Re: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.

Hereditary breast and ovarian cancers are associated mainly with the inactivation of BRCA1 or BRCA2 tumor suppressor genes, but sporadic forms have also been associated with alterations in these genes (1). DNA microarrays (2) have the potential to reveal the complex mechanisms of oncogenesis. Jazaeri et al. (3) show that gene expression profiles of ovarian tumors are distinct between BRCA1and BRCA2-linked forms and allow segregation of sporadic samples into two subgroups, BRCA1like and BRCA2-like. This segregation suggests that the BRCA-associated molecular pathways are different at the RNA level for the two genes and may be altered in a similar way in sporadic tumors. This discovery could have a major impact on our understanding of oncogenesis. However, certain study design problems may limit the strength of the conclusion. First, the labeling of sporadic cases was based on a negative test for only three founder mutations. The high prevalence of hereditary cancers among the tested population (Ashkenazi Jews) or the presence of other types of mutations or missed mutations could make the panel of so-called sporadic samples a mixture of BRCA-associated samples and true sporadic samples. Information about the patient’s family history of ovarian cancer would increase the probability that samples analyzed as such are indeed sporadic. Second, a larger number of sporadic forms could strengthen the validity of the results by allowing the demonstration of more heterogeneity in the expression profiles. Third, the separation of BRCA1and BRCA2-linked tumors and the absence of a third intermediary subgroup suggest that one of the two gene pathways should be active in the subgroup where the other is inactivated, as reported (4). However, the distinction is not exclusive because ovarian cancer has been diagnosed in women with both 185delAG (BRCA1) and 6174delT (BRCA2) germline mutations (5). The analysis of the expression level of BRCA1 in Jazaeri’s BRCA2-linked samples and the converse could clarify this point. In both breast and ovarian tumors, the BRCA pathways seem to be major targets of carcinogenesis, but their roles remain unclear, notably in sporadic forms. Hedenfalk et al. (6) have previously compared gene expression profiles of hereditary and sporadic breast cancers. Sporadic cancers were not included in the BRCA-linked subgroups, but such an inclusion appears compatible with the pattern obtained. We wondered whether the gene expression patterns that were used to discriminate between BRCA1 and BRCA2 tumors are different or similar in breast and ovarian tissue. Comparison of the two lists of discriminator genes (3,6) identified five common genes (Table 1): three were systematically overexpressed in BRCA1-mutated tumors compared with BRCA2-mutated tumors, one was systematically overexpressed in BRCA2mutated tumors, and the last one was overexpressed in BRCA1-mutated breast tumors and in BRCA2-mutated ovarian tumors. The experimental designs (different patients and mutations and different gene sets and technologies) make any conclusion difficult. Because of the high number of patients with hereditary forms who develop both breast and ovarian tumors, we think that an alternative approach would be to simultaneously examine breast and ovarian tumors from the same patient. This model may be one of the best models to use to solve the puzzle of the “similarity or difference” of the molecular basis between hereditary and sporadic cancers, a clinically relevant question that could be particularly helpTable 1. Discriminator genes between BRCA1-mutated and BRCA2-mutated tumors common to ovarian and breast cancers*