A reciprocal, balanced, constitutional chromosome translocation, t(2;3)(q33;q21), which is associated with familial clear cell renal cancer, has been described and the genomic regions surrounding the 2q and 3q breakpoints have been characterized. Based on the genomic map of the 2q break, EST AI468595 was positioned near the 2q33 translocation and the full-length gene and cDNA were isolated. This 57-kb gene, designated the DIRC1 gene, was disrupted between exons 1 and 2 by the familial translocation. The 1.5-kb mRNA encodes an 11-kDa predicted protein of 104 amino acids. Low-level expression of DIRC1 was detected by reverse transcriptase-polymerase chain reaction amplification in adult placenta, testis, ovary, and prostate and in fetal kidney, spleen, and skeletal muscle. A GFP-Dirc1 fusion protein was expressed in vitro and a polyclonal anti-Dirc1 peptide serum was prepared. A panel of cancer and cancer-derived cell line DNAs was examined for DIRC1 mutations, but only a rare polymorphism was observed. Two familial tumors showed loss of the derivative 3 chromosome, as observed in a Dutch kindred with t(2;3)-associated renal cancers. Mutations in the second DIRC1 allele were not detected. Further studies will be required to determine if disruption of the DIRC1 gene contributed to development of the associated familial clear cell renal cancers.

A Polish family was identified in which multifocal clear cell renal carcinoma segregated with a balanced constitutional chromosome translocation, t(2;3)(q33;q21), similar to the renal cell cancer-associated t(2;3)(q35;q21) reported in a Dutch family. Bacterial artificial chromosome (BAC) contigs encompassing the 2q and 3q breakpoints were constructed and BACs crossing the breakpoints were partially sequenced. All known regional markers, genes, and expressed sequence tags (ESTs) were mapped relative to the contigs, as well as to the breakpoint sequences. Two single ESTs mapped within the 2q breakpoint BAC, whereas the repeat-rich 3q breakpoint region was gene poor. Physical mapping suggested that the 3q break was in 3q13, possibly near the border with 3q21. Physical mapping illustrated that the 2q break was closely telomeric to the 2q31 FRA2G site, consistent with the G-band assignment. Characterization of full-length cDNAs for the ESTs near the 2q break will determine if a gene(s) is altered by this familial translocation.

Deletions of the short arm of chromosome 3 (3p) have been recognized as characteristic features of clear cell renal cell carcinomas (clear cell RCC). We analysed 55 clear-cell RCCs and 30 non-clear-cell kidney tumours (10 papillary and 7 chromophobic RCCs, 11 oncocytomas and 2 collecting duct carcinomas) in loss of heterozygosity (LOH) studies using microsatellite markers for previously observed regions of common deletions on 3p in kidney tumours (3p25, 3p21.3, 3p14.2 and 3p12-13). Alterations were found in all 55 cases of clear-cell RCCs at two to four of the 3p regions. Extensive losses were not found in non-clear-cell tumours except for collecting duct carcinomas; 1 of 10 papillary RCCs showed interstitial deletion limited to a single 3p21.3 locus. LOH analyses using microsatellite markers for regions of common deletions at 3p may be of value in differential diagnosis of kidney tumours.

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