Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Marco Matejcic; Edward J. Saunders; Tokhir Dadaev; Mark N. Brook; Kan Wang; Xin Sheng; Ali Amin Al Olama; Fredrick R. Schumacher; Sue A. Ingles; Koveela Govindasami; The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium; Jyotsna Batra

doi:10.1038/s41467-018-06863-1

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Marco Matejcic, Edward J. Saunders, Tokhir Dadaev, Mark N. Brook, Kan Wang, Xin Sheng, Ali Amin Al Olama, Fredrick R. Schumacher, Sue A. Ingles, Koveela Govindasami, The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Jyotsna Batra

Research output: Contribution to journal › Article › Research › peer-review

Abstract

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10⁻¹⁵), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

Original language	English
Article number	4616
Pages (from-to)	1-11
Number of pages	11
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06863-1
Publication status	Published - 1 Dec 2018
Externally published	Yes

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Germline variation at 8q24 and prostate cancer risk in men of European ancestryFinal published version, 1.58 MBLicence: CC BY

Cite this

Matejcic, M., Saunders, E. J., Dadaev, T., Brook, M. N., Wang, K., Sheng, X., Olama, A. A. A., Schumacher, F. R., Ingles, S. A., Govindasami, K., The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, & Batra, J. (2018). Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nature Communications, 9(1), 1-11. Article 4616. https://doi.org/10.1038/s41467-018-06863-1

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title = "Germline variation at 8q24 and prostate cancer risk in men of European ancestry",

abstract = "Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.",

author = "Marco Matejcic and Saunders, {Edward J.} and Tokhir Dadaev and Brook, {Mark N.} and Kan Wang and Xin Sheng and Olama, {Ali Amin Al} and Schumacher, {Fredrick R.} and Ingles, {Sue A.} and Koveela Govindasami and {The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium} and Sara Benlloch and Berndt, {Sonja I.} and Demetrius Albanes and Stella Koutros and Kenneth Muir and Stevens, {Victoria L.} and Gapstur, {Susan M.} and Tangen, {Catherine M.} and Jyotsna Batra and Judith Clements and Henrik Gronberg and Nora Pashayan and Johanna Schleutker and Alicja Wolk and Catharine West and Lorelei Mucci and Peter Kraft and G{\'e}raldine Cancel-Tassin and Sorensen, {Karina D.} and Lovise Maehle and Grindedal, {Eli M.} and Strom, {Sara S.} and Neal, {David E.} and Hamdy, {Freddie C.} and Donovan, {Jenny L.} and Travis, {Ruth C.} and Hamilton, {Robert J.} and Barry Rosenstein and Lu, {Yong Jie} and Giles, {Graham G.} and Kibel, {Adam S.} and Ana Vega and Bensen, {Jeanette T.} and Manolis Kogevinas and Penney, {Kathryn L.} and Park, {Jong Y.} and Stanford, {Janet L.} and Cezary Cybulski and Nordestgaard, {B{\o}rge G.} and Hermann Brenner and Christiane Maier and Jeri Kim and Teixeira, {Manuel R.} and Neuhausen, {Susan L.} and {De Ruyck}, Kim and Azad Razack and Newcomb, {Lisa F.} and Davor Lessel and Radka Kaneva and Nawaid Usmani and Frank Claessens and Townsend, {Paul A.} and Dominguez, {Manuela G.} and Roobol, {Monique J.} and Florence Menegaux and Khaw, {Kay Tee} and Cannon-Albright, {Lisa A.} and Hardev Pandha and Thibodeau, {Stephen N.} and Schaid, {Daniel J.} and Henderson, {Brian E.} and Stern, {Mariana C.} and Alison Thwaites and Michelle Guy and Ian Whitmore and Angela Morgan and Cyril Fisher and Steve Hazel and Naomi Livni and Margaret Cook and Laura Fachal and Stephanie Weinstein and {Beane Freeman}, {Laura E.} and Hoover, {Robert N.} and Machiela, {Mitchell J.} and Artitaya Lophatananon and Carter, {Brian D.} and Phyllis Goodman and Leire Moya and Srilakshmi Srinivasan and Kedda, {Mary Anne} and Trina Yeadon and Allison Eckert and Martin Eklund and Carin Cavalli-Bjoerkman and Dunning, {Alison M.} and Csilla Sipeky and Niclas Hakansson and Rebecca Elliott and Hardeep Ranu",

year = "2018",

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doi = "10.1038/s41467-018-06863-1",

language = "English",

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issn = "2041-1723",

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Matejcic, M, Saunders, EJ, Dadaev, T, Brook, MN, Wang, K, Sheng, X, Olama, AAA, Schumacher, FR, Ingles, SA, Govindasami, K, The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium & Batra, J 2018, 'Germline variation at 8q24 and prostate cancer risk in men of European ancestry', Nature Communications, vol. 9, no. 1, 4616, pp. 1-11. https://doi.org/10.1038/s41467-018-06863-1

TY - JOUR

T1 - Germline variation at 8q24 and prostate cancer risk in men of European ancestry

AU - Matejcic, Marco

AU - Saunders, Edward J.

AU - Dadaev, Tokhir

AU - Brook, Mark N.

AU - Wang, Kan

AU - Sheng, Xin

AU - Olama, Ali Amin Al

AU - Schumacher, Fredrick R.

AU - Ingles, Sue A.

AU - Govindasami, Koveela

AU - The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium

AU - Benlloch, Sara

AU - Berndt, Sonja I.

AU - Albanes, Demetrius

AU - Koutros, Stella

AU - Muir, Kenneth

AU - Stevens, Victoria L.

AU - Gapstur, Susan M.

AU - Tangen, Catherine M.

AU - Batra, Jyotsna

AU - Clements, Judith

AU - Gronberg, Henrik

AU - Pashayan, Nora

AU - Schleutker, Johanna

AU - Wolk, Alicja

AU - West, Catharine

AU - Mucci, Lorelei

AU - Kraft, Peter

AU - Cancel-Tassin, Géraldine

AU - Sorensen, Karina D.

AU - Maehle, Lovise

AU - Grindedal, Eli M.

AU - Strom, Sara S.

AU - Neal, David E.

AU - Hamdy, Freddie C.

AU - Donovan, Jenny L.

AU - Travis, Ruth C.

AU - Hamilton, Robert J.

AU - Rosenstein, Barry

AU - Lu, Yong Jie

AU - Giles, Graham G.

AU - Kibel, Adam S.

AU - Vega, Ana

AU - Bensen, Jeanette T.

AU - Kogevinas, Manolis

AU - Penney, Kathryn L.

AU - Park, Jong Y.

AU - Stanford, Janet L.

AU - Cybulski, Cezary

AU - Nordestgaard, Børge G.

AU - Brenner, Hermann

AU - Maier, Christiane

AU - Kim, Jeri

AU - Teixeira, Manuel R.

AU - Neuhausen, Susan L.

AU - De Ruyck, Kim

AU - Razack, Azad

AU - Newcomb, Lisa F.

AU - Lessel, Davor

AU - Kaneva, Radka

AU - Usmani, Nawaid

AU - Claessens, Frank

AU - Townsend, Paul A.

AU - Dominguez, Manuela G.

AU - Roobol, Monique J.

AU - Menegaux, Florence

AU - Khaw, Kay Tee

AU - Cannon-Albright, Lisa A.

AU - Pandha, Hardev

AU - Thibodeau, Stephen N.

AU - Schaid, Daniel J.

AU - Henderson, Brian E.

AU - Stern, Mariana C.

AU - Thwaites, Alison

AU - Guy, Michelle

AU - Whitmore, Ian

AU - Morgan, Angela

AU - Fisher, Cyril

AU - Hazel, Steve

AU - Livni, Naomi

AU - Cook, Margaret

AU - Fachal, Laura

AU - Weinstein, Stephanie

AU - Beane Freeman, Laura E.

AU - Hoover, Robert N.

AU - Machiela, Mitchell J.

AU - Lophatananon, Artitaya

AU - Carter, Brian D.

AU - Goodman, Phyllis

AU - Moya, Leire

AU - Srinivasan, Srilakshmi

AU - Kedda, Mary Anne

AU - Yeadon, Trina

AU - Eckert, Allison

AU - Eklund, Martin

AU - Cavalli-Bjoerkman, Carin

AU - Dunning, Alison M.

AU - Sipeky, Csilla

AU - Hakansson, Niclas

AU - Elliott, Rebecca

AU - Ranu, Hardeep

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

AB - Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

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U2 - 10.1038/s41467-018-06863-1

DO - 10.1038/s41467-018-06863-1

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VL - 9

SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4616

ER -

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Abstract

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Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Abstract

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Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry

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