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The Eker rat hereditary renal carcinoma is an excellent example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis ( TSC2) gene gives rise to the dominantly inherited cancer in the Eker rat model. The function of the TSC2/Tsc2 gene product (called 'tuberine' in the human case) is not yet understood, although it contains a short amino acid sequence homologous to the ras family GTPase-activating proteins (GAP3). In the study, we isolated subtracted cDNA clones having increased expression in eker renal carcinoma cells, using a modified representational difference analysis method to search for additional genes specifically involved in renal carcinogenesis. Here we identified four genes: the third component of the complement (C3) gene, the fos-related antigen 1 ( fra-1) gene, an unknown gene (designated as being expressed in renal carcinoma: erc) and the calpactine I heavy-chain (Annexin II) gene. [ABSTRACT FROM AUTHOR]

Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls (p = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and BRCA1-characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic BRCA1-mutation. Our findings add to the current knowledge of BRCA1, and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling. [ABSTRACT FROM AUTHOR]