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Association Between BRCA1 Mutations and Ratio of Female to Male Births in Offspring of Families With Breast Cancer, Ovarian Cancer, or Both
Miguel de la Hoya, PhD;
Juan M. Fernández, BS;
Alicia Tosar, PhD;
Javier Godino, BS;
Ana Sánchez de Abajo, BS;
Jose A. Vidart, MD, PhD;
Pedro Pérez-Segura, MD, PhD;
Eduardo Díaz-Rubio, MD, PhD;
Trinidad Caldés, PhD
JAMA. 2003;290:929-931.
ABSTRACT
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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 = .004).
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.
INTRODUCTION
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.
METHODS
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  2 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).
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Table 1. Sex Ratio in BRCA1 Pedigrees
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Table 2. Sex Ratio in BRCA2 Pedigrees
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RESULTS
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%; 2= 11.19; P<.001) or BRCA-unrelated pedigrees (67% vs 52%; 2= 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 (2 = 8.35; P = .004).
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Figure. Sex Ratio of Births Observed in 68 Breast and/or Ovarian Cancer Pedigrees
Error bars indicate 95% confidence intervals.
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COMMENT
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.
AUTHOR INFORMATION
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Corresponding Author and Reprints: Trinidad Caldés, PhD, Laboratory of Molecular Oncology, Hospital Clínico San Carlos, Martin Lagos s/n, Madrid 28040, Spain (e-mail: tcaldes{at}hcsc.es).
Author Contributions: Study concept and design: de la Hoya, Caldes.
Acquisition of data: de la Hoya, Fernández, Tosar, Godino, Sánchez de Abajo, Pérez-Segura, Caldes.
Analysis and interpretation of data: de la Hoya, Vidart, Pérez-Segura, Diaz-Rubio, Caldes.
Drafting of the manuscript: de la Hoya, Caldes.
Critical revision of the manuscript for important intellectual content: Fernández, Tosar, Godino, Sánchez de Abajo, Vidart, Pérez-Segura, Diaz-Rubio, Caldes.
Statistical expertise: de la Hoya.
Obtained funding: de la Hoya, Diaz-Rubio, Caldes.
Administrative, technical, or material support: Fernández, Tosar, Godino, Sánchez de Abajo, Vidart, Pérez-Segura, Diaz-Rubio.
Study supervision: Caldes.
Funding/Support: This work was supported by Aventis, Fondo de Investigación Sanitaria grant 01/3040, and Comunidad de Madrid grant 08.1/0018.1/2000.
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.
REFERENCES
1. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171-182.
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2. de la Hoya M, Osorio A, Godino J, et al. Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002;97:466-471.
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3. Lee JT. Homozygous TSIX mutant mice reveal a sex-ratio distortion and revert to random X-inactivation. Nat Genet. 2002;32:195-200.
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4. Buller RE, Sood AK, Lallas T, et al. Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. J Natl Cancer Inst. 1999;91:339-346.
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5. Ganesan S, Silver DP, Greenberg RA, et al. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell. 2002;111:393-405.
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