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To the Editor: It is possible that improper heterochromatinization of X chromosomes in XY bodies of male heterozygous BRCA1 carriers may lead such male sperm cells to be less viable, given that products of the BRCA1 gene are presumed to play a role in this process.¹ Thus, male heterozygous carriers would be expected to have a greater proportion of female offspring. Indeed, de la Hoya et al² reported an excess of females among the offspring of BRCA1 mutation carriers but no such sex-ratio distortion affects the offspring of BRCA2 carriers. However, these results might have reflected an ascertainment bias of carriers through affected females.³ Because penetrance is higher at younger ages in BRCA1 than in BRCA2 female carriers,⁴ this bias could be stronger in BRCA1 than in BRCA2-associated families.

Selection bias among male BRCA1 and BRCA2 mutation carriers may arise because men with daughters are more likely to be tested. This excess is expected to be higher in BRCA1 than BRCA2 families as BRCA2 male carriers may themselves be affected. To avoid such ascertainment bias, we studied men without affected daughters among a set of families with BRCA1 or BRCA2 mutations. The bias due to this specific motivation should be smaller in the offspring of female carriers, but the selection bias due to ascertainment through affected females should nevertheless exist. Therefore, we also studied the sex ratio among the offspring of female carriers as a control for the offspring of male carriers.

Methods
We analyzed the sex ratio in pedigrees with germline mutations of BRCA1 or BRCA2 from 3 cancer clinics in metropolitan Paris (Institut Gustave-Roussy, Villejuif; Institut Curie, Paris; and Centre René Huguenin, Saint-Cloud). The members of these families had been seeking genetic counseling and had been self- or physician-referred. They belonged to families with a known BRCA mutation or their family history was compatible with a hereditary predisposition. BRCA testing was offered to families that fulfilled criteria recommended by French guidelines⁵: (1) 3 or more individuals affected by breast or ovarian cancer among first-degree relatives (second if through the paternal branch); (2) 2 affected first-degree relatives, 1 with bilateral breast cancer or with a diagnosis before the age of 40 years; (3) ovarian cancer at any age. After extensive counseling concerning both the medical and psychosocial implications of a positive result, participants signed an informed consent for genetic testing. As our study did not involve therapeutic interventions, it was exempt under French law from institutional review board approval. Our sample size had a power greater than 90% to detect a female to male ratio of 0.67 among the offspring of male carriers for both BRCA1 and BRCA2 families.²

Results
Since 1995, a total of 592 families carrying a mutation in either the BRCA1 (382) or BRCA2 (210) gene were identified. The number of male carriers and of their male and female offspring, according to the BRCA status, are provided in Table 1. When all male carriers were included, there was an excess of female offspring, with a sex ratio of 0.69 (² = 7.21, P = .01) for BRCA1 and 0.80 (² = 2.05, P = .16) for BRCA2. In contrast, when only males with no affected daughters were considered, the sex ratio was 0.94, very close to the expected sex ratio of 1.0 (Table 1). For offspring of all female carriers, we also found an excess of female offspring with a sex ratio of 0.77 (² = 16.99, P<.001) for BRCA1 and 0.78 (²₁ = 9.04, P = .01) for BRCA2. However, when only women without affected daughters were examined, the sex ratio remained lower than expected with estimates of 0.83 (²₁ = 7.41, P = .01) for BRCA1 and 0.81 (²₁ = 5.68, P = .02) for BRCA2.

View this table: [in this window] [in a new window] Table. Sex Ratio Among the Offspring of Male or Female BRCA1 and BRCA2 Carriers

Comment
We found a predicted excess of females among the offspring of male carriers that was more marked in BRCA1 than in BRCA2 families. Using a method that corrects for ascertainment bias via affected female offspring, we did not find any sex-ratio distortion among the offspring of male carriers of BRCA1 or BRCA2 mutations. Thus, our data do not support the hypothesis of a deficiency of the Y chromosome in the germ cells of male BRCA1 carriers.

Among the offspring of female carriers, we found a large excess of females in both BRCA1 and BRCA2 families. Surprisingly, this excess remained significant after removing the offspring of carrier women with affected daughters for both BRCA1 and BRCA2 genes from the sample. This excess might be due to the bias suggested by Mealiffe³ that women with breast cancer who have female offspring have a greater motivation to undergo genetic testing. Our results indicate that sex-ratio observations must be carefully interpreted in diseases that selectively affect one sex vs the other.

Jean Feunteun, PhD
feunteun{at}igr.fr

Agnès Chompret, MD; Anne Helbling-Leclerc, PhD
Institut Gustave-Roussy
Villejuif, France

Dominique Stoppa-Lyonnet, MD, PhD; Muriel Belotti, PhD
Institut Curie
Paris, France

Catherine Noguès, MD
Centre René Huguenin
Saint-Cloud, France

Catherine Bonaïti-Pellié, MD, PhD
INSERM U535
Villejuif, France

1. Ganesan S, Silver DP, Greenberg RA, et al. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell. 2002;111:393-405. FULL TEXT | ISI | PUBMED 2. De La Hoya M, Fernandez JM, Tosar A, et al. Association between BRCA1 mutations and ratio of female to male births in offspring of families with breast cancer, ovarian cancer, or both. JAMA. 2003;290:929-931. FREE FULL TEXT 3. Mealiffe ME. Sex ratios in families with BRCA mutations. JAMA. 2003;290:2544-2545. FREE FULL TEXT 4. Antoniou AC, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-1130. FULL TEXT | ISI | PUBMED 5. Eisinger F, Alby N, Bremond A, et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol. 1998;9:939-950. FREE FULL TEXT

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2004;292:687-688.

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