PO.MCB08.04 · 分子与细胞生物学

一项大规模测序研究鉴定出一个新的非编码结构变异作为黑色素瘤的高外显率易感变异

A large-scale sequencing study identifies a novel non-coding structural variant as a high-penetrance susceptibility variant for melanoma

编号 5939 展板 27 时间 4/21 02:00–05:00 区域 Section 21 主讲 Linh Bui-Raborn, PhD

分会场 Genetic and Transcriptomic Dissection of Cancer Evolution

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作者与单位 Authors & Affiliations

Linh T. Bui-Raborn¹, Lorenza Pastorino², Donato Calista³, Huu Phuc Hoang¹, Bruna Dalmasso⁴, Jessica Scales¹, Sophie Papiernik¹, Xiaoyu Wang¹, Rohit Thakur¹, Stefania Pellegrini⁵, Mai Xu¹, Joshuah Yon¹, William Bruno², Tongwu Zhang¹, Zaida García-Casado⁶, Enrica Teresa Tanda⁷, Francesco Spagnolo⁸, Monia Di Prete⁹, Irene Bottillo¹⁰, Siranoush Manukian¹¹, Maria Chiara Scaini⁵, Katerina P. Kypreou¹², Lucia Di Nardo¹³, Miriam Potrony¹⁴, Paula Aguilera-Peiró¹⁵, Nesreen Shahrour¹, Tam-Anh Tran¹, Weiyin Zhou¹, Wen Lou¹, Aurélie L. Vogt¹, Jia Liu¹, Kristine Jones¹, Monica Rodolfo¹⁶, Irene Stefanaki¹², Cristina Pellegrini¹⁷, Carlo Cota⁹, Chiara Menin⁵, Maria Concetta Fargnoli⁹, Ketty Peris¹⁸, Susana Puig¹⁴, Eduardo Nagore¹⁹, Paola Grammatico²⁰, The Melanostrum Consortium, Jianxin Shi¹, Paola Ghiorzo², Kevin M. Brown¹, Maria Teresa Landi¹

¹Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD,²Department of Internal Medicine and Medical Specialties, University of Genoa; IRCCS Ospedale Policlinico San Martino, Genoa, Italy,³Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy,⁴IRCCS Ospedale Policlinico San Martino, Genoa, Italy,⁵Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy,⁶Laboratory of Molecular Biology, Instituto Valenciano de Oncología, València, Spain,⁷Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy,⁸Medical Oncology 2, IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy,⁹Dermatopathology Research Unit, San Gallicano Dermatological Institute IRCCS, Rome, Italy,¹⁰Laboratory of Medical Genetics, Experimental Medicine Department, San Camillo-Forlanini Hospital, Sapienza University, Rome, Italy,¹¹Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,¹²1st University Clinic of Dermatological and Venereal Diseases, Andreas Syggros Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece,¹³Immunology Research Core Facility - Gemelli Science and Technology Park (GSTeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy,¹⁴Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, IDIBAPS, Barcelona, Spain,¹⁵Dermatology, Hospital Clínic de Barcelona, Barcelona, Spain,¹⁶Unit of Translational Immunology, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,¹⁷Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy,¹⁸Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy,¹⁹Dermatology, Instituto Valenciano de Oncología, València, Spain,²⁰Experimental Medicine Department, Laboratory of Medical Genetics, Sapienza University of Rome, San Camillo-Forlanini Hospital, Rome, Italy

摘要 Abstract

中文摘要

约10%的皮肤恶性黑色素瘤病例为家族性。CDKN2A中的变异约占黑色素瘤易感家族的40%，另有10%可由其他已确立的基因解释。引人注目的是，许多无法解释的家族仍显示出与染色体带9p21（该区带含有CDKN2A）的遗传连锁，提示该区域内高外显率的非编码变异可能促成家族性风险。作为一项针对地中海地区高危黑色素瘤家族的大规模研究的一部分，我们对来自意大利热那亚一个四病例家族（该家族在已知易感基因中无变异）的一例黑色素瘤病例进行了胚系全基因组测序（WGS）。我们鉴定出一个新的100kb缺失，定位于9p21、距CDKN2A 205kb处，并在另外两个可获得的病例中验证了共分离。该缺失不编码蛋白，但含有注释的黑色素细胞增强子元件和开放染色质，我们利用H3K27Ac Hi-ChIP发现它们在黑色素细胞中与CDKN2A的p16和p14转录本的启动子发生相互作用。为在全外显子测序（WES）数据中鉴定更多缺失携带者，我们搜索了在发现家族中共分离的邻近外显子变异以作为该缺失的替代标记，鉴定出MTAP中一个罕见的共分离错义变异（rs755147810；chr9: 21,802,755:T:G；p.Ser3Ala；gnomADv4.1非芬兰欧洲人MAF：3.4x10^-6）。我们在3,574例地中海高危黑色素瘤患者和2,673例对照的WES数据中评估了该变异，鉴定出17例额外的意大利黑色素瘤病例（大多来自热那亚）和1例对照，随后确认rs755147810的所有携带者均携带该缺失。我们在另外四个家族的所有可获得病例中验证了该缺失的共分离（3/3、2/2、2/2和2/2例）。当考虑来自意大利、西班牙和希腊的非亲缘个体时（3,219例病例和2,266例对照；P=4.34x10^-4；OR=13.88），以及仅意大利样本时（2,170例病例，1,888例对照；P=4.14x10^-4；OR=14.01），MTAP变异与黑色素瘤风险的关联均高度显著。对携带者中共享单倍型的分析提示存在一个奠基者单倍型，其最近共同祖先（MRCA）可追溯至约26代之前，即17世纪，当时意大利屡遭毁灭性瘟疫暴发的侵袭，严重影响了主要的城市和商业中心。估计的MRCA时间框架与这次重大人口崩溃的巧合提示，瘟疫流行的人口学效应可能促成了这一遗传变异在现代人群中的持续存在。总之，我们的研究提供了一个远端高外显率非编码变异赋予黑色素瘤易感性的证据，对促进高危个体的筛查和早期检测工作具有潜在的转化影响。

查看英文原文 English abstract

Approximately 10% of cutaneous malignant melanoma cases are familial. Variants in CDKN2A account for ~40% of melanoma-prone families, with 10% more explained by other established genes. Strikingly, many unexplained families nonetheless show genetic linkage to chromosomal band 9p21, which harbors CDKN2A , suggesting that high-penetrance non-coding variants in the region may contribute to familial risk.As a part of a large-scale study of high-risk melanoma families from the Mediterranean region, we conducted germline whole-genome sequencing (WGS) on a melanoma case from a four-case family from Genoa, Italy, that is negative for variation in known susceptibility genes. We identified a novel 100kb deletion mapping to 9p21 205kb from CDKN2A and verified cosegregation in the two other available cases. The deletion is not protein-coding but contains annotated melanocyte enhancer elements and open chromatin that we find to interact with the promoters of the p16 and p14 transcripts of CDKN2A in melanocytes using H3K27Ac Hi-ChIP.To identify additional deletion carriers in whole-exome sequencing (WES) data, we searched for nearby exonic variants that cosegregate in the discovery family to serve as a proxy of the deletion, identifying a rare cosegregating missense variant in MTAP (rs755147810; chr9: 21,802,755:T:G; p.Ser3Ala; gnomADv4.1 Non-Finish European MAF: 3.4x10 -6 ). We assessed this variant in WES data from 3,574 high-risk Mediterranean melanoma patients and 2,673 controls, identifying 17 additional Italian melanoma cases (mostly from Genoa) and a single control, and subsequently confirmed all carriers of rs755147810 harbored the deletion. We verified cosegregation of the deletion in all available cases from four additional families (3/3, 2/2, 2/2 and 2/2 cases). The association of the MTAP variant with melanoma risk was highly significant when considering unrelated individuals from Italy, Spain, and Greece (3,219 cases and 2,266 controls; P = 4.34 x 10 -4 ; OR = 13.88) as well as Italian samples alone (2,170 cases, 1,888 controls; P = 4.14 x 10 -4 ; OR = 14.01). Analysis of a shared haplotype among carriers suggests a founder haplotype with the most recent common ancestor (MRCA) dating approximately 26 generations, i.e. the 17 th century, when Italy was repeatedly struck by devastating outbreaks of plague that profoundly affected major urban and commercial centers. The coincidence of the estimated MRCA timeframe with this major population collapse suggests that the demographic effects of the plague epidemic may have contributed to the persistence of this genetic variant in modern populations.In conclusion, our study provides evidence of a distant high-penetrance non-coding variant conferring melanoma susceptibility, with potential translational impact on facilitating screening and early-detection efforts in high-risk individuals.

利益披露 Disclosure

L. T. Bui-Raborn, None.. L. Pastorino, None.. D. Calista, None.. H. Hoang, None.. B. Dalmasso, None.. J. Scales, None.. S. Papiernik, None.. X. Wang, None.. R. Thakur, None.. S. Pellegrini, None.. M. Xu, None.. J. Yon, None.. W. Bruno, None.. T. Zhang, None.. Z. García-Casado, None.. E. Teresa Tanda, None.. F. Spagnolo, None.. M. Di Prete, None.. I. Bottillo, None.. S. Manukian, None.. M. Chiara Scaini, None.. K. P. Kypreou, None.. L. Di Nardo, None.. M. Potrony, None.. P. Aguilera-Peiró, None.. N. Shahrour, None.. T. Tran, None.. W. Zhou, None.. W. Lou, None.. A. L. Vogt, None.. J. Liu, None.. K. Jones, None.. M. Rodolfo, None.. I. Stefanaki, None.. C. Pellegrini, None.. C. Cota, None.. C. Menin, None.. M. Concetta Fargnoli, None.. K. Peris, None.. S. Puig, None.. E. Nagore, None.. P. Grammatico, None.. J. Shi, None.. P. Ghiorzo, None.. K. M. Brown, None.. M. Landi, None.

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