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.
Additional file 1: Table S1. Ethics committees that granted approval
for the access and use of the data for this study. Table S2. Participant
counts by center and mutation. Table S3. Primers used for PCR and
Sanger sequencing. Table S4. Primers used in micro-satellite analysis for
loss of heterozygosity. Table S5. Micro-satellite loss of heterozygosity and
sequencing analysis results.