Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

被引：15

作者：

Chen, Hongjie ^{[1
]}

Majumdar, Arunabha ^{[2
,3
]}

Wang, Lu ^{[4
]}

Kar, Siddhartha ^{[5
]}

Brown, Kevin M. ^{[6
]}

Feng, Helian ^{[7
]}

Turman, Constance ^{[8
]}

Dennis, Joe ^{[9
]}

Easton, Douglas ^{[9
]}

Michailidou, Kyriaki ^{[10
,11
]}

Simard, Jacques ^{[12
,13
]}

Bishop, Timothy ^{[14
]}

Cheng, Iona C. ^{[15
]}

Huyghe, Jeroen R. ^{[16
]}

Schmit, Stephanie L. ^{[17
]}

O'Mara, Tracy A. ^{[18
]}

Spurdle, Amanda B. ^{[18
]}

Gharahkhani, Puya ^{[19
]}

Schumacher, Johannes ^{[20
]}

Jankowski, Janusz ^{[21
,22
]}

Gockel, Ines ^{[23
]}

Bondy, Melissa L. ^{[24
]}

Houlston, Richard S. ^{[25
]}

Jenkins, Robert B. ^{[26
]}

Melin, Beatrice ^{[27
]}

Lesseur, Corina ^{[28
,29
]}

Ness, Andy R. ^{[30
,31
,32
]}

Diergaarde, Brenda ^{[33
,34
]}

Olshan, Andrew F. ^{[35
,36
]}

Amos, Christopher, I ^{[37
]}

Christiani, David C. ^{[8
,38
]}

Landi, Maria T. ^{[6
]}

McKay, James D. ^{[29
]}

Brossard, Myriam ^{[39
,40
]}

Iles, Mark M. ^{[41
]}

Law, Matthew H. ^{[19
,42
,43
]}

MacGregor, Stuart ^{[19
]}

Beesley, Jonathan ^{[18
]}

Jones, Michelle R. ^{[44
]}

Tyrer, Jonathan ^{[45
]}

Winham, Stacey J. ^{[46
]}

Klein, Alison P. ^{[47
,48
]}

Petersen, Gloria ^{[46
]}

Li, Donghui ^{[49
]}

Wolpin, Brian M. ^{[50
]}

Eeles, Rosalind A. ^{[51
,52
]}

Haiman, Christopher A. ^{[53
]}

Kote-Jarai, Zsofia ^{[51
,52
]}

Schumacher, Fredrick R. ^{[54
,55
]}

Brennan, Paul ^{[30
,31
]}

机构：

[1] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[3] Indian Inst Technol Hyderabad, Dept Math, Kandi, Telangana, India

[4] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA

[5] Univ Bristol, Bristol Med Sch, Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England

[6] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[7] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[8] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[9] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England

[10] Cyprus Inst Neurol & Genet, Biostat Unit, Nicosia, Cyprus

[11] Cyprus Sch Mol Med, Nicosia, Cyprus

[12] Univ Laval, Fac Med, Dept Mol Med, Quebec City, PQ, Canada

[13] Univ Laval, CHU Quebec, Ctr Rech, Quebec City, PQ, Canada

[14] Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England

[15] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA

[16] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA

[17] Cleveland Clin, Lerner Res Inst, Genom Med Inst, Cleveland, OH 44106 USA

[18] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia

[19] QIMR Berghofer Med Res Inst, Stat Genet, Brisbane, Qld, Australia

[20] Univ Hosp Marburg, Ctr Human Genet, Marburg, Germany

[21] United Arab Emirates Univ, Coll Med & Hlth Sci, Abu Dhabi, U Arab Emirates

[22] UCL, Comprehens Clin Trials Unit, London, England

[23] Univ Hosp Leipzig, Dept Visceral Transplant Thorac & Vasc Surg, Leipzig, Germany

[24] Stanford Univ, Dept Epidemiol & Populat Hlth, Palo Alto, CA 94304 USA

[25] Inst Canc Res, Div Genet & Epidemiol, London, England

[26] Mayo Clin, Dept Lab Med & Pathol, Mayo Clin Comprehens Canc Ctr, Rochester, MN USA

[27] Umea Univ, Dept Radiat Sci, Umea, Sweden

[28] Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, New York, NY 10029 USA

[29] World Hlth Org, Int Agcy Res Canc, Lyon, France

[30] Univ Hosp Bristol & Weston NHS Fdn Trust, Natl Inst Hlth Res NIHR Bristol Biomed Res Ctr, Bristol, Avon, England

[31] Univ Bristol, Bristol, Avon, England

[32] Univ Bristol, Bristol Dent Sch, Bristol, Avon, England

[33] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA USA

[34] UPMC Hillman Canc Ctr, Pittsburgh, PA USA

[35] Univ North Carolina Chapel Hill, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA

[36] UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA

[37] Baylor Coll Med, Inst Clin & Translat Res, Houston, TX 77030 USA

[38] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA

[39] Univ Paris 05, Inst Natl Sante & Rech Med INSERM, Genet Epidemiol & Funct Genom Multifactorial Dis, UMRS 1124, Paris, France

[40] Sinai Hlth Syst, Lunenfeld Tanenbuaum Res Inst, Prosserman Ctr Populat Hlth Res, Toronto, ON, Canada

[41] Univ Leeds, Leeds Inst Data Analyt, Leeds, W Yorkshire, England

[42] Queensland Univ Technol, Fac Hlth, Sch Biomed Sci, Kelvin Grove, Qld, Australia

[43] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Kelvin Grove, Qld, Australia

[44] Cedars Sinai Med Ctr, Ctr Bioinformat & Funct Genom, Dept Biomed Sci, Los Angeles, CA 90048 USA

[45] Univ Cambridge, Dept Oncol, Cambridge, England

[46] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[47] Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA

[48] Johns Hopkins Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD USA

[49] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[50] Dana Farber Harvard Canc Ctr, Dept Med Oncol, Boston, MA USA

来源：

HUMAN GENETICS AND GENOMICS ADVANCES | 2021年 / 2卷 / 03期

关键词：

GENOME-WIDE ASSOCIATION; METAANALYSIS IDENTIFIES 5; GENETIC RISK VARIANTS; SUSCEPTIBILITY LOCI; TELOMERE LENGTH; TERT-CLPTM1L LOCUS; PROSTATE; BREAST; LUNG; 8Q24;

D O I：

10.1016/j.xhgg.2021.100041

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

引用

页数：17

共 80 条

[1] Multiple loci on 8q24 associated with prostate cancer susceptibility [J].

Al Olama, Ali Amin ;

Kote-Jarai, Zsofia ;

Giles, Graham G. ;

Guy, Michelle ;

Morrison, Jonathan ;

Severi, Gianluca ;

Leongamornlert, Daniel A. ;

Tymrakiewicz, Malgorzata ;

Jhavar, Sameer ;

Saunders, Ed ;

Hopper, John L. ;

Southey, Melissa C. ;

Muir, Kenneth R. ;

English, Dallas R. ;

Dearnaley, David P. ;

Ardern-Jones, Audrey T. ;

Hall, Amanda L. ;

O'Brien, Lynne T. ;

Wilkinson, Rosemary A. ;

Sawyer, Emma ;

Lophatananon, Artitaya ;

Horwich, Alan ;

Huddart, Robert A. ;

Khoo, Vincent S. ;

Parker, Christopher C. ;

Woodhouse, Christopher J. ;

Thompson, Alan ;

Christmas, Tim ;

Ogden, Chris ;

Cooper, Colin ;

Donovan, Jenny L. ;

Hamdy, Freddie C. ;

Neal, David E. ;

Eeles, Rosalind A. ;

Easton, Douglas F. .

NATURE GENETICS, 2009, 41 (10) :1058-1060

[2] A global reference for human genetic variation [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Wang, Jun ;

Wilson, Richard K. ;

Boerwinkle, Eric ;

Doddapaneni, Harsha ;

Han, Yi ;

Korchina, Viktoriya ;

Kovar, Christie ;

Lee, Sandra ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Zhu, Yiming ;

Chang, Yuqi ;

Feng, Qiang ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Lan, Tianming ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Liu, Shengmao ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Tang, Meifang ;

Wang, Bo .

NATURE, 2015, 526 (7571) :68-+

[3] Co-exposure to multiple metals, TERT-CLPTM1L variants, and their joint influence on leukocyte telomere length [J].

Bai, Yansen ;

Fu, Wenshan ;

Guan, Xin ;

Wu, Xiulong ;

Li, Guyanan ;

Wei, Wei ;

Feng, Yue ;

Meng, Hua ;

Li, Hang ;

Li, Mengying ;

Fu, Ming ;

Jie, Jiali ;

Wang, Chenming ;

Zhang, Xiaomin ;

He, Meian ;

Gun, Huan .

ENVIRONMENT INTERNATIONAL, 2020, 140

[4] Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions [J].

Barrett, Jennifer H. ;

Taylor, John C. ;

Bright, Chloe ;

Harland, Mark ;

Dunning, Alison M. ;

Akslen, Lars A. ;

Andresen, Per A. ;

Avril, Marie-Francoise ;

Azizi, Esther ;

Scarra, Giovanna Bianchi ;

Brossard, Myriam ;

Brown, Kevin M. ;

Debniak, Tadeusz ;

Elder, David E. ;

Friedman, Eitan ;

Ghiorzo, Paola ;

Gillanders, Elizabeth M. ;

Gruis, Nelleke A. ;

Hansson, Johan ;

Helsing, Per ;

Hocevar, Marko ;

Hoiom, Veronica ;

Ingvar, Christian ;

Landi, Maria Teresa ;

Lang, Julie ;

Lathrop, G. Mark ;

Lubinski, Jan ;

Mackie, Rona M. ;

Molven, Anders ;

Novakovic, Srdjan ;

Olsson, Hakan ;

Puig, Susana ;

Anton Puig-Butille, Joan ;

van der Stoep, Nienke ;

van Doorn, Remco ;

van Workum, Wilbert ;

Goldstein, Alisa M. ;

Kanetsky, Peter A. ;

Pharoah, Paul D. P. ;

Demenais, Florence ;

Hayward, Nicholas K. ;

Newton Bishop, Julia A. ;

Bishop, D. Timothy ;

Iles, Mark M. .

INTERNATIONAL JOURNAL OF CANCER, 2015, 136 (06) :1351-1360

[5]

Beesley J., 2011, FUNCTIONAL POLYMORPH

[6] Approximately independent linkage disequilibrium blocks in human populations [J].

Berisa, Tomaz ;

Pickrell, Joseph K. .

BIOINFORMATICS, 2016, 32 (02) :283-285

[7] A Subset-Based Approach Improves Power and Interpretation for the Combined Analysis of Genetic Association Studies of Heterogeneous Traits [J].

Bhattacharjee, Samsiddhi ;

Rajaraman, Preetha ;

Jacobs, Kevin B. ;

Wheeler, William A. ;

Melin, Beatrice S. ;

Hartge, Patricia ;

Yeager, Meredith ;

Chung, Charles C. ;

Chanock, Stephen J. ;

Chatterjee, Nilanjan .

AMERICAN JOURNAL OF HUMAN GENETICS, 2012, 90 (05) :821-835

[8] Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer [J].

Bojesen, Stig E. ;

Pooley, Karen A. ;

Johnatty, Sharon E. ;

Beesley, Jonathan ;

Michailidou, Kyriaki ;

Tyrer, Jonathan P. ;

Edwards, Stacey L. ;

Pickett, Hilda A. ;

Shen, Howard C. ;

Smart, Chanel E. ;

Hillman, Kristine M. ;

Mai, Phuong L. ;

Lawrenson, Kate ;

Stutz, Michael D. ;

Lu, Yi ;

Karevan, Rod ;

Woods, Nicholas ;

Johnston, Rebecca L. ;

French, Juliet D. ;

Chen, Xiaoqing ;

Weischer, Maren ;

Nielsen, Sune F. ;

Maranian, Melanie J. ;

Ghoussaini, Maya ;

Ahmed, Shahana ;

Baynes, Caroline ;

Bolla, Manjeet K. ;

Wang, Qin ;

Dennis, Joe ;

McGuffog, Lesley ;

Barrowdale, Daniel ;

Lee, Andrew ;

Healey, Sue ;

Lush, Michael ;

Tessier, Daniel C. ;

Vincent, Daniel ;

Bacot, Francis ;

Vergote, Ignace ;

Lambrechts, Sandrina ;

Despierre, Evelyn ;

Risch, Harvey A. ;

Gonzalez-Neira, Anna ;

Rossing, Mary Anne ;

Pita, Guillermo ;

Doherty, Jennifer A. ;

Alvarez, Nuria ;

Larson, Melissa C. ;

Fridley, Brooke L. ;

Schoof, Nils ;

Chang-Claude, Jenny .

NATURE GENETICS, 2013, 45 (04) :371-384

[9]

Bulik-Sullivan B., 2015, ATLAS GENETIC CORREL

[10] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

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