Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Timothy R Rebbeck; Tara M Friebel; Nandita Mitra; Fei Wan; Stephanie Chen; Irene L Andrulis; Paraskevi Apostolou; Norbert Arnold; Banu K Arun; Daniel Barrowdale; Javier Benitez; Raanan Berger; Pascaline Berthet; Ake Borg; Saundra S Buys; Trinidad Caldes; Jonathan Carter; Jocelyne Chiquette; Kathleen B M Claes; Fergus J Couch; Cezary Cybulski; Mary B Daly; Miguel de la Hoya; Orland Diez; Susan M Domchek; Katherine L Nathanson; Katarzyna Durda; Steve Ellis; D Gareth Evans; Lenka Foretova; Eitan Friedman; Debra Frost; Patricia A Ganz; Judy Garber; Gord Glendon; Andrew K Godwin; Mark H Greene; Jacek Gronwald; Eric Hahnen; Emily Hallberg; Ute Hamann; Thomas V O Hansen; Evgeny N Imyanitov; Claudine Isaacs; Anna Jakubowska; Ramunas Janavicius; Katarzyna Jaworska-Bieniek; Esther M John; Beth Y Karlan; Bella Kaufman; EMBRACE

doi:10.1186/s13058-016-0768-3

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Timothy R Rebbeck
, Tara M Friebel
, Nandita Mitra
, Fei Wan
, Stephanie Chen
, Irene L Andrulis
, Paraskevi Apostolou
, Norbert Arnold
, Banu K Arun
, Daniel Barrowdale
, Javier Benitez
, Raanan Berger
, Pascaline Berthet
, Ake Borg
, Saundra S Buys
, Trinidad Caldes
, Jonathan Carter
, Jocelyne Chiquette
, Kathleen B M Claes
, Fergus J Couch

Cezary Cybulski, Mary B Daly, Miguel de la Hoya, Orland Diez, Susan M Domchek, Katherine L Nathanson, Katarzyna Durda, Steve Ellis, D Gareth Evans, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A Ganz, Judy Garber, Gord Glendon, Andrew K Godwin, Mark H Greene, Jacek Gronwald, Eric Hahnen, Emily Hallberg, Ute Hamann, Thomas V O Hansen, Evgeny N Imyanitov, Claudine Isaacs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Esther M John, Beth Y Karlan, Bella Kaufman, EMBRACE

Division of Evolution, Infection and Genomics

Mount Sinai Hospital of University of Toronto
Spanish National Cancer Research Centre
Centre François Baclesse
Huntsman Cancer Institute
IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Hôpital du Saint-Sacrement
Fox Chase Cancer Centre
Vall D'Hebron Institute of Oncology
University of California (UCLA)
National Institutes of Health
DKFZ (Deutsches Krebsforschungszentrum Heidelberg)
N.N. Petrov Institute of Oncology
Cancer Prevention Institute of California
Manchester Academic Health Science Centre (MAHSC)
Dana-Farber Cancer Institute
Harvard T.H. Chan School of Public Health
Lund University
Skåne University Hospital
University of Kansas Medical Center
University of Pennsylvania
National Centre for Scientific Research Demokritos
Christian-Albrechts Universitaet
University of Texas MD Anderson Cancer Center
Royal Prince Alfred Hospital
Mayo Clinic (HQ)
Copenhagen University Hospital
Ghent University
Group Health Research Institute
Vilnius University Hospital
Georgetown University
Mount Sinai Hospital
Masaryk Memorial Cancer Institute
Chaim Sheba Medical Center
University of Southern California
QIMR Berghofer Medical Research Institute
Pomeranian Medical University
University of Cambridge
West Virginia University
Universitat zu Koln University of Cologne
Cedars-Sinai Medical Center

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Abstract

BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.

METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.

RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.

CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

Original language	English
Pages (from-to)	112
Journal	Breast Cancer Research
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s13058-016-0768-3
Publication status	Published - 11 Nov 2016

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Rebbeck, T. R., Friebel, T. M., Mitra, N., Wan, F., Chen, S., Andrulis, I. L., Apostolou, P., Arnold, N., Arun, B. K., Barrowdale, D., Benitez, J., Berger, R., Berthet, P., Borg, A., Buys, S. S., Caldes, T., Carter, J., Chiquette, J., Claes, K. B. M., ... EMBRACE (2016). Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Research, 18(1), 112. https://doi.org/10.1186/s13058-016-0768-3

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abstract = "BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 \%). {"}Cases{"} were defined as TH, and {"}controls{"} were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 {"}controls{"} carried a BRCA1 mutation found in the TH {"}case{"}. Matched SH2 {"}controls{"} carried a BRCA2 mutation found in the TH {"}case{"}. After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.RESULTS: The majority of TH (45.2 \%) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.",

author = "Rebbeck, \{Timothy R\} and Friebel, \{Tara M\} and Nandita Mitra and Fei Wan and Stephanie Chen and Andrulis, \{Irene L\} and Paraskevi Apostolou and Norbert Arnold and Arun, \{Banu K\} and Daniel Barrowdale and Javier Benitez and Raanan Berger and Pascaline Berthet and Ake Borg and Buys, \{Saundra S\} and Trinidad Caldes and Jonathan Carter and Jocelyne Chiquette and Claes, \{Kathleen B M\} and Couch, \{Fergus J\} and Cezary Cybulski and Daly, \{Mary B\} and \{de la Hoya\}, Miguel and Orland Diez and Domchek, \{Susan M\} and Nathanson, \{Katherine L\} and Katarzyna Durda and Steve Ellis and Evans, \{D Gareth\} and Lenka Foretova and Eitan Friedman and Debra Frost and Ganz, \{Patricia A\} and Judy Garber and Gord Glendon and Godwin, \{Andrew K\} and Greene, \{Mark H\} and Jacek Gronwald and Eric Hahnen and Emily Hallberg and Ute Hamann and Hansen, \{Thomas V O\} and Imyanitov, \{Evgeny N\} and Claudine Isaacs and Anna Jakubowska and Ramunas Janavicius and Katarzyna Jaworska-Bieniek and John, \{Esther M\} and Karlan, \{Beth Y\} and Bella Kaufman and EMBRACE",

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day = "11",

doi = "10.1186/s13058-016-0768-3",

language = "English",

volume = "18",

pages = "112",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "Springer Nature",

number = "1",

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Rebbeck, TR, Friebel, TM, Mitra, N, Wan, F, Chen, S, Andrulis, IL, Apostolou, P, Arnold, N, Arun, BK, Barrowdale, D, Benitez, J, Berger, R, Berthet, P, Borg, A, Buys, SS, Caldes, T, Carter, J, Chiquette, J, Claes, KBM, Couch, FJ, Cybulski, C, Daly, MB, de la Hoya, M, Diez, O, Domchek, SM, Nathanson, KL, Durda, K, Ellis, S, Evans, DG, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Hahnen, E, Hallberg, E, Hamann, U, Hansen, TVO, Imyanitov, EN, Isaacs, C, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, John, EM, Karlan, BY, Kaufman, B & EMBRACE 2016, 'Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women', Breast Cancer Research, vol. 18, no. 1, pp. 112. https://doi.org/10.1186/s13058-016-0768-3

TY - JOUR

T1 - Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

AU - Rebbeck, Timothy R

AU - Friebel, Tara M

AU - Mitra, Nandita

AU - Wan, Fei

AU - Chen, Stephanie

AU - Andrulis, Irene L

AU - Apostolou, Paraskevi

AU - Arnold, Norbert

AU - Arun, Banu K

AU - Barrowdale, Daniel

AU - Benitez, Javier

AU - Berger, Raanan

AU - Berthet, Pascaline

AU - Borg, Ake

AU - Buys, Saundra S

AU - Caldes, Trinidad

AU - Carter, Jonathan

AU - Chiquette, Jocelyne

AU - Claes, Kathleen B M

AU - Couch, Fergus J

AU - Cybulski, Cezary

AU - Daly, Mary B

AU - de la Hoya, Miguel

AU - Diez, Orland

AU - Domchek, Susan M

AU - Nathanson, Katherine L

AU - Durda, Katarzyna

AU - Ellis, Steve

AU - Evans, D Gareth

AU - Foretova, Lenka

AU - Friedman, Eitan

AU - Frost, Debra

AU - Ganz, Patricia A

AU - Garber, Judy

AU - Glendon, Gord

AU - Godwin, Andrew K

AU - Greene, Mark H

AU - Gronwald, Jacek

AU - Hahnen, Eric

AU - Hallberg, Emily

AU - Hamann, Ute

AU - Hansen, Thomas V O

AU - Imyanitov, Evgeny N

AU - Isaacs, Claudine

AU - Jakubowska, Anna

AU - Janavicius, Ramunas

AU - Jaworska-Bieniek, Katarzyna

AU - John, Esther M

AU - Karlan, Beth Y

AU - Kaufman, Bella

AU - EMBRACE

PY - 2016/11/11

Y1 - 2016/11/11

N2 - BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

AB - BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

UR - https://www.scopus.com/pages/publications/85000995840

U2 - 10.1186/s13058-016-0768-3

DO - 10.1186/s13058-016-0768-3

M3 - Article

C2 - 27836010

SN - 1465-5411

VL - 18

SP - 112

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

ER -

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

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