de la Hoya M, Fernández JM, Tosar A, Godino J, Sánchez de Abajo A, Vidart JA, Pérez-Segura P, Díaz-Rubio E, Caldés T. Association Between BRCA1 Mutations and Ratio of Female to Male Births in Offspring of Families With Breast Cancer, Ovarian Cancer, or Both. JAMA. 2003;290(7):929–931. doi:10.1001/jama.290.7.929
Author Affiliation: Molecular Oncology Unit (Drs de la Hoya, Tosar, and Caldés, Messrs Fernández and Godino, and Ms Sánchez de Abajo) and Departments of Gynecology (Dr Vidart) and Clinical Oncology (Drs Pérez-Segura and Díaz-Rubio), Hospital Clínico San Carlos, Madrid, Spain.
Context Defects in X-chromosome inactivation distort sex ratio in mice. The BRCA1 gene is also involved in X-chromosome inactivation,
suggesting the possibility that some sex-ratio distortion may be associated
with BRCA1-related human cancer syndromes.
Objective To determine whether BRCA1 mutations are associated
with distortion of the sex ratio of births in families with breast cancer,
ovarian cancer, or both.
Design and Setting Analysis of germline mutations in participants from Spain who had been
screened for BRCA between 1998 and 2002.
Participants Sixty-eight families with at least 3 breast cancer cases or ovarian
cancer cases, or both types of cancer in 2 generations (germline mutations: BRCA1, n = 17; BRCA2, n = 15;
and BRCA unrelated, n = 36). An average of 4 relatives
per family were tested for the corresponding BRCA mutation.
Main Outcome Measure Male and female births registered in breast and/or ovarian pedigrees
tested for the presence of BRCA1 and BRCA2 germline mutations.
Results Of BRCA1-related breast and/or ovarian cancer
pedigrees, there was a 2-fold excess of female births (218 female vs 109 male
births). Of BRCA2-related or BRCA-unrelated breast and/or ovarian cancer pedigrees, there was not an
excess of female births (175 female/150 male and 344 female/315 male, respectively).
Of 327 BRCA1 births, 218 (67%) were female births
compared with 54% among BRCA2 pedigrees (175/327; P<.001) and 52% among BRCA-unrelated
pedigrees (344/659; P<.001). Female births increased
in the offspring of BRCA1 carriers compared with BRCA2 carriers (67% vs 52%; P =
Conclusion In these families with breast and/or ovarian cancer, mutations in BRCA1 but not BRCA2 were associated
with a sex ratio skewed against male births.
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
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.