Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

Honglin Song; Ed Dicks; Susan J Ramus; Jonathan P Tyrer; Maria P Intermaggio; Jane Hayward; Christopher K Edlund; David Conti; Patricia Harrington; Lindsay Fraser; Susan Philpott; Christopher Anderson; Adam Rosenthal; Aleksandra Gentry-Maharaj; David D Bowtell; Kathryn Alsop; Mine S Cicek; Julie M Cunningham; Brooke L Fridley; Jennifer Alsop; Mercedes Jimenez-Linan; Estrid Høgdall; Claus K Høgdall; Allan Jensen; Susanne Krüger Kjaer; Jan Lubiński; Tomasz Huzarski; Anna Jakubowska; Jacek Gronwald; Samantha Poblete; Shashi Lele; Lara Sucheston-Campbell; Kirsten B Moysich; Kunle Odunsi; Ellen L Goode; Usha Menon; Ian J Jacobs; Simon A Gayther; Paul D P Pharoah

doi:10.1200/JCO.2015.61.2408

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

Honglin Song, Ed Dicks, Susan J Ramus, Jonathan P Tyrer, Maria P Intermaggio, Jane Hayward, Christopher K Edlund, David Conti, Patricia Harrington, Lindsay Fraser, Susan Philpott, Christopher Anderson, Adam Rosenthal, Aleksandra Gentry-Maharaj, David D Bowtell, Kathryn Alsop, Mine S Cicek, Julie M Cunningham, Brooke L Fridley, Jennifer AlsopMercedes Jimenez-Linan, Estrid Høgdall, Claus K Høgdall, Allan Jensen, Susanne Krüger Kjaer, Jan Lubiński, Tomasz Huzarski, Anna Jakubowska, Jacek Gronwald, Samantha Poblete, Shashi Lele, Lara Sucheston-Campbell, Kirsten B Moysich, Kunle Odunsi, Ellen L Goode, Usha Menon, Ian J Jacobs, Simon A Gayther, Paul D P Pharoah

Institut for Klinisk Medicin

170 Citationer (Scopus)

Abstract

Purpose: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. Patients and Methods: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK-FOCSS) after quality-control analysis. Results: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK-FOCSS participants (RAD51C, n = 7; RAD51D , n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). Conclusion: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Oncology
Vol/bind	33
Udgave nummer	26
Sider (fra-til)	2901-7
Antal sider	7
ISSN	0732-183X
DOI	https://doi.org/10.1200/JCO.2015.61.2408
Status	Udgivet - 10 sep. 2015

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Song, H., Dicks, E., Ramus, S. J., Tyrer, J. P., Intermaggio, M. P., Hayward, J., Edlund, C. K., Conti, D., Harrington, P., Fraser, L., Philpott, S., Anderson, C., Rosenthal, A., Gentry-Maharaj, A., Bowtell, D. D., Alsop, K., Cicek, M. S., Cunningham, J. M., Fridley, B. L., ... Pharoah, P. D. P. (2015). Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. Journal of Clinical Oncology, 33(26), 2901-7. https://doi.org/10.1200/JCO.2015.61.2408

Song, H, Dicks, E, Ramus, SJ, Tyrer, JP, Intermaggio, MP, Hayward, J, Edlund, CK, Conti, D, Harrington, P, Fraser, L, Philpott, S, Anderson, C, Rosenthal, A, Gentry-Maharaj, A, Bowtell, DD, Alsop, K, Cicek, MS, Cunningham, JM, Fridley, BL, Alsop, J, Jimenez-Linan, M, Høgdall, E, Høgdall, CK, Jensen, A, Kjaer, SK, Lubiński, J, Huzarski, T, Jakubowska, A, Gronwald, J, Poblete, S, Lele, S, Sucheston-Campbell, L, Moysich, KB, Odunsi, K, Goode, EL, Menon, U, Jacobs, IJ, Gayther, SA & Pharoah, PDP 2015, 'Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population', Journal of Clinical Oncology, bind 33, nr. 26, s. 2901-7. https://doi.org/10.1200/JCO.2015.61.2408

@article{f89dcfcf78f54013a1655bfd5f2cae8e,

title = "Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population",

abstract = "Purpose: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. Patients and Methods: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK-FOCSS) after quality-control analysis. Results: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK-FOCSS participants (RAD51C, n = 7; RAD51D , n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). Conclusion: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.",

keywords = "Adult, Aged, DNA-Binding Proteins, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Middle Aged, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms",

author = "Honglin Song and Ed Dicks and Ramus, {Susan J} and Tyrer, {Jonathan P} and Intermaggio, {Maria P} and Jane Hayward and Edlund, {Christopher K} and David Conti and Patricia Harrington and Lindsay Fraser and Susan Philpott and Christopher Anderson and Adam Rosenthal and Aleksandra Gentry-Maharaj and Bowtell, {David D} and Kathryn Alsop and Cicek, {Mine S} and Cunningham, {Julie M} and Fridley, {Brooke L} and Jennifer Alsop and Mercedes Jimenez-Linan and Estrid H{\o}gdall and H{\o}gdall, {Claus K} and Allan Jensen and Kjaer, {Susanne Kr{\"u}ger} and Jan Lubi{\'n}ski and Tomasz Huzarski and Anna Jakubowska and Jacek Gronwald and Samantha Poblete and Shashi Lele and Lara Sucheston-Campbell and Moysich, {Kirsten B} and Kunle Odunsi and Goode, {Ellen L} and Usha Menon and Jacobs, {Ian J} and Gayther, {Simon A} and Pharoah, {Paul D P}",

note = "{\textcopyright} 2015 by American Society of Clinical Oncology.",

year = "2015",

month = sep,

day = "10",

doi = "10.1200/JCO.2015.61.2408",

language = "English",

volume = "33",

pages = "2901--7",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "26",

}

TY - JOUR

T1 - Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

AU - Song, Honglin

AU - Dicks, Ed

AU - Ramus, Susan J

AU - Tyrer, Jonathan P

AU - Intermaggio, Maria P

AU - Hayward, Jane

AU - Edlund, Christopher K

AU - Conti, David

AU - Harrington, Patricia

AU - Fraser, Lindsay

AU - Philpott, Susan

AU - Anderson, Christopher

AU - Rosenthal, Adam

AU - Gentry-Maharaj, Aleksandra

AU - Bowtell, David D

AU - Alsop, Kathryn

AU - Cicek, Mine S

AU - Cunningham, Julie M

AU - Fridley, Brooke L

AU - Alsop, Jennifer

AU - Jimenez-Linan, Mercedes

AU - Høgdall, Estrid

AU - Høgdall, Claus K

AU - Jensen, Allan

AU - Kjaer, Susanne Krüger

AU - Lubiński, Jan

AU - Huzarski, Tomasz

AU - Jakubowska, Anna

AU - Gronwald, Jacek

AU - Poblete, Samantha

AU - Lele, Shashi

AU - Sucheston-Campbell, Lara

AU - Moysich, Kirsten B

AU - Odunsi, Kunle

AU - Goode, Ellen L

AU - Menon, Usha

AU - Jacobs, Ian J

AU - Gayther, Simon A

AU - Pharoah, Paul D P

PY - 2015/9/10

Y1 - 2015/9/10

N2 - Purpose: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. Patients and Methods: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK-FOCSS) after quality-control analysis. Results: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK-FOCSS participants (RAD51C, n = 7; RAD51D , n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). Conclusion: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

AB - Purpose: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. Patients and Methods: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK-FOCSS) after quality-control analysis. Results: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK-FOCSS participants (RAD51C, n = 7; RAD51D , n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). Conclusion: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

KW - Adult

KW - Aged

KW - DNA-Binding Proteins

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Humans

KW - Middle Aged

KW - Neoplasms, Glandular and Epithelial

KW - Ovarian Neoplasms

U2 - 10.1200/JCO.2015.61.2408

DO - 10.1200/JCO.2015.61.2408

M3 - Journal article

C2 - 26261251

SN - 0732-183X

VL - 33

SP - 2901

EP - 2907

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 26

ER -

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

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