Recent studies have suggested the existence of a tumor suppressor gene located at chromosome region 5q21. DNA probes from this region were used to study a panel of sporadic colorectal carcinomas. One of these probes, cosmid 5.71, detected a somatically rearranged restriction fragment in the DNA from a single tumor. Further analysis of the 5.71 cosmid revealed two regions that were highly conserved in rodent DNA. These sequences were used to identify a gene, MCC ( m utated in c olorectal c ancer), which encodes an 829-amino acid protein with a short region of similarity to the G protein-coupled m3 muscarinic acetylcholine receptor. The rearrangement in the tumor disrupted the coding region of the MCC gene. Moreover, two colorectal tumors were found with somatically acquired point mutations in MCC that resulted in amino acid substitutions. MCC is thus a candidate for the putative colorectal tumor suppressor gene located at 5q21. Further studies will be required to determine whether the gene is mutated in other sporadic tumors or in the germ line of patients with an inherited predisposition to colonic tumorigenesis.

BRCA1, a breast and ovarian cancer susceptibility locus, has been isolated and maps to 17q21. A physical map of the BRCA1 region which extended from the proximal boundary at D17S776 to the distal boundary at D17S78 was constructed and consists of 51 sequence tagged sites (STSs) from P1 and YAC ends, nine new short-tandem repeat (STR) polymorphic markers, and eight identified genes. The contig, which spans the estimated 2.3 Mb region, contains 29 P1s, 11 YACs, two BACs, and one cosmid. Based on key recombinants in two linked families, BRCA1 was further localized to a region bounded by D17S1321 on the proximal side and D17S1325 on the distal side. Within this estimated 600 kb region, the contig was composed completely of P1s and BACs ordered by STS-content mapping and confirmed by DNA restriction fragment fingerprinting.

We have isolated a novel human gene that is expressed specifically in primary spermatocytes in the testis. The cDNA contains an open reading frame of 1356 bp, encoding a 452-amino-acid protein that includes a basic Helix-Loop-Helix (bHLH) motif. The gene, which was mapped to chromosome region 20q13.3→qter by fluorescence in situ hybridization, consists of six exons and spans approximately 24 kb of genomic DNA. Immunohistochemical staining located the gene product exclusively in cell nuclei of primary spermatocytes at the pachytene stage, but not in those at the leptonema stage. We named this gene TCFL5 (transcription factor-like 5, basic helix-loop-helix). The cell-type and stage-specific expression of TCFL5 indicates that this protein may function in a crucial role in spermatogenesis as a transcription factor by regulating cell proliferation or differentiation of cells through binding to a specific DNA sequence like other bHLH molecules.

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Familial adenomatous polyposis (FAP), which includes familial polyposis coli (FPC) and the Gardner syndrome (GS), is a genetically determined premalignant disease of the colon inherited by a locus (APC) mapping within 5q15-q22. To elucidate the role of 5q loss in FAP tumorigenesis, we analysed 51 colorectal tumors and seven desmoids from 19 cases of FPC and five GS patients, as well as 15 sporadic colon cancers. RFLP analysis revealed a high incidence of allelic deletion in hereditary colon cancers as well as in sporadic colon cancers with a peak at the APC locus. APC loss resulted primarily from interstitial deletion or mitotic recombination. Combined tumor and pedigree analysis in a GS family revealed loss of normal 5q alleles in three tumors, including a desmoid tumor, which suggests the involvement of hemizygosity or homozygosity of the defective APC gene in colon carcinogenesis and, possibly, in extracolonic neoplasms associated with FAP.