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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.

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.

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.

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