X-linked genes in breast and ovarian cancer etiology

Basic Sciences

Investigators

Abstract

A number of recent observations suggest that X-linked genes may play some role in the observed organ distribution of cancer in BRCA1/2 mutation carriers. Although certainly not unique to these organs, ovarian and breast cancer tumors show LOH on several segments of the X chromosome. In a recent study of mRNA expression profiles of ovarian cancer, comparing tumors in BRCA1 or BRCA2 heterozygous mutation carriers with sporadic ovarian cancers, three of the top nine genes whose expression discriminates BRCA1 from sporadic ovarian cancers are in a small segment of Xp11.23. And the very recent publication of the finding that the BRCA1 protein interacts with XIST, the RNA responsible for initiating X-inactivation in females shines a new light on two earlier, small studies suggesting that women with ovarian cancer and early-onset breast cancer have higher rates of skewed X-inactivation compared to controls. If BRCA1 is involved in the establishment or maintenance of X-inactivation, the mechanism that humans have for dosage compensation (since males have only one X-chromosome), alterations of this process may lead to de novo problems with expression of X-linked genes, or secondarily to clonal expansion of cells expressing a particular allele of an X-linked gene that conveys a growth advantage. We plan to analyze X-linked genes for methylation and allele-specific expression differences in fresh tumors and tumor cell lines, and to compare the expression of X-linked transcripts in lymphoblastoid cell lines from individuals heterozygous for BRCA1 mutations.