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”. Aftermatching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370SH2.
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.