Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Shuai Li; Valentina Silvestri; Goska Leslie; Timothy R. Rebbeck; Susan L. Neuhausen; John L. Hopper; Henriette Roed Nielsen; Andrew Lee; Xin Yang; Lesley McGuffog; Michael T. Parsons; Irene L. Andrulis; Norbert Arnold; Muriel Belotti; Åke Borg; Bruno Buecher; Saundra S. Buys; Sandrine M. Caputo; Wendy K. Chung; Chrystelle Colas; Sarah V. Colonna; Jackie Cook; Mary B. Daly; Miguel de la Hoya; Antoine de Pauw; Hélène Delhomelle; Jacqueline Eason; Christoph Engel; D. Gareth Evans; Ulrike Faust; Tanja N. Fehm; Florentia Fostira; George Fountzilas; Megan Frone; Vanesa Garcia-Barberan; Pilar Garre; Marion Gauthier-Villars; Andrea Gehrig; Gord Glendon; David E. Goldgar; Lisa Golmard; Mark H. Greene; Eric Hahnen; Ute Hamann; Helen Hanson; Tiara Hassan; Julia Hentschel; Judit Horvath; Louise Izatt; Ramunas Janavicius; Yue Jiao; Esther M. John; Beth Y. Karlan; Sung-Won Kim; Irene Konstantopoulou; Ava Kwong; Anthony Laugé; Jong Won Lee; Fabienne Lesueur; Noura Mebirouk; Alfons Meindl; Emmanuelle Mouret-Fourme; Hannah Musgrave; Joanne Ngeow Yuen Yie; Dieter Niederacher; Sue K. Park; Inge Sokilde Pedersen; Juliane Ramser; Susan J. Ramus; Johanna Rantala; Muhammad U. Rashid; Florian Reichl; Julia Ritter; Andreas Rump; Marta Santamariña; Claire Saule; Gunnar Schmidt; Rita K. Schmutzler; Leigha Senter; Saba Shariff; Christian F. Singer; Melissa C. Southey; Dominique Stoppa-Lyonnet; Christian Sutter; Yen Tan; Soo Hwang Teo; Mary Beth Terry; Mads Thomassen; Marc Tischkowitz; Amanda E. Toland; Diana Torres; Ana Vega; Sebastian A. Wagner; Shan Wang-Gohrke; Barbara Wappenschmidt; Bernhard H. F. Weber; Drakoulis Yannoukakos; Amanda B. Spurdle; Douglas F. Easton; Georgia Chenevix-Trench; Laura Ottini; Antonis C. Antoniou

doi:10.1200/JCO.21.02112

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Shuai Li, Valentina Silvestri, Goska Leslie, Timothy R. Rebbeck, Susan L. Neuhausen, John L. Hopper, Henriette Roed Nielsen, Andrew Lee, Xin Yang, Lesley McGuffog, Michael T. Parsons, Irene L. Andrulis, Norbert Arnold, Muriel Belotti, Åke Borg, Bruno Buecher, Saundra S. Buys, Sandrine M. Caputo, Wendy K. Chung, Chrystelle ColasSarah V. Colonna, Jackie Cook, Mary B. Daly, Miguel de la Hoya, Antoine de Pauw, Hélène Delhomelle, Jacqueline Eason, Christoph Engel, D. Gareth Evans, Ulrike Faust, Tanja N. Fehm, Florentia Fostira, George Fountzilas, Megan Frone, Vanesa Garcia-Barberan, Pilar Garre, Marion Gauthier-Villars, Andrea Gehrig, Gord Glendon, David E. Goldgar, Lisa Golmard, Mark H. Greene, Eric Hahnen, Ute Hamann, Helen Hanson, Tiara Hassan, Julia Hentschel, Judit Horvath, Louise Izatt, Ramunas Janavicius, Yue Jiao, Esther M. John, Beth Y. Karlan, Sung-Won Kim, Irene Konstantopoulou, Ava Kwong, Anthony Laugé, Jong Won Lee, Fabienne Lesueur, Noura Mebirouk, Alfons Meindl, Emmanuelle Mouret-Fourme, Hannah Musgrave, Joanne Ngeow Yuen Yie, Dieter Niederacher, Sue K. Park, Inge Sokilde Pedersen, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Muhammad U. Rashid, Florian Reichl, Julia Ritter, Andreas Rump, Marta Santamariña, Claire Saule, Gunnar Schmidt, Rita K. Schmutzler, Leigha Senter, Saba Shariff, Christian F. Singer, Melissa C. Southey, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Tan, Soo Hwang Teo, Mary Beth Terry, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Ana Vega, Sebastian A. Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Bernhard H. F. Weber, Drakoulis Yannoukakos, Amanda B. Spurdle, Douglas F. Easton, Georgia Chenevix-Trench, Laura Ottini, Antonis C. Antoniou^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.

METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.

RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.

CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Original language	English
Journal	Journal of Clinical Oncology
Volume	40
Issue number	14
Pages (from-to)	1529-1541
Number of pages	13
ISSN	0732-183X
DOIs	https://doi.org/10.1200/JCO.21.02112
Publication status	Published - 10 May 2022

Keywords

BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms
Breast Neoplasms, Male
Female
Genetic Predisposition to Disease
Heterozygote
Humans
Infant, Newborn
Male
Mutation
Ovarian Neoplasms/epidemiology
Pancreatic Neoplasms/epidemiology
Risk

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Li et al. (2022). Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic VariantsFinal published version, 307 KBLicence: CC BY 4.0

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Li, S., Silvestri, V., Leslie, G., Rebbeck, T. R., Neuhausen, S. L., Hopper, J. L., Nielsen, H. R., Lee, A., Yang, X., McGuffog, L., Parsons, M. T., Andrulis, I. L., Arnold, N., Belotti, M., Borg, Å., Buecher, B., Buys, S. S., Caputo, S. M., Chung, W. K., ... Antoniou, A. C. (2022). Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. Journal of Clinical Oncology, 40(14), 1529-1541. Advance online publication. https://doi.org/10.1200/JCO.21.02112

@article{fe880c1e4b7e4a20b76a73e574edbaf2,

title = "Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants",

abstract = "PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.",

keywords = "BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms, Breast Neoplasms, Male, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Ovarian Neoplasms/epidemiology, Pancreatic Neoplasms/epidemiology, Risk",

author = "Shuai Li and Valentina Silvestri and Goska Leslie and Rebbeck, {Timothy R.} and Neuhausen, {Susan L.} and Hopper, {John L.} and Nielsen, {Henriette Roed} and Andrew Lee and Xin Yang and Lesley McGuffog and Parsons, {Michael T.} and Andrulis, {Irene L.} and Norbert Arnold and Muriel Belotti and {\AA}ke Borg and Bruno Buecher and Buys, {Saundra S.} and Caputo, {Sandrine M.} and Chung, {Wendy K.} and Chrystelle Colas and Colonna, {Sarah V.} and Jackie Cook and Daly, {Mary B.} and {de la Hoya}, Miguel and {de Pauw}, Antoine and H{\'e}l{\`e}ne Delhomelle and Jacqueline Eason and Christoph Engel and Evans, {D. Gareth} and Ulrike Faust and Fehm, {Tanja N.} and Florentia Fostira and George Fountzilas and Megan Frone and Vanesa Garcia-Barberan and Pilar Garre and Marion Gauthier-Villars and Andrea Gehrig and Gord Glendon and Goldgar, {David E.} and Lisa Golmard and Greene, {Mark H.} and Eric Hahnen and Ute Hamann and Helen Hanson and Tiara Hassan and Julia Hentschel and Judit Horvath and Louise Izatt and Ramunas Janavicius and Yue Jiao and John, {Esther M.} and Karlan, {Beth Y.} and Sung-Won Kim and Irene Konstantopoulou and Ava Kwong and Anthony Laug{\'e} and Lee, {Jong Won} and Fabienne Lesueur and Noura Mebirouk and Alfons Meindl and Emmanuelle Mouret-Fourme and Hannah Musgrave and {Ngeow Yuen Yie}, Joanne and Dieter Niederacher and Park, {Sue K.} and Pedersen, {Inge Sokilde} and Juliane Ramser and Ramus, {Susan J.} and Johanna Rantala and Rashid, {Muhammad U.} and Florian Reichl and Julia Ritter and Andreas Rump and Marta Santamari{\~n}a and Claire Saule and Gunnar Schmidt and Schmutzler, {Rita K.} and Leigha Senter and Saba Shariff and Singer, {Christian F.} and Southey, {Melissa C.} and Dominique Stoppa-Lyonnet and Christian Sutter and Yen Tan and Teo, {Soo Hwang} and Terry, {Mary Beth} and Mads Thomassen and Marc Tischkowitz and Toland, {Amanda E.} and Diana Torres and Ana Vega and Wagner, {Sebastian A.} and Shan Wang-Gohrke and Barbara Wappenschmidt and Weber, {Bernhard H. F.} and Drakoulis Yannoukakos and Spurdle, {Amanda B.} and Easton, {Douglas F.} and Georgia Chenevix-Trench and Laura Ottini and Antoniou, {Antonis C.}",

year = "2022",

month = may,

day = "10",

doi = "10.1200/JCO.21.02112",

language = "English",

volume = "40",

pages = "1529--1541",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "14",

}

Li, S, Silvestri, V, Leslie, G, Rebbeck, TR, Neuhausen, SL, Hopper, JL, Nielsen, HR, Lee, A, Yang, X, McGuffog, L, Parsons, MT, Andrulis, IL, Arnold, N, Belotti, M, Borg, Å, Buecher, B, Buys, SS, Caputo, SM, Chung, WK, Colas, C, Colonna, SV, Cook, J, Daly, MB, de la Hoya, M, de Pauw, A, Delhomelle, H, Eason, J, Engel, C, Evans, DG, Faust, U, Fehm, TN, Fostira, F, Fountzilas, G, Frone, M, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Gehrig, A, Glendon, G, Goldgar, DE, Golmard, L, Greene, MH, Hahnen, E, Hamann, U, Hanson, H, Hassan, T, Hentschel, J, Horvath, J, Izatt, L, Janavicius, R, Jiao, Y, John, EM, Karlan, BY, Kim, S-W, Konstantopoulou, I, Kwong, A, Laugé, A, Lee, JW, Lesueur, F, Mebirouk, N, Meindl, A, Mouret-Fourme, E, Musgrave, H, Ngeow Yuen Yie, J, Niederacher, D, Park, SK, Pedersen, IS, Ramser, J, Ramus, SJ, Rantala, J, Rashid, MU, Reichl, F, Ritter, J, Rump, A, Santamariña, M, Saule, C, Schmidt, G, Schmutzler, RK, Senter, L, Shariff, S, Singer, CF, Southey, MC, Stoppa-Lyonnet, D, Sutter, C, Tan, Y, Teo, SH, Terry, MB, Thomassen, M, Tischkowitz, M, Toland, AE, Torres, D, Vega, A, Wagner, SA, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Spurdle, AB, Easton, DF, Chenevix-Trench, G, Ottini, L & Antoniou, AC 2022, 'Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants', Journal of Clinical Oncology, vol. 40, no. 14, pp. 1529-1541. https://doi.org/10.1200/JCO.21.02112

TY - JOUR

T1 - Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

AU - Li, Shuai

AU - Silvestri, Valentina

AU - Leslie, Goska

AU - Rebbeck, Timothy R.

AU - Neuhausen, Susan L.

AU - Hopper, John L.

AU - Nielsen, Henriette Roed

AU - Lee, Andrew

AU - Yang, Xin

AU - McGuffog, Lesley

AU - Parsons, Michael T.

AU - Andrulis, Irene L.

AU - Arnold, Norbert

AU - Belotti, Muriel

AU - Borg, Åke

AU - Buecher, Bruno

AU - Buys, Saundra S.

AU - Caputo, Sandrine M.

AU - Chung, Wendy K.

AU - Colas, Chrystelle

AU - Colonna, Sarah V.

AU - Cook, Jackie

AU - Daly, Mary B.

AU - de la Hoya, Miguel

AU - de Pauw, Antoine

AU - Delhomelle, Hélène

AU - Eason, Jacqueline

AU - Engel, Christoph

AU - Evans, D. Gareth

AU - Faust, Ulrike

AU - Fehm, Tanja N.

AU - Fostira, Florentia

AU - Fountzilas, George

AU - Frone, Megan

AU - Garcia-Barberan, Vanesa

AU - Garre, Pilar

AU - Gauthier-Villars, Marion

AU - Gehrig, Andrea

AU - Glendon, Gord

AU - Goldgar, David E.

AU - Golmard, Lisa

AU - Greene, Mark H.

AU - Hahnen, Eric

AU - Hamann, Ute

AU - Hanson, Helen

AU - Hassan, Tiara

AU - Hentschel, Julia

AU - Horvath, Judit

AU - Izatt, Louise

AU - Janavicius, Ramunas

AU - Jiao, Yue

AU - John, Esther M.

AU - Karlan, Beth Y.

AU - Kim, Sung-Won

AU - Konstantopoulou, Irene

AU - Kwong, Ava

AU - Laugé, Anthony

AU - Lee, Jong Won

AU - Lesueur, Fabienne

AU - Mebirouk, Noura

AU - Meindl, Alfons

AU - Mouret-Fourme, Emmanuelle

AU - Musgrave, Hannah

AU - Ngeow Yuen Yie, Joanne

AU - Niederacher, Dieter

AU - Park, Sue K.

AU - Pedersen, Inge Sokilde

AU - Ramser, Juliane

AU - Ramus, Susan J.

AU - Rantala, Johanna

AU - Rashid, Muhammad U.

AU - Reichl, Florian

AU - Ritter, Julia

AU - Rump, Andreas

AU - Santamariña, Marta

AU - Saule, Claire

AU - Schmidt, Gunnar

AU - Schmutzler, Rita K.

AU - Senter, Leigha

AU - Shariff, Saba

AU - Singer, Christian F.

AU - Southey, Melissa C.

AU - Stoppa-Lyonnet, Dominique

AU - Sutter, Christian

AU - Tan, Yen

AU - Teo, Soo Hwang

AU - Terry, Mary Beth

AU - Thomassen, Mads

AU - Tischkowitz, Marc

AU - Toland, Amanda E.

AU - Torres, Diana

AU - Vega, Ana

AU - Wagner, Sebastian A.

AU - Wang-Gohrke, Shan

AU - Wappenschmidt, Barbara

AU - Weber, Bernhard H. F.

AU - Yannoukakos, Drakoulis

AU - Spurdle, Amanda B.

AU - Easton, Douglas F.

AU - Chenevix-Trench, Georgia

AU - Ottini, Laura

AU - Antoniou, Antonis C.

PY - 2022/5/10

Y1 - 2022/5/10

N2 - PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

AB - PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms

KW - Breast Neoplasms, Male

KW - Female

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Infant, Newborn

KW - Male

KW - Mutation

KW - Ovarian Neoplasms/epidemiology

KW - Pancreatic Neoplasms/epidemiology

KW - Risk

U2 - 10.1200/JCO.21.02112

DO - 10.1200/JCO.21.02112

M3 - Journal article

C2 - 35077220

SN - 0732-183X

VL - 40

SP - 1529

EP - 1541

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 14

ER -

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

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