing the original draft: M.P. and L.M. All authors have read, reviewed, and agreed to the published version of the manuscript.Corresponding authorCorrespondence to.

监督：L.M.和B.Z.撰写原稿：M.P.和L.M.所有作者都阅读，审查并同意手稿的出版版本。对应作者对应。

Lisa Mirabello.Ethics declarations

丽莎·米拉贝洛。道德宣言

Competing interests

相互竞争的利益

M.P. is currently an employee of GlaxoSmithKline, J.F.B. and S.B. are now employees of AstraZeneca, and Amulya Shastry is now a doctoral student at Boston University, but they all completed the work associated with this project while employed at the National Cancer Institute. P.E.C. has received HPV tests and assays at a reduced or no cost for research from Roche, Becton Dickinson, Cepheid and Arbor Vita Corporation.

M、 P.目前是葛兰素史克的员工，J.F.B.和S.B.现在是阿斯利康的员工，Amulya Shastry现在是波士顿大学的博士生，但他们都在国家癌症研究所工作期间完成了与该项目相关的工作。P、 E.C.已从罗氏、Becton Dickinson、Cepheid和Arbor Vita Corporation以较低或无成本的研究费用接受了HPV检测和分析。

All other authors declare no competing interests..

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Reprints and permissionsAbout this articleCite this articlePinheiro, M., Wentzensen, N., Dean, M. et al. Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type.

转载和许可本文引用本文Pinheiro，M.，Wentzensen，N.，Dean，M。等人。与感染结果和HPV类型相关的3929个HPV阳性宫颈细胞中的体细胞突变。

Nat Commun 15, 7895 (2024). https://doi.org/10.1038/s41467-024-51713-yDownload citationReceived: 05 December 2023Accepted: 13 August 2024Published: 12 September 2024DOI: https://doi.org/10.1038/s41467-024-51713-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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