Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

被引：9

作者：

Kar, Siddhartha P. ^{[1
,2
]}

Considine, Daniel P. C. ^{[3
]}

Tyrer, Jonathan P. ^{[4
]}

Plummer, Jasmine T. ^{[5
,6
]}

Chen, Stephanie ^{[5
,6
]}

Dezem, Felipe S. ^{[5
,6
]}

Barbeira, Alvaro N. ^{[7
]}

Rajagopal, Padma S. ^{[8
]}

Rosenow, Will T. ^{[9
]}

Moreno, Fernando ^{[10
]}

Bodelon, Clara ^{[11
]}

Chang-Claude, Jenny ^{[12
,13
]}

Chenevix-Trench, Georgia ^{[14
]}

DeFazio, Anna ^{[15
,16
]}

Doerk, Thilo ^{[17
]}

Ekici, Arif B. ^{[18
,19
]}

Ewing, Ailith ^{[20
,21
]}

Fountzilas, George ^{[22
]}

Goode, Ellen L. ^{[23
]}

Hartman, Mikael ^{[24
,25
,26
]}

Heitz, Florian ^{[27
,28
]}

Hillemanns, Peter ^{[29
]}

Hogdall, Estrid ^{[30
,31
]}

Hogdall, Claus K. ^{[32
]}

Huzarski, Tomasz ^{[33
,34
]}

Jensen, Allan ^{[35
]}

Karlan, Beth Y. ^{[36
]}

Khusnutdinova, Elza ^{[37
,38
]}

Kiemeney, Lambertus A. ^{[39
]}

Kjaer, Susanne K. ^{[30
,40
]}

Klapdor, Rudiger ^{[29
]}

Kobel, Martin ^{[41
]}

Li, Jingmei ^{[24
,25
,42
]}

Liebrich, Clemens ^{[43
]}

May, Taymaa ^{[44
]}

Olsson, Hakan ^{[45
]}

Permuth, Jennifer B. ^{[46
]}

Peterlongo, Paolo ^{[47
]}

Radice, Paolo ^{[48
]}

Ramus, Susan J. ^{[49
,50
]}

Riggan, Marjorie J. ^{[51
]}

Risch, Harvey A. ^{[52
]}

Saloustros, Emmanouil ^{[53
]}

Simard, Jacques ^{[54
]}

Szafron, Lukasz M. ^{[55
]}

Titus, Linda ^{[56
]}

Thompson, Cheryl L. ^{[57
]}

Vierkant, Robert A. ^{[58
]}

Winham, Stacey J. ^{[59
]}

Zheng, Wei ^{[60
]}

机构：

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

[2] Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England

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

[4] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England

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

[6] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA

[7] Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

[8] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL USA

[9] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[10] Hosp Clin San Carlos, Dept Oncol, Madrid, Spain

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

[12] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[13] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Canc Epidemiol Grp, Hamburg, Germany

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

[15] Univ Sydney, Ctr Canc Res, Westmead Inst Med Res, Sydney, NSW, Australia

[16] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia

[17] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany

[18] Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany

[19] Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen, Erlangen, Germany

[20] Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[21] Univ Edinburgh, Canc Res UK Edinburgh Ctr, Inst Genet & Canc, Edinburgh, Midlothian, Scotland

[22] Aristotle Univ Thessaloniki, Hellen Fdn Canc Res, Lab Mol Oncol, Sch Med, Thessaloniki, Greece

[23] Mayo Clin, Div Epidemiol, Dept Quantitat Hlth Sci, Rochester, MN USA

[24] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore, Singapore

[25] Natl Univ Hlth Syst, Singapore, Singapore

[26] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore

[27] Kliniken Essen Mitte Evang, Dept Gynecol & Gynecol Oncol, Essen, Germany

[28] Charite Campus Virchow Klinikum, Dept Gynecol, Ctr Oncol Surg, Berlin, Germany

[29] Hannover Med Sch, Dept Gynecol & Obstet, Hannover, Germany

[30] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark

[31] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark

[32] Univ Copenhagen, Rigshosp, Juliane Marie Ctr, Dept Gynecol, Copenhagen, Denmark

[33] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland

[34] Univ Zielona Gora, Dept Genet & Pathol, Zielona Gora, Poland

[35] Danish Canc Soc Res Ctr, Dept Lifestyle Reprod & Canc, Copenhagen, Denmark

[36] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA

[37] Russian Acad Sci, Inst Biochem & Genet, Ufa Fed Res Ctr, Ufa, Russia

[38] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia

[39] Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands

[40] Univ Copenhagen, Rigshosp, Dept Gynaecol, Copenhagen, Denmark

[41] Univ Calgary, Foothills Med Ctr, Dept Pathol & Lab Med, Calgary, AB, Canada

[42] Genome Inst Singapore, Human Genet, Singapore, Singapore

[43] Klinikum Wolfsburg, Dept Obstet & Gynecol, Wolfsburg, Germany

[44] Univ Hlth Network, Princess Margaret Hosp, Div Gynecol Oncol, Toronto, ON, Canada

[45] Lund Univ, Dept Clin Sci, Div Oncol, Lund, Sweden

[46] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[47] IFOM FIRC Inst Mol Oncol, Genome Diagnost Program, Milan, Italy

[48] Fdn IRCCS Ist Nazl Tumori INT, Dept Res, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy

[49] Univ New South Wales, Fac Med, Sch Womens & Childrens Hlth, Sydney, NSW, Australia

[50] Univ New South Wales, Lowy Canc Res Ctr, Adult Canc Program, Sydney, NSW, Australia

来源：

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

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

GENOME-WIDE ASSOCIATION; CCNE1; AMPLIFICATION; RISK; LOCI; MULTIPLE; REPLICATION; MAMMAGLOBIN; DISCOVERY; REVEALS; DISEASE;

D O I：

10.1016/j.xhgg.2021.100042

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

引用

页数：12

共 57 条

[1] Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability
Achuthankutty, Divya
Thakur, Roshan Singh
Haahr, Peter
Hoffmann, Saskia
Drainas, Alexandros P.
Bizard, Anna H.
Weischenfeldt, Joachim
Hickson, Ian D.
Mailand, Niels
[J]. JOURNAL OF CELL BIOLOGY, 2019, 218 (12) : 3943 - 3953
[2] Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors
Andreassen, Ole A.
Djurovic, Srdjan
Thompson, Wesley K.
Schork, Andrew J.
Kendler, Kenneth S.
O'Donovan, Michael C.
Rujescu, Dan
Werge, Thomas
van de Bunt, Martijn
Morris, Andrew P.
McCarthy, Mark I.
Roddey, J. Cooper
McEvoy, Linda K.
Desikan, Rahul S.
Dale, Anders M.
[J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 92 (02) : 197 - 209
[3] Atkins I., 2019, CANCER
[4] Integrating predicted transcriptome from multiple tissues improves association detection
Barbeira, Alvaro N.
Pividori, Milton D.
Zheng, Jiamao
Wheeler, Heather E.
Nicolae, Dan L.
Im, Hae Kyung
[J]. PLOS GENETICS, 2019, 15 (01):
[5] ETAA1 acts at stalled replication forks to maintain genome integrity
Bass, Thomas E.
Luzwick, Jessica W.
Kavanaugh, Gina
Carroll, Clinton
Dungrawala, Huzefa
Glick, Gloria G.
Feldkamp, Michael D.
Putney, Reid
Chazin, Walter J.
Cortez, David
[J]. NATURE CELL BIOLOGY, 2016, 18 (11) : 1185 - +
[6] Integrated genomic analyses of ovarian carcinoma
Bell, D.
Berchuck, A.
Birrer, M.
Chien, J.
Cramer, D. W.
Dao, F.
Dhir, R.
DiSaia, P.
Gabra, H.
Glenn, P.
Godwin, A. K.
Gross, J.
Hartmann, L.
Huang, M.
Huntsman, D. G.
Iacocca, M.
Imielinski, M.
Kalloger, S.
Karlan, B. Y.
Levine, D. A.
Mills, G. B.
Morrison, C.
Mutch, D.
Olvera, N.
Orsulic, S.
Park, K.
Petrelli, N.
Rabeno, B.
Rader, J. S.
Sikic, B. I.
Smith-McCune, K.
Sood, A. K.
Bowtell, D.
Penny, R.
Testa, J. R.
Chang, K.
Dinh, H. H.
Drummond, J. A.
Fowler, G.
Gunaratne, P.
Hawes, A. C.
Kovar, C. L.
Lewis, L. R.
Morgan, M. B.
Newsham, I. F.
Santibanez, J.
Reid, J. G.
Trevino, L. R.
Wu, Y. -Q.
Wang, M.
[J]. NATURE, 2011, 474 (7353) : 609 - 615
[7] The genesis and evolution of high-grade serous ovarian cancer
Bowtell, David D. L.
[J]. NATURE REVIEWS CANCER, 2010, 10 (11) : 803 - 808
[8] Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer
Childs, Erica J.
Mocci, Evelina
Campa, Daniele
Bracci, Paige M.
Gallinger, Steven
Goggins, Michael
Li, Donghui
Neale, Rachel E.
Olson, Sara H.
Scelo, Ghislaine
Amundadottir, Laufey T.
Bamlet, William R.
Bijlsma, Maarten F.
Blackford, Amanda
Borges, Michael
Brennan, Paul
Brenner, Hermann
Bueno-de-Mesquita, H. Bas
Canzian, Federico
Capurso, Gabriele
Cavestro, Giulia M.
Chaffee, Kari G.
Chanock, Stephen J.
Cleary, Sean P.
Cotterchio, Michelle
Foretova, Lenka
Fuchs, Charles
Funel, Niccola
Gazouli, Maria
Hassan, Manal
Herman, Joseph M.
Holcatova, Ivana
Holly, Elizabeth A.
Hoover, Robert N.
Hung, Rayjean J.
Janout, Vladimir
Key, Timothy J.
Kupcinskas, Juozas
Kurtz, Robert C.
Landi, Stefano
Lu, Lingeng
Malecka-Panas, Ewa
Mambrini, Andrea
Mohelnikova-Duchonova, Beatrice
Neoptolemos, John P.
Oberg, Ann L.
Orlow, Irene
Pasquali, Claudio
Pezzilli, Raffaele
Rizzato, Cosmeri
[J]. NATURE GENETICS, 2015, 47 (08) : 911 - +
[9] MECHANISMS OF DISEASE Susceptibility Pathways in Fanconi's Anemia and Breast Cancer
D'Andrea, Alan D.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (20) : 1909 - 1919
[10] Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner
de Jong, Simone
Chepelev, Iouri
Janson, Esther
Strengman, Eric
van den Berg, Leonard H.
Veldink, Jan H.
Ophoff, Roel A.
[J]. BMC GENOMICS, 2012, 13

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