Copy number variants are ovarian cancer risk alleles at known and novel risk loci

Amber A. Devries; Joe Dennis; Jonathan P. Tyrer; Pei Chen Peng; Simon G. Coetzee; Alberto L. Reyes; Jasmine T. Plummer; Brian D. Davis; Stephanie S. Chen; Felipe Segato Dezem; Katja K.H. Aben; Hoda Anton-Culver; Natalia N. Antonenkova; Matthias W. Beckmann; Alicia Beeghly-Fadiel; Andrew Berchuck; Natalia V. Bogdanova; Nadja Bogdanova-Markov; James D. Brenton; Ralf Butzow; Ian Campbell; Jenny Chang-Claude; Georgia Chenevix-Trench; Linda S. Cook; Anna Defazio; Jennifer A. Doherty; Thilo Dork; Diana M. Eccles; A. Heather Eliassen; Peter A. Fasching; Renee T. Fortner; Graham G. Giles; Ellen L. Goode; Marc T. Goodman; Jacek Gronwald; Niclas Hakansson; Michelle A.T. Hildebrandt; Chad Huff; David G. Huntsman; Allan Jensen; Siddhartha Kar; Beth Y. Karlan; Elza K. Khusnutdinova; Lambertus A. Kiemeney; Susanne K. Kjaer; Jolanta Kupryjanczyk; Marilyne Labrie; Diether Lambrechts; Nhu D. Le; Jan Lubinski; Taymaa May; Usha Menon; Roger L. Milne; Francesmary Modugno; Alvaro N. Monteiro; Kirsten B. Moysich; Kunle Odunsi; Hakan Olsson; Celeste L. Pearce; Tanja Pejovic; Susan J. Ramus; Elio Riboli; Marjorie J. Riggan; Isabelle Romieu; Dale P. Sandler; Joellen M. Schildkraut; V. Wendy Setiawan; Weiva Sieh; Honglin Song; Rebecca Sutphen; Kathryn L. Terry; Pamela J. Thompson; Linda Titus; Shelley S. Tworoger; Els Van Nieuwenhuysen; Digna Velez Edwards; Penelope M. Webb; Nicolas Wentzensen; Alice S. Whittemore; Alicja Wolk; Anna H. Wu; Argyrios Ziogas; Matthew L. Freedman; Kate Lawrenson; Paul D.P. Pharoah; Douglas F. Easton; Simon A. Gayther; Michelle R. Jones

doi:10.1093/jnci/djac160

Copy number variants are ovarian cancer risk alleles at known and novel risk loci

Amber A. Devries, Joe Dennis, Jonathan P. Tyrer, Pei Chen Peng, Simon G. Coetzee, Alberto L. Reyes, Jasmine T. Plummer, Brian D. Davis, Stephanie S. Chen, Felipe Segato Dezem, Katja K.H. Aben, Hoda Anton-Culver, Natalia N. Antonenkova, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Andrew Berchuck, Natalia V. Bogdanova, Nadja Bogdanova-Markov, James D. Brenton, Ralf ButzowIan Campbell, Jenny Chang-Claude, Georgia Chenevix-Trench, Linda S. Cook, Anna Defazio, Jennifer A. Doherty, Thilo Dork, Diana M. Eccles, A. Heather Eliassen, Peter A. Fasching, Renee T. Fortner, Graham G. Giles, Ellen L. Goode, Marc T. Goodman, Jacek Gronwald, Niclas Hakansson, Michelle A.T. Hildebrandt, Chad Huff, David G. Huntsman, Allan Jensen, Siddhartha Kar, Beth Y. Karlan, Elza K. Khusnutdinova, Lambertus A. Kiemeney, Susanne K. Kjaer, Jolanta Kupryjanczyk, Marilyne Labrie, Diether Lambrechts, Nhu D. Le, Jan Lubinski, Taymaa May, Usha Menon, Roger L. Milne, Francesmary Modugno, Alvaro N. Monteiro, Kirsten B. Moysich, Kunle Odunsi, Hakan Olsson, Celeste L. Pearce, Tanja Pejovic, Susan J. Ramus, Elio Riboli, Marjorie J. Riggan, Isabelle Romieu, Dale P. Sandler, Joellen M. Schildkraut, V. Wendy Setiawan, Weiva Sieh, Honglin Song, Rebecca Sutphen, Kathryn L. Terry, Pamela J. Thompson, Linda Titus, Shelley S. Tworoger, Els Van Nieuwenhuysen, Digna Velez Edwards, Penelope M. Webb, Nicolas Wentzensen, Alice S. Whittemore, Alicja Wolk, Anna H. Wu, Argyrios Ziogas, Matthew L. Freedman, Kate Lawrenson, Paul D.P. Pharoah, Douglas F. Easton, Simon A. Gayther, Michelle R. Jones

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

3 Scopus citations

Abstract

Background: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Methods: Single nucleotide polymorphism array data from 13071 EOC cases and 17306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. Results: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P <. 001) were identified for rare CNVs. Risk-associated CNVs were enriched (P <. 05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. Conclusions: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Original language	English (US)
Pages (from-to)	1533-1544
Number of pages	12
Journal	Journal of the National Cancer Institute
Volume	114
Issue number	11
DOIs	https://doi.org/10.1093/jnci/djac160
State	Published - Nov 1 2022

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1093/jnci/djac160

Cite this

Devries, A. A., Dennis, J., Tyrer, J. P., Peng, P. C., Coetzee, S. G., Reyes, A. L., Plummer, J. T., Davis, B. D., Chen, S. S., Dezem, F. S., Aben, K. K. H., Anton-Culver, H., Antonenkova, N. N., Beckmann, M. W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N. V., Bogdanova-Markov, N., Brenton, J. D., ... Jones, M. R. (2022). Copy number variants are ovarian cancer risk alleles at known and novel risk loci. Journal of the National Cancer Institute, 114(11), 1533-1544. https://doi.org/10.1093/jnci/djac160

Devries, AA, Dennis, J, Tyrer, JP, Peng, PC, Coetzee, SG, Reyes, AL, Plummer, JT, Davis, BD, Chen, SS, Dezem, FS, Aben, KKH, Anton-Culver, H, Antonenkova, NN, Beckmann, MW, Beeghly-Fadiel, A, Berchuck, A, Bogdanova, NV, Bogdanova-Markov, N, Brenton, JD, Butzow, R, Campbell, I, Chang-Claude, J, Chenevix-Trench, G, Cook, LS, Defazio, A, Doherty, JA, Dork, T, Eccles, DM, Eliassen, AH, Fasching, PA, Fortner, RT, Giles, GG, Goode, EL, Goodman, MT, Gronwald, J, Hakansson, N, Hildebrandt, MAT, Huff, C, Huntsman, DG, Jensen, A, Kar, S, Karlan, BY, Khusnutdinova, EK, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Labrie, M, Lambrechts, D, Le, ND, Lubinski, J, May, T, Menon, U, Milne, RL, Modugno, F, Monteiro, AN, Moysich, KB, Odunsi, K, Olsson, H, Pearce, CL, Pejovic, T, Ramus, SJ, Riboli, E, Riggan, MJ, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Sieh, W, Song, H, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, Tworoger, SS, Van Nieuwenhuysen, E, Edwards, DV, Webb, PM, Wentzensen, N, Whittemore, AS, Wolk, A, Wu, AH, Ziogas, A, Freedman, ML, Lawrenson, K, Pharoah, PDP, Easton, DF, Gayther, SA & Jones, MR 2022, 'Copy number variants are ovarian cancer risk alleles at known and novel risk loci', Journal of the National Cancer Institute, vol. 114, no. 11, pp. 1533-1544. https://doi.org/10.1093/jnci/djac160

@article{0ebb5ac957144f6499519b96ab49e1bd,

title = "Copy number variants are ovarian cancer risk alleles at known and novel risk loci",

abstract = "Background: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Methods: Single nucleotide polymorphism array data from 13071 EOC cases and 17306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. Results: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P <. 001) were identified for rare CNVs. Risk-associated CNVs were enriched (P <. 05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. Conclusions: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.",

author = "Devries, {Amber A.} and Joe Dennis and Tyrer, {Jonathan P.} and Peng, {Pei Chen} and Coetzee, {Simon G.} and Reyes, {Alberto L.} and Plummer, {Jasmine T.} and Davis, {Brian D.} and Chen, {Stephanie S.} and Dezem, {Felipe Segato} and Aben, {Katja K.H.} and Hoda Anton-Culver and Antonenkova, {Natalia N.} and Beckmann, {Matthias W.} and Alicia Beeghly-Fadiel and Andrew Berchuck and Bogdanova, {Natalia V.} and Nadja Bogdanova-Markov and Brenton, {James D.} and Ralf Butzow and Ian Campbell and Jenny Chang-Claude and Georgia Chenevix-Trench and Cook, {Linda S.} and Anna Defazio and Doherty, {Jennifer A.} and Thilo Dork and Eccles, {Diana M.} and Eliassen, {A. Heather} and Fasching, {Peter A.} and Fortner, {Renee T.} and Giles, {Graham G.} and Goode, {Ellen L.} and Goodman, {Marc T.} and Jacek Gronwald and Niclas Hakansson and Hildebrandt, {Michelle A.T.} and Chad Huff and Huntsman, {David G.} and Allan Jensen and Siddhartha Kar and Karlan, {Beth Y.} and Khusnutdinova, {Elza K.} and Kiemeney, {Lambertus A.} and Kjaer, {Susanne K.} and Jolanta Kupryjanczyk and Marilyne Labrie and Diether Lambrechts and Le, {Nhu D.} and Jan Lubinski and Taymaa May and Usha Menon and Milne, {Roger L.} and Francesmary Modugno and Monteiro, {Alvaro N.} and Moysich, {Kirsten B.} and Kunle Odunsi and Hakan Olsson and Pearce, {Celeste L.} and Tanja Pejovic and Ramus, {Susan J.} and Elio Riboli and Riggan, {Marjorie J.} and Isabelle Romieu and Sandler, {Dale P.} and Schildkraut, {Joellen M.} and Setiawan, {V. Wendy} and Weiva Sieh and Honglin Song and Rebecca Sutphen and Terry, {Kathryn L.} and Thompson, {Pamela J.} and Linda Titus and Tworoger, {Shelley S.} and {Van Nieuwenhuysen}, Els and Edwards, {Digna Velez} and Webb, {Penelope M.} and Nicolas Wentzensen and Whittemore, {Alice S.} and Alicja Wolk and Wu, {Anna H.} and Argyrios Ziogas and Freedman, {Matthew L.} and Kate Lawrenson and Pharoah, {Paul D.P.} and Easton, {Douglas F.} and Gayther, {Simon A.} and Jones, {Michelle R.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Oxford University Press.",

year = "2022",

month = nov,

day = "1",

doi = "10.1093/jnci/djac160",

language = "English (US)",

volume = "114",

pages = "1533--1544",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "11",

}

TY - JOUR

T1 - Copy number variants are ovarian cancer risk alleles at known and novel risk loci

AU - Devries, Amber A.

AU - Dennis, Joe

AU - Tyrer, Jonathan P.

AU - Peng, Pei Chen

AU - Coetzee, Simon G.

AU - Reyes, Alberto L.

AU - Plummer, Jasmine T.

AU - Davis, Brian D.

AU - Chen, Stephanie S.

AU - Dezem, Felipe Segato

AU - Aben, Katja K.H.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N.

AU - Beckmann, Matthias W.

AU - Beeghly-Fadiel, Alicia

AU - Berchuck, Andrew

AU - Bogdanova, Natalia V.

AU - Bogdanova-Markov, Nadja

AU - Brenton, James D.

AU - Butzow, Ralf

AU - Campbell, Ian

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Cook, Linda S.

AU - Defazio, Anna

AU - Doherty, Jennifer A.

AU - Dork, Thilo

AU - Eccles, Diana M.

AU - Eliassen, A. Heather

AU - Fasching, Peter A.

AU - Fortner, Renee T.

AU - Giles, Graham G.

AU - Goode, Ellen L.

AU - Goodman, Marc T.

AU - Gronwald, Jacek

AU - Hakansson, Niclas

AU - Hildebrandt, Michelle A.T.

AU - Huff, Chad

AU - Huntsman, David G.

AU - Jensen, Allan

AU - Kar, Siddhartha

AU - Karlan, Beth Y.

AU - Khusnutdinova, Elza K.

AU - Kiemeney, Lambertus A.

AU - Kjaer, Susanne K.

AU - Kupryjanczyk, Jolanta

AU - Labrie, Marilyne

AU - Lambrechts, Diether

AU - Le, Nhu D.

AU - Lubinski, Jan

AU - May, Taymaa

AU - Menon, Usha

AU - Milne, Roger L.

AU - Modugno, Francesmary

AU - Monteiro, Alvaro N.

AU - Moysich, Kirsten B.

AU - Odunsi, Kunle

AU - Olsson, Hakan

AU - Pearce, Celeste L.

AU - Pejovic, Tanja

AU - Ramus, Susan J.

AU - Riboli, Elio

AU - Riggan, Marjorie J.

AU - Romieu, Isabelle

AU - Sandler, Dale P.

AU - Schildkraut, Joellen M.

AU - Setiawan, V. Wendy

AU - Sieh, Weiva

AU - Song, Honglin

AU - Sutphen, Rebecca

AU - Terry, Kathryn L.

AU - Thompson, Pamela J.

AU - Titus, Linda

AU - Tworoger, Shelley S.

AU - Van Nieuwenhuysen, Els

AU - Edwards, Digna Velez

AU - Webb, Penelope M.

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S.

AU - Wolk, Alicja

AU - Wu, Anna H.

AU - Ziogas, Argyrios

AU - Freedman, Matthew L.

AU - Lawrenson, Kate

AU - Pharoah, Paul D.P.

AU - Easton, Douglas F.

AU - Gayther, Simon A.

AU - Jones, Michelle R.

PY - 2022/11/1

Y1 - 2022/11/1

N2 - Background: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Methods: Single nucleotide polymorphism array data from 13071 EOC cases and 17306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. Results: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P <. 001) were identified for rare CNVs. Risk-associated CNVs were enriched (P <. 05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. Conclusions: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

AB - Background: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Methods: Single nucleotide polymorphism array data from 13071 EOC cases and 17306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. Results: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P <. 001) were identified for rare CNVs. Risk-associated CNVs were enriched (P <. 05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. Conclusions: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

UR - http://www.scopus.com/inward/record.url?scp=85157958594&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85157958594&partnerID=8YFLogxK

U2 - 10.1093/jnci/djac160

DO - 10.1093/jnci/djac160

M3 - Article

C2 - 36210504

AN - SCOPUS:85157958594

SN - 0027-8874

VL - 114

SP - 1533

EP - 1544

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 11

ER -

Copy number variants are ovarian cancer risk alleles at known and novel risk loci

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this