Affiliations of authors: J. Boyd, Departments of Surgery and Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY; S. A. Narod, Centre for Research on Women's Health, Women's College Hospital, University of Toronto, Canada.
Correspondence to: Jeff Boyd, Ph.D., Department of Surgery, Box 201, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 or Steven A. Narod, M.D., Centre for Research on Women's Health, Women's College Hospital, 790 Bay St., Rm. 750A, Toronto, ON M5G 1N8, Canada.
Buller et al. (1) suggest a novel mechanism for genetic susceptibility to ovarian cancer. In our view, the data presented are puzzling and do not support a new model for susceptibility to ovarian cancer. There are two models under which germline mutation of an X-chromosome tumor suppressor may contribute to cancer predisposition through nonrandom X-chromosome inactivation (NXCI). In one model, approximately 30% of females (authors' data) undergo NXCI for reasons unrelated to a cancer predisposing allele, and some fraction of these carry a mutant tumor suppressor allele that manifests when the normal allele undergoes NXCI. In the second model, cells with the mutant allele present on the active X chromosome have a proliferative advantage over cells with a normal active allele during tissue morphogenesis, resulting in apparent increased rates of NXCI. This model implies that the mutant cancer susceptibility allele occurs frequently in the population, if 30% of control subjects manifest this phenomenon.
Three sets of data are presented, each requiring one or the other of these models. In the first, NXCI is found in 53% of invasive ovarian cancer patients compared with 28% of borderline tumor patients and 33% of healthy controls, leading to the conclusion that NXCI predisposes to invasive (but not borderline) ovarian cancer. From these data, we calculate an odds ratio of 2.3 for NXCI-linked ovarian cancer, which would increase the average lifetime risk of about 1.4% to only 2%-3%. We cannot hope to explain familial clustering of ovarian cancer through segregation of such a low penetrance trait.
Nevertheless, family histories of "many" of the ovarian cancer patients with NXCI are remarkable for an excess of breast and ovarian cancers. The number of such cases is not given, but implied is that a rare X-chromosome predisposition allele with high penetrance is associated with familial ovarian cancer. The pedigrees in Fig. 4 (1) are typical of the breast and ovarian cancer syndrome, the majority of which are linked to BRCA1 or BRCA2 (2). In Fig. 5, X-chromosome allelotype data are presented from three of the families shown in Fig. 4. In families 8 and 23, the allelotypes are informative for only one affected individual in each family. In family 15, the active X chromosome (which must contain the putative mutant tumor suppressor allele) is different for the two affected family members. The authors interpret this observation as evidence that "NXCI may play a complex role in some hereditary breast and ovarian cancer families," when, in fact, these data provide strong evidence that no X-linked ovarian cancer predisposition allele is segregating in this family. Additionally, family 15 demonstrates male to male transmission of the putative susceptibility trait, which is incompatible with X linkage.
Finally, nine of 11 ovarian cancer patients with a documented germline mutation of BRCA1 also have NXCI, implying genetic modification of BRCA1 penetrance by an X-chromosome predisposition allele. The data are not presented, although the title of the article suggests otherwise. To be observed in 80% of the BRCA1 carriers with ovarian cancer, a low-penetrance X-chromosome allele must occur at a high frequency in the population studied. The suggestion that "the association of NXCI with germline BRCA1 mutation could in part explain why there are increases in prostate cancer, and colon cancer in addition to breast and ovarian cancer in hereditary breast and ovarian cancer families" is without foundation.
Because we cannot accept that a model involving an X-linked tumor suppressor gene is a viable explanation for the observed association of NXCI with ovarian cancer, other explanations are sought. Postnatal alterations in lymphocyte X-inactivation patterns may result from cancer chemotherapy or aging. As Brown reminds us in an editorial (3), the apparent prevalence of NXCI increases with age, from 10% in neonates to more than 45% in elderly women. Borderline tumors occur at a generally younger age than invasive ovarian cancers, yet Buller et al. did not control for age differences in their analysis. Other possibilities include gene-specific methylation of the androgen receptor as a result of the aging process (4), in which case androgen receptor methylation as a surrogate for NXCI may be inappropriate, and alterations of DNA methylation with storage, which was not controlled for in this study.
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.
2 Narod SA, Ford D, Devilee P, Barkardottir RB, Eyfjord J, Lenoir G, et al. Genetic heterogeneity of breast-ovarian cancer revisited. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;57:957-8.[Medline]
3
Brown CJ. Skewed X-chromosome inactivation: cause or
consequence? J Natl Cancer Inst 1999;91:304-5.
4 Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP. Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 1998;58:5489-94.[Abstract]
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