Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

Honglin Song; Ed M. Dicks; Jonathan Tyrer; Maria Intermaggio; Georgia Chenevix-Trench; David D. Bowtell; Nadia Traficante; Aocs Group; James Brenton; Teodora Goranova; Karen Hosking; Anna Piskorz; Elke Van Oudenhove; Jen Doherty; Holly R. Harris; Mary Anne Rossing; Matthias Duerst; Thilo Dork; Natalia V. Bogdanova; Francesmary Modugno; Kirsten Moysich; Kunle Odunsi; Roberta Ness; Beth Y. Karlan; Jenny Lester; Allan Jensen; Susanne Krüger Kjaer; Estrid Høgdall; Ian G. Campbell; Conxi Lázaro; Miguel Angel Pujara; Julie Cunningham; Robert Vierkant; Stacey J. Winham; Michelle Hildebrandt; Chad Huff; Donghui Li; Xifeng Wu; Yao Yu; Jennifer B. Permuth; Douglas A. Levine; Joellen M. Schildkraut; Marjorie J. Riggan; Andrew Berchuck; Penelope M. Webb; Opal Study Group; Cezary Cybulski; Jacek Gronwald; Anna Jakubowska; Jan Lubinski; Jennifer Alsop; Patricia Harrington; Isaac Chan; Usha Menon; Celeste L. Pearce; Anna H. Wu; Anna De Fazio; Catherine J. Kennedy; Ellen Goode; Susan Ramus; Simon Gayther; Paul Pharoah

doi:10.1136/jmedgenet-2019-106739

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

Honglin Song, Ed M. Dicks, Jonathan Tyrer, Maria Intermaggio, Georgia Chenevix-Trench, David D. Bowtell, Nadia Traficante, Aocs Group, James Brenton, Teodora Goranova, Karen Hosking, Anna Piskorz, Elke Van Oudenhove, Jen Doherty, Holly R. Harris, Mary Anne Rossing, Matthias Duerst, Thilo Dork, Natalia V. Bogdanova, Francesmary ModugnoKirsten Moysich, Kunle Odunsi, Roberta Ness, Beth Y. Karlan, Jenny Lester, Allan Jensen, Susanne Krüger Kjaer, Estrid Høgdall, Ian G. Campbell, Conxi Lázaro, Miguel Angel Pujara, Julie Cunningham, Robert Vierkant, Stacey J. Winham, Michelle Hildebrandt, Chad Huff, Donghui Li, Xifeng Wu, Yao Yu, Jennifer B. Permuth, Douglas A. Levine, Joellen M. Schildkraut, Marjorie J. Riggan, Andrew Berchuck, Penelope M. Webb, Opal Study Group, Cezary Cybulski, Jacek Gronwald, Anna Jakubowska, Jan Lubinski, Jennifer Alsop, Patricia Harrington, Isaac Chan, Usha Menon, Celeste L. Pearce, Anna H. Wu, Anna De Fazio, Catherine J. Kennedy, Ellen Goode, Susan Ramus, Simon Gayther, Paul Pharoah

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Abstract

Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Original language	English (US)
Pages (from-to)	305-313
Number of pages	9
Journal	Journal of medical genetics
Volume	58
Issue number	5
DOIs	https://doi.org/10.1136/jmedgenet-2019-106739
State	Published - May 1 2021

Keywords

cancer: endocrine
genetic epidemiology

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1136/jmedgenet-2019-106739

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Song, H., Dicks, E. M., Tyrer, J., Intermaggio, M., Chenevix-Trench, G., Bowtell, D. D., Traficante, N., Group, A., Brenton, J., Goranova, T., Hosking, K., Piskorz, A., Van Oudenhove, E., Doherty, J., Harris, H. R., Rossing, M. A., Duerst, M., Dork, T., Bogdanova, N. V., ... Pharoah, P. (2021). Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. Journal of medical genetics, 58(5), 305-313. https://doi.org/10.1136/jmedgenet-2019-106739

Song, H, Dicks, EM, Tyrer, J, Intermaggio, M, Chenevix-Trench, G, Bowtell, DD, Traficante, N, Group, A, Brenton, J, Goranova, T, Hosking, K, Piskorz, A, Van Oudenhove, E, Doherty, J, Harris, HR, Rossing, MA, Duerst, M, Dork, T, Bogdanova, NV, Modugno, F, Moysich, K, Odunsi, K, Ness, R, Karlan, BY, Lester, J, Jensen, A, Krüger Kjaer, S, Høgdall, E, Campbell, IG, Lázaro, C, Pujara, MA, Cunningham, J, Vierkant, R, Winham, SJ, Hildebrandt, M , Huff, C , Li, D, Wu, X, Yu, Y, Permuth, JB, Levine, DA, Schildkraut, JM, Riggan, MJ, Berchuck, A, Webb, PM, Group, OS, Cybulski, C, Gronwald, J, Jakubowska, A, Lubinski, J, Alsop, J, Harrington, P, Chan, I, Menon, U, Pearce, CL, Wu, AH, De Fazio, A, Kennedy, CJ, Goode, E, Ramus, S, Gayther, S & Pharoah, P 2021, 'Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer', Journal of medical genetics, vol. 58, no. 5, pp. 305-313. https://doi.org/10.1136/jmedgenet-2019-106739

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title = "Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer",

abstract = "Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.",

keywords = "cancer: endocrine, genetic epidemiology",

author = "Honglin Song and Dicks, {Ed M.} and Jonathan Tyrer and Maria Intermaggio and Georgia Chenevix-Trench and Bowtell, {David D.} and Nadia Traficante and Aocs Group and James Brenton and Teodora Goranova and Karen Hosking and Anna Piskorz and {Van Oudenhove}, Elke and Jen Doherty and Harris, {Holly R.} and Rossing, {Mary Anne} and Matthias Duerst and Thilo Dork and Bogdanova, {Natalia V.} and Francesmary Modugno and Kirsten Moysich and Kunle Odunsi and Roberta Ness and Karlan, {Beth Y.} and Jenny Lester and Allan Jensen and {Kr{\"u}ger Kjaer}, Susanne and Estrid H{\o}gdall and Campbell, {Ian G.} and Conxi L{\'a}zaro and Pujara, {Miguel Angel} and Julie Cunningham and Robert Vierkant and Winham, {Stacey J.} and Michelle Hildebrandt and Chad Huff and Donghui Li and Xifeng Wu and Yao Yu and Permuth, {Jennifer B.} and Levine, {Douglas A.} and Schildkraut, {Joellen M.} and Riggan, {Marjorie J.} and Andrew Berchuck and Webb, {Penelope M.} and Group, {Opal Study} and Cezary Cybulski and Jacek Gronwald and Anna Jakubowska and Jan Lubinski and Jennifer Alsop and Patricia Harrington and Isaac Chan and Usha Menon and Pearce, {Celeste L.} and Wu, {Anna H.} and {De Fazio}, Anna and Kennedy, {Catherine J.} and Ellen Goode and Susan Ramus and Simon Gayther and Paul Pharoah",

note = "Publisher Copyright: {\textcopyright} ",

year = "2021",

month = may,

day = "1",

doi = "10.1136/jmedgenet-2019-106739",

language = "English (US)",

volume = "58",

pages = "305--313",

journal = "Journal of medical genetics",

issn = "0022-2593",

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number = "5",

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TY - JOUR

T1 - Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

AU - Song, Honglin

AU - Dicks, Ed M.

AU - Tyrer, Jonathan

AU - Intermaggio, Maria

AU - Chenevix-Trench, Georgia

AU - Bowtell, David D.

AU - Traficante, Nadia

AU - Group, Aocs

AU - Brenton, James

AU - Goranova, Teodora

AU - Hosking, Karen

AU - Piskorz, Anna

AU - Van Oudenhove, Elke

AU - Doherty, Jen

AU - Harris, Holly R.

AU - Rossing, Mary Anne

AU - Duerst, Matthias

AU - Dork, Thilo

AU - Bogdanova, Natalia V.

AU - Modugno, Francesmary

AU - Moysich, Kirsten

AU - Odunsi, Kunle

AU - Ness, Roberta

AU - Karlan, Beth Y.

AU - Lester, Jenny

AU - Jensen, Allan

AU - Krüger Kjaer, Susanne

AU - Høgdall, Estrid

AU - Campbell, Ian G.

AU - Lázaro, Conxi

AU - Pujara, Miguel Angel

AU - Cunningham, Julie

AU - Vierkant, Robert

AU - Winham, Stacey J.

AU - Hildebrandt, Michelle

AU - Huff, Chad

AU - Li, Donghui

AU - Wu, Xifeng

AU - Yu, Yao

AU - Permuth, Jennifer B.

AU - Levine, Douglas A.

AU - Schildkraut, Joellen M.

AU - Riggan, Marjorie J.

AU - Berchuck, Andrew

AU - Webb, Penelope M.

AU - Group, Opal Study

AU - Cybulski, Cezary

AU - Gronwald, Jacek

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Alsop, Jennifer

AU - Harrington, Patricia

AU - Chan, Isaac

AU - Menon, Usha

AU - Pearce, Celeste L.

AU - Wu, Anna H.

AU - De Fazio, Anna

AU - Kennedy, Catherine J.

AU - Goode, Ellen

AU - Ramus, Susan

AU - Gayther, Simon

AU - Pharoah, Paul

PY - 2021/5/1

Y1 - 2021/5/1

N2 - Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

AB - Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

KW - cancer: endocrine

KW - genetic epidemiology

UR - http://www.scopus.com/inward/record.url?scp=85090958622&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85090958622&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2019-106739

DO - 10.1136/jmedgenet-2019-106739

M3 - Article

C2 - 32546565

AN - SCOPUS:85090958622

SN - 0022-2593

VL - 58

SP - 305

EP - 313

JO - Journal of medical genetics

JF - Journal of medical genetics

IS - 5

ER -

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

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