Publication

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

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., Couch, F. J., Cybulski, C., Daly, M. B., de la Hoya, M., Diez, O., Domchek, S. M., Nathanson, K. L., Durda, K., Ellis, S., Evans, D. G., Foretova, L., Friedman, E., Frost, D., Ganz, P. A., Garber, J., Glendon, G., Godwin, A. K., Greene, M. H., Gronwald, J., Hahnen, E., Hallberg, E., Hamann, U., Hansen, T. V. O., Imyanitov, E. N., Isaacs, C., Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., EMBRACE, HEBON & kConFab Investigators, 11-Nov-2016, In : Breast cancer research. 18, 112, 19 p., 112.

Research output: Contribution to journalArticleAcademicpeer-review

  • 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
  • EMBRACE
  • HEBON
  • kConFab Investigators

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 languageEnglish
Article number112
Number of pages19
JournalBreast cancer research
Volume18
Issue number112
Publication statusPublished - 11-Nov-2016

    Keywords

  • Hereditary breast and ovarian cancer, Transheterozygosity, BRCA1, BRCA2, UNKNOWN CLINICAL-SIGNIFICANCE, CANCER SUSCEPTIBILITY GENE, SPORADIC BREAST-CANCER, DNA-SEQUENCE VARIANTS, WILD-TYPE CHROMOSOME, OVARIAN-CANCER, FANCONI-ANEMIA, DOUBLE HETEROZYGOSITY, GERMLINE MUTATIONS, HETEROGENIC LOSS

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