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Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

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 13 071 EOC ca...

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Autores principales: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9949586/
https://www.ncbi.nlm.nih.gov/pubmed/36210504
http://dx.doi.org/10.1093/jnci/djac160
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author DeVries, Amber A
Dennis, Joe
Tyrer, Jonathan P
Peng, Pei-Chen
Coetzee, Simon G
Reyes, Alberto L
Plummer, Jasmine T
Davis, Brian D
Chen, Stephanie S
Dezem, Felipe Segato
Aben, Katja K H
Anton-Culver, Hoda
Antonenkova, Natalia N
Beckmann, Matthias W
Beeghly-Fadiel, Alicia
Berchuck, Andrew
Bogdanova, Natalia V
Bogdanova-Markov, Nadja
Brenton, James D
Butzow, Ralf
Campbell, Ian
Chang-Claude, Jenny
Chenevix-Trench, Georgia
Cook, Linda S
DeFazio, Anna
Doherty, Jennifer A
Dörk, Thilo
Eccles, Diana M
Eliassen, A Heather
Fasching, Peter A
Fortner, Renée T
Giles, Graham G
Goode, Ellen L
Goodman, Marc T
Gronwald, Jacek
Håkansson, Niclas
Hildebrandt, Michelle A T
Huff, Chad
Huntsman, David G
Jensen, Allan
Kar, Siddhartha
Karlan, Beth Y
Khusnutdinova, Elza K
Kiemeney, Lambertus A
Kjaer, Susanne K
Kupryjanczyk, Jolanta
Labrie, Marilyne
Lambrechts, Diether
Le, Nhu D
Lubiński, Jan
May, Taymaa
Menon, Usha
Milne, Roger L
Modugno, Francesmary
Monteiro, Alvaro N
Moysich, Kirsten B
Odunsi, Kunle
Olsson, Håkan
Pearce, Celeste L
Pejovic, Tanja
Ramus, Susan J
Riboli, Elio
Riggan, Marjorie J
Romieu, Isabelle
Sandler, Dale P
Schildkraut, Joellen M
Setiawan, V Wendy
Sieh, Weiva
Song, Honglin
Sutphen, Rebecca
Terry, Kathryn L
Thompson, Pamela J
Titus, Linda
Tworoger, Shelley S
Van Nieuwenhuysen, Els
Edwards, Digna Velez
Webb, Penelope M
Wentzensen, Nicolas
Whittemore, Alice S
Wolk, Alicja
Wu, Anna H
Ziogas, Argyrios
Freedman, Matthew L
Lawrenson, Kate
Pharoah, Paul D P
Easton, Douglas F
Gayther, Simon A
Jones, Michelle R
author_facet DeVries, Amber A
Dennis, Joe
Tyrer, Jonathan P
Peng, Pei-Chen
Coetzee, Simon G
Reyes, Alberto L
Plummer, Jasmine T
Davis, Brian D
Chen, Stephanie S
Dezem, Felipe Segato
Aben, Katja K H
Anton-Culver, Hoda
Antonenkova, Natalia N
Beckmann, Matthias W
Beeghly-Fadiel, Alicia
Berchuck, Andrew
Bogdanova, Natalia V
Bogdanova-Markov, Nadja
Brenton, James D
Butzow, Ralf
Campbell, Ian
Chang-Claude, Jenny
Chenevix-Trench, Georgia
Cook, Linda S
DeFazio, Anna
Doherty, Jennifer A
Dörk, Thilo
Eccles, Diana M
Eliassen, A Heather
Fasching, Peter A
Fortner, Renée T
Giles, Graham G
Goode, Ellen L
Goodman, Marc T
Gronwald, Jacek
Håkansson, Niclas
Hildebrandt, Michelle A T
Huff, Chad
Huntsman, David G
Jensen, Allan
Kar, Siddhartha
Karlan, Beth Y
Khusnutdinova, Elza K
Kiemeney, Lambertus A
Kjaer, Susanne K
Kupryjanczyk, Jolanta
Labrie, Marilyne
Lambrechts, Diether
Le, Nhu D
Lubiński, Jan
May, Taymaa
Menon, Usha
Milne, Roger L
Modugno, Francesmary
Monteiro, Alvaro N
Moysich, Kirsten B
Odunsi, Kunle
Olsson, Håkan
Pearce, Celeste L
Pejovic, Tanja
Ramus, Susan J
Riboli, Elio
Riggan, Marjorie J
Romieu, Isabelle
Sandler, Dale P
Schildkraut, Joellen M
Setiawan, V Wendy
Sieh, Weiva
Song, Honglin
Sutphen, Rebecca
Terry, Kathryn L
Thompson, Pamela J
Titus, Linda
Tworoger, Shelley S
Van Nieuwenhuysen, Els
Edwards, Digna Velez
Webb, Penelope M
Wentzensen, Nicolas
Whittemore, Alice S
Wolk, Alicja
Wu, Anna H
Ziogas, Argyrios
Freedman, Matthew L
Lawrenson, Kate
Pharoah, Paul D P
Easton, Douglas F
Gayther, Simon A
Jones, Michelle R
author_sort DeVries, Amber A
collection PubMed
description 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 13 071 EOC cases and 17 306 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 (P(EOC) = 1.60E-21; OR(EOC) = 8.24), RAD51C (P(high-grade serous ovarian cancer [HGSOC]) = 5.5E-4; odds ratio [OR](HGSOC) = 5.74 del), and BRCA2 (P(HGSOC) = 7.0E-4; OR(HGSOC) = 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.
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spelling pubmed-99495862023-02-24 Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci DeVries, Amber A Dennis, Joe Tyrer, Jonathan P Peng, Pei-Chen Coetzee, Simon G Reyes, Alberto L Plummer, Jasmine T Davis, Brian D Chen, Stephanie S Dezem, Felipe Segato Aben, Katja K H Anton-Culver, Hoda Antonenkova, Natalia N Beckmann, Matthias W Beeghly-Fadiel, Alicia Berchuck, Andrew Bogdanova, Natalia V Bogdanova-Markov, Nadja Brenton, James D Butzow, Ralf Campbell, Ian Chang-Claude, Jenny Chenevix-Trench, Georgia Cook, Linda S DeFazio, Anna Doherty, Jennifer A Dörk, Thilo Eccles, Diana M Eliassen, A Heather Fasching, Peter A Fortner, Renée T Giles, Graham G Goode, Ellen L Goodman, Marc T Gronwald, Jacek Håkansson, Niclas Hildebrandt, Michelle A T Huff, Chad Huntsman, David G Jensen, Allan Kar, Siddhartha Karlan, Beth Y Khusnutdinova, Elza K Kiemeney, Lambertus A Kjaer, Susanne K Kupryjanczyk, Jolanta Labrie, Marilyne Lambrechts, Diether Le, Nhu D Lubiński, Jan May, Taymaa Menon, Usha Milne, Roger L Modugno, Francesmary Monteiro, Alvaro N Moysich, Kirsten B Odunsi, Kunle Olsson, Håkan Pearce, Celeste L Pejovic, Tanja Ramus, Susan J Riboli, Elio Riggan, Marjorie J Romieu, Isabelle Sandler, Dale P Schildkraut, Joellen M Setiawan, V Wendy Sieh, Weiva Song, Honglin Sutphen, Rebecca Terry, Kathryn L Thompson, Pamela J Titus, Linda Tworoger, Shelley S Van Nieuwenhuysen, Els Edwards, Digna Velez Webb, Penelope M Wentzensen, Nicolas Whittemore, Alice S Wolk, Alicja Wu, Anna H Ziogas, Argyrios Freedman, Matthew L Lawrenson, Kate Pharoah, Paul D P Easton, Douglas F Gayther, Simon A Jones, Michelle R J Natl Cancer Inst Articles 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 13 071 EOC cases and 17 306 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 (P(EOC) = 1.60E-21; OR(EOC) = 8.24), RAD51C (P(high-grade serous ovarian cancer [HGSOC]) = 5.5E-4; odds ratio [OR](HGSOC) = 5.74 del), and BRCA2 (P(HGSOC) = 7.0E-4; OR(HGSOC) = 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. Oxford University Press 2022-10-10 /pmc/articles/PMC9949586/ /pubmed/36210504 http://dx.doi.org/10.1093/jnci/djac160 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Articles
DeVries, Amber A
Dennis, Joe
Tyrer, Jonathan P
Peng, Pei-Chen
Coetzee, Simon G
Reyes, Alberto L
Plummer, Jasmine T
Davis, Brian D
Chen, Stephanie S
Dezem, Felipe Segato
Aben, Katja K H
Anton-Culver, Hoda
Antonenkova, Natalia N
Beckmann, Matthias W
Beeghly-Fadiel, Alicia
Berchuck, Andrew
Bogdanova, Natalia V
Bogdanova-Markov, Nadja
Brenton, James D
Butzow, Ralf
Campbell, Ian
Chang-Claude, Jenny
Chenevix-Trench, Georgia
Cook, Linda S
DeFazio, Anna
Doherty, Jennifer A
Dörk, Thilo
Eccles, Diana M
Eliassen, A Heather
Fasching, Peter A
Fortner, Renée T
Giles, Graham G
Goode, Ellen L
Goodman, Marc T
Gronwald, Jacek
Håkansson, Niclas
Hildebrandt, Michelle A T
Huff, Chad
Huntsman, David G
Jensen, Allan
Kar, Siddhartha
Karlan, Beth Y
Khusnutdinova, Elza K
Kiemeney, Lambertus A
Kjaer, Susanne K
Kupryjanczyk, Jolanta
Labrie, Marilyne
Lambrechts, Diether
Le, Nhu D
Lubiński, Jan
May, Taymaa
Menon, Usha
Milne, Roger L
Modugno, Francesmary
Monteiro, Alvaro N
Moysich, Kirsten B
Odunsi, Kunle
Olsson, Håkan
Pearce, Celeste L
Pejovic, Tanja
Ramus, Susan J
Riboli, Elio
Riggan, Marjorie J
Romieu, Isabelle
Sandler, Dale P
Schildkraut, Joellen M
Setiawan, V Wendy
Sieh, Weiva
Song, Honglin
Sutphen, Rebecca
Terry, Kathryn L
Thompson, Pamela J
Titus, Linda
Tworoger, Shelley S
Van Nieuwenhuysen, Els
Edwards, Digna Velez
Webb, Penelope M
Wentzensen, Nicolas
Whittemore, Alice S
Wolk, Alicja
Wu, Anna H
Ziogas, Argyrios
Freedman, Matthew L
Lawrenson, Kate
Pharoah, Paul D P
Easton, Douglas F
Gayther, Simon A
Jones, Michelle R
Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
title Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
title_full Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
title_fullStr Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
title_full_unstemmed Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
title_short Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
title_sort copy number variants are ovarian cancer risk alleles at known and novel risk loci
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9949586/
https://www.ncbi.nlm.nih.gov/pubmed/36210504
http://dx.doi.org/10.1093/jnci/djac160
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