Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D

Xin Yang; Honglin Song; Goska Leslie; Christoph Engel; Eric Hahnen; Bernd Auber; Judit Horváth; Karin Kast; DIeter Niederacher; Clare Turnbull; Richard Houlston; Helen Hanson; Chey Loveday; Jill S. Dolinsky; Holly Laduca; Susan J. Ramus; Usha Menon; Adam N. Rosenthal; Ian Jacobs; Simon A. Gayther; Ed DIcks; Heli Nevanlinna; Kristiina Aittomäki; Liisa M. Pelttari; Hans Ehrencrona; Åke Borg; Anders Kvist; Barbara Rivera; Thomas V.O. Hansen; Malene Djursby; Andrew Lee; Joe Dennis; David D. Bowtell; Nadia Traficante; Orland DIez; Judith Balmaña; Stephen B. Gruber; Georgia Chenevix-Trench; Kconfab Investigators; Allan Jensen; Susanne K. Kjær; Estrid Høgdall; Laurent Castéra; Judy Garber; Ramunas Janavicius; Ana Osorio; Lisa Golmard; Ana Vega; Fergus J. Couch; Mark Robson; Jacek Gronwald; Susan M. Domchek; Julie O. Culver; Miguel De La Hoya; Douglas F. Easton; William D. Foulkes; Marc Tischkowitz; Alfons Meindl; Rita K. Schmutzler; Paul D.P. Pharoah; Antonis C. Antoniou

doi:10.1093/jnci/djaa030

Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D

Xin Yang, Honglin Song, Goska Leslie, Christoph Engel, Eric Hahnen, Bernd Auber, Judit Horváth, Karin Kast, DIeter Niederacher, Clare Turnbull, Richard Houlston, Helen Hanson, Chey Loveday, Jill S. Dolinsky, Holly Laduca, Susan J. Ramus, Usha Menon, Adam N. Rosenthal, Ian Jacobs, Simon A. GaytherEd DIcks, Heli Nevanlinna, Kristiina Aittomäki, Liisa M. Pelttari, Hans Ehrencrona, Åke Borg, Anders Kvist, Barbara Rivera, Thomas V.O. Hansen, Malene Djursby, Andrew Lee, Joe Dennis, David D. Bowtell, Nadia Traficante, Orland DIez, Judith Balmaña, Stephen B. Gruber, Georgia Chenevix-Trench, Kconfab Investigators, Allan Jensen, Susanne K. Kjær, Estrid Høgdall, Laurent Castéra, Judy Garber, Ramunas Janavicius, Ana Osorio, Lisa Golmard, Ana Vega, Fergus J. Couch, Mark Robson, Jacek Gronwald, Susan M. Domchek, Julie O. Culver, Miguel De La Hoya, Douglas F. Easton, William D. Foulkes, Marc Tischkowitz, Alfons Meindl, Rita K. Schmutzler, Paul D.P. Pharoah, Antonis C. Antoniou

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Abstract

Background: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P =. 002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Original language	English (US)
Pages (from-to)	1242-1250
Number of pages	9
Journal	Journal of the National Cancer Institute
Volume	112
Issue number	12
DOIs	https://doi.org/10.1093/jnci/djaa030
State	Published - Dec 1 2020

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1093/jnci/djaa030

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Yang, X., Song, H., Leslie, G., Engel, C., Hahnen, E., Auber, B., Horváth, J., Kast, K., Niederacher, DI., Turnbull, C., Houlston, R., Hanson, H., Loveday, C., Dolinsky, J. S., Laduca, H., Ramus, S. J., Menon, U., Rosenthal, A. N., Jacobs, I., ... Antoniou, A. C. (2020). Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D. Journal of the National Cancer Institute, 112(12), 1242-1250. https://doi.org/10.1093/jnci/djaa030

Yang, X, Song, H, Leslie, G, Engel, C, Hahnen, E, Auber, B, Horváth, J, Kast, K, Niederacher, DI, Turnbull, C, Houlston, R, Hanson, H, Loveday, C, Dolinsky, JS, Laduca, H, Ramus, SJ, Menon, U, Rosenthal, AN, Jacobs, I, Gayther, SA, DIcks, E, Nevanlinna, H, Aittomäki, K, Pelttari, LM, Ehrencrona, H, Borg, Å, Kvist, A, Rivera, B, Hansen, TVO, Djursby, M, Lee, A, Dennis, J, Bowtell, DD, Traficante, N, DIez, O, Balmaña, J, Gruber, SB, Chenevix-Trench, G, Investigators, K, Jensen, A, Kjær, SK, Høgdall, E, Castéra, L, Garber, J, Janavicius, R, Osorio, A, Golmard, L, Vega, A, Couch, FJ, Robson, M, Gronwald, J, Domchek, SM, Culver, JO, De La Hoya, M, Easton, DF, Foulkes, WD, Tischkowitz, M, Meindl, A, Schmutzler, RK, Pharoah, PDP & Antoniou, AC 2020, 'Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D', Journal of the National Cancer Institute, vol. 112, no. 12, pp. 1242-1250. https://doi.org/10.1093/jnci/djaa030

@article{0a4bd88c41a84d898a211fc68edb6035,

title = "Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D",

abstract = "Background: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P =. 002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.",

author = "Xin Yang and Honglin Song and Goska Leslie and Christoph Engel and Eric Hahnen and Bernd Auber and Judit Horv{\'a}th and Karin Kast and DIeter Niederacher and Clare Turnbull and Richard Houlston and Helen Hanson and Chey Loveday and Dolinsky, {Jill S.} and Holly Laduca and Ramus, {Susan J.} and Usha Menon and Rosenthal, {Adam N.} and Ian Jacobs and Gayther, {Simon A.} and Ed DIcks and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Pelttari, {Liisa M.} and Hans Ehrencrona and {\AA}ke Borg and Anders Kvist and Barbara Rivera and Hansen, {Thomas V.O.} and Malene Djursby and Andrew Lee and Joe Dennis and Bowtell, {David D.} and Nadia Traficante and Orland DIez and Judith Balma{\~n}a and Gruber, {Stephen B.} and Georgia Chenevix-Trench and Kconfab Investigators and Allan Jensen and Kj{\ae}r, {Susanne K.} and Estrid H{\o}gdall and Laurent Cast{\'e}ra and Judy Garber and Ramunas Janavicius and Ana Osorio and Lisa Golmard and Ana Vega and Couch, {Fergus J.} and Mark Robson and Jacek Gronwald and Domchek, {Susan M.} and Culver, {Julie O.} and {De La Hoya}, Miguel and Easton, {Douglas F.} and Foulkes, {William D.} and Marc Tischkowitz and Alfons Meindl and Schmutzler, {Rita K.} and Pharoah, {Paul D.P.} and Antoniou, {Antonis C.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s) 2020. Published by Oxford University Press.",

year = "2020",

month = dec,

day = "1",

doi = "10.1093/jnci/djaa030",

language = "English (US)",

volume = "112",

pages = "1242--1250",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "12",

}

TY - JOUR

T1 - Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D

AU - Yang, Xin

AU - Song, Honglin

AU - Leslie, Goska

AU - Engel, Christoph

AU - Hahnen, Eric

AU - Auber, Bernd

AU - Horváth, Judit

AU - Kast, Karin

AU - Niederacher, DIeter

AU - Turnbull, Clare

AU - Houlston, Richard

AU - Hanson, Helen

AU - Loveday, Chey

AU - Dolinsky, Jill S.

AU - Laduca, Holly

AU - Ramus, Susan J.

AU - Menon, Usha

AU - Rosenthal, Adam N.

AU - Jacobs, Ian

AU - Gayther, Simon A.

AU - DIcks, Ed

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Pelttari, Liisa M.

AU - Ehrencrona, Hans

AU - Borg, Åke

AU - Kvist, Anders

AU - Rivera, Barbara

AU - Hansen, Thomas V.O.

AU - Djursby, Malene

AU - Lee, Andrew

AU - Dennis, Joe

AU - Bowtell, David D.

AU - Traficante, Nadia

AU - DIez, Orland

AU - Balmaña, Judith

AU - Gruber, Stephen B.

AU - Chenevix-Trench, Georgia

AU - Investigators, Kconfab

AU - Jensen, Allan

AU - Kjær, Susanne K.

AU - Høgdall, Estrid

AU - Castéra, Laurent

AU - Garber, Judy

AU - Janavicius, Ramunas

AU - Osorio, Ana

AU - Golmard, Lisa

AU - Vega, Ana

AU - Couch, Fergus J.

AU - Robson, Mark

AU - Gronwald, Jacek

AU - Domchek, Susan M.

AU - Culver, Julie O.

AU - De La Hoya, Miguel

AU - Easton, Douglas F.

AU - Foulkes, William D.

AU - Tischkowitz, Marc

AU - Meindl, Alfons

AU - Schmutzler, Rita K.

AU - Pharoah, Paul D.P.

AU - Antoniou, Antonis C.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Background: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P =. 002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

AB - Background: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P =. 002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

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U2 - 10.1093/jnci/djaa030

DO - 10.1093/jnci/djaa030

M3 - Article

C2 - 32107557

AN - SCOPUS:85098475561

SN - 0027-8874

VL - 112

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EP - 1250

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 12

ER -

Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D

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