CORRESPONDENCE

RESPONSE: Re: Association Between Nonrandom X-Chromosome Inactivation and BRCA1 Mutation in Germline DNA of Patients With Ovarian Cancer

Richard E. Buller, Anil K. Sood, Thomas Lallas, Thomas Buekers, Jeffrey S. Skilling

Affiliations of authors: R. E. Buller (Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Department of Pharmacology), A. K. Sood, T. Lallas, T. Buekers, J. S. Skilling (Division of Gynecologic Oncology), Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, Iowa City.

Correspondence to: Richard E. Buller, M.D., Ph.D., Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 200 Hawkins Dr., #4630 JCP, Iowa City, IA 52242-1009 (e-mail: richard-buller{at}uiowa.edu).

Narod and Boyd (1) have challenged our proposed model of an X-linked tumor suppressor gene invoked to explain the association between nonrandom X-chromosome inactivation and ovarian cancer. They have suggested alternative explanations but focused narrowly on a model wherein the germline mutation of an X-linked tumor suppressor gene contributes to hereditary cancers. We would reiterate from our published article (1) that there are two ways in which an X-linked tumor suppressor gene contributes to ovarian cancer. The first way provides a subset of sporadic ovarian cancers that are rendered null at the X-linked tumor suppressor gene locus by virtue of nonrandom X-chromosome inactivation and concomitant loss of the active allele. The calculated odds ratio of 2.3 suggested by Narod and Boyd does not conflict with this model. A second mechanism relates to hereditary ovarian cancer. In this case, a germline mutation of the X-linked tumor suppressor gene associated with nonrandom X-chromosome inactivation does not require loss of heterozygosity. We would accept it as a rare event. Unless the authors' own data (2) have been revised, they and others are unable to explain all cases of hereditary breast and ovarian cancers on the basis of germline BRCA1 and BRCA2 mutations. Thus, the existence of a putative yet elusive BRCA3 gene must be invoked. Where better to hide than on the X chromosome? Until very recently, the X chromosome could be considered a genetically privileged hiding site because of the paucity of markers for high resolution mapping and linkage analysis. Indeed, a putative hereditary prostate cancer susceptibility tumor suppressor gene has only recently been mapped to the X chromosome (3).

Narod and Boyd have clearly misinterpreted the genotype data from Family 15. They state that the active X chromosome is "different for the two family members." This conclusion can only be true if the probands share a common androgen receptor (AR) allelotype. A careful evaluation of Fig. 5 in our article (1) shows that four different allelotypes are expressed between the two probands. Thus, it is impossible to conclude which X chromosome is active. One can only say that the X-linked tumor suppressor gene is not the AR gene itself. Narod and Boyd are correct that male-to-male transmission is incompatible with X linkage. However, the hereditary breast and ovarian cancers in Family 15 are explained by the germline BRCA1 mutation, as shown in the caption to Fig. 5 of our article. Thus, an X-linked tumor suppressor gene is not required for this family. Nonetheless, nonrandom X-chromosome inactivation may still contribute to the penetrance of disease. These data suggest that nonrandom X-chromosome inactivation may be autosomally determined. Hence, our conclusion that nonrandom X-chromosome inactivation is "complex."

Finally, Narod and Boyd were critical of our failure to control for age. Table 1Go shows a breakdown of nonrandom X-chromosome inactivation based upon the study group with attention to age at diagnosis (1). Nonrandom X-chromosome inactivation is independent of age and dependent on health status. Women who develop invasive ovarian cancer are more likely to demonstrate nonrandom X-chromosome inactivation regardless of age at diagnosis. Further investigation of the phenomenon of nonrandom X-chromosome inactivation and its relationship to ovarian cancer and cancer in general are warranted.


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Table 1. Comparison of frequency of nonrandom X-chromosome inactivation by study group and age at analysis

 

REFERENCES

1 Buller RE, Sood AK, Lallas T, Buekers T, Skilling JS. Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. J Natl Cancer Inst 1999;91:339-46.[Abstract/Free Full Text]

2 Serova OM, Mazoyer S, Puget N, Dubois V, Tonin P, Shugart YY, et al. Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet 1997;60:486-95.[Medline]

3 Xu J, Meyers D, Freije D, Isaacs S, Wiley K, Nusskern D, et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998;20:175-9.[Medline]



             
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