Association Between BRCA1 Mutations and Ratio of Female to Male Births in Offspring of Families With Breast Cancer, Ovarian Cancer, or Both FREE

The biology of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 is not well understood. These genes encode proteins likely involved in DNA repair, transcription regulation, and cell cycle and checkpoint control.¹ Except for cancer susceptibility, no other phenotype associated with BRCA1 mutations has been reported in humans. In this study, we analyzed the sex ratio in the offspring of families with BRCA1 and BRCA2 mutation carriers.

We analyzed the sex ratio in 68 breast and/or ovarian cancer pedigrees between 1998 and 2002 who were previously screened for germline mutations in both BRCA1 and BRCA2. These Spanish families were selected for genetic testing because they have at least 3 breast and/or ovarian cancer cases reported in 2 generations. Participants signed an informed consent to have their blood tested for BRCA1 and/or BRCA2. Approval for the study was obtained from the local ethics committee. Of the 68 pedigrees, our cohort included 17 BRCA1-related, 15 BRCA2-related, and 36 BRCA-unrelated families. All mutations are considered as pathogenic on the Breast Cancer Informative Core Web site (http://www.nhgri.gov/Intramural_research/Lab_transfer/Bic/; mutation descriptions appear in Table 1 and Table 2). A total of 121 relatives have been tested for the corresponding mutation (on average, 4 relatives per BRCA1- or BRCA2-positive family). Mutation screening methods have been described elsewhere.¹ For the overall sex ratio of births, we considered all male and female births reported in each pedigree. To determine the sex ratio of births in the offspring of carriers, we considered either BRCA carriers confirmed by genetic testing (n = 56) or nontested obligated carriers (n = 26). The χ² test was used in all statistical analyses and was performed using Epi Info statistical software (Version 5.01; Centers for Disease Control and Prevention, Atlanta, Ga).

Overall, BRCA1 pedigrees were strongly skewed against male births: 218 females vs 109 males (Table 1). By contrast, BRCA2 pedigrees (175 female vs 150 male births), and BRCA-unrelated pedigrees (344 female vs 315 male births) were close to the expected 50% sex ratio (Table 2). The excess of female births observed in BRCA1 pedigrees is significant when compared with BRCA2 pedigrees (67% vs 54%; χ²= 11.19; P<.001) or BRCA-unrelated pedigrees (67% vs 52%; χ²= 18.66; P<.001) (Figure 1). The sex ratio was also skewed against male births in the offspring of BRCA1 carriers: 133 female (67%) vs 65 male (33%) (Table 1). On the other hand, the offspring of BRCA2 carriers have shown no evidence of sex-ratio abnormalities: 84 (52%) female births vs 77 (48%) male births (Table 2). These data support an association between BRCA1 defects (but not BRCA2 defects) and sex ratio skewed against male births in the offspring (χ² = 8.35; P = .004).

Taken together, our data confirm a sex-ratio distortion associated with BRCA1 mutations. Our findings were unexpected, but may be partly explained by recent data suggesting both a link between X-chromosome inactivation (XCI) and sex ratio² and a role for BRCA1 in XCI.^3- 4 Although XCI is a poorly understood biological process, XIST and TSIX genes (acting on chromosome inactivation) are known to have opposite roles in XCI regulation. In current XCI models, XIST RNA accumulation along an X chromosome promotes silencing along that chromosome. The expression of TSIX (its antisense counterpart) blocks XIST accumulation and therefore inhibits XCI. An association between BRCA1 and XCI dysfunction was first described in patients with BRCA1 germline mutations and/or ovarian cancer.³ Recently, a direct role for BRCA1 in XCI has been suggested as XIST RNA concentration in the inactive X chromosome is dependent on BRCA1 status.⁵

Defects in XCI may distort sex ratio as has been shown in homozygous TSIX mutant mice.² Lee³ demonstrated that by abolishing TSIX activity, the sex ratio is skewed against female births. One hypothesis is that BRCA1 haploinsufficiency affects the ability of XIST RNA to accumulate along the X chromosome, mimics XIST inhibition, and produces an opposite sex-ratio distortion; ie, a sex ratio skewed against male births.

In conclusion, we report, for the first time to our knowledge, a phenotype associated with BRCA1 but not BRCA2 or BRCA-unrelated breast and/or ovarian cancer, resulting in a sex ratio skewed against male births in the offspring of mutation carriers.