Identification of a Chromosome 18q Gene that Is Altered in Colorectal Cancers

Abstract

Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

“…14 Three candidate tumor-suppressor genes have been identified in this region: DCC, Smad4/DPC4 and Smad2/MADR2/JV18-1. 20,21,23 The Smad4/DPC4 gene is homozygously mutated in portions of both exocrine and endocrine D1S1612 D6S1281 D12S374 D18S481 D1S552 GATA163B10 D12S391 D18S843 D1S1622 FA3A1 D12S373 D18S877 D1S551 D6S1053 D12S1042 D18S851 D1S1589 D6S1009 PAH D18S858 D1S549 D6S1003 D12S395 D18S64 D6S1277 GATA32F05 D18S541 GATA165C07 D18S844 D2S1356 D7S513 D13S317 D2S1394 D7S1802 D13S173 D19S247 D2S1649 GATA137H0...…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…DCC was discovered in 1990 as a putative cell-surface receptor encoded by a gene frequently deleted through allelic loss in colorectal carcinoma (Fearon et al, 1990). Observation that DCC expression is reduced or lost in colorectal cancer led to the proposal that DCC expression represented a constraint for disease progression and is therefore a tumor suppressor.…”

“…Located on chromosome 18q, DCC is submitted to loss of heterozygosity in over 70% of colorectal cancers (Fearon et al, 1990). DCC is also submitted to loss of heterozygosity and/or to decreased expression in various other cancers including gastric, prostate, endometrial, ovarian, esophageal, breast and testicular cancer, as well as neuroblastoma and hematological malignancies (Mehlen and Fearon, 2004).…”

Colorectal carcinoma in Hong Kong: epidemiology and genetic mutations

“…Most tumours have acquired (non-germline) inactivating mutations in adenomatous polyposis coli (APC) (Ashton Rickardt et al, 1989;Nishisho et al, 1991;Powell et al, 1992); activating mutations in the Ki-ras oncogene are present in about 40% of carcinomas (Bos et al, 1987;Forrester et al, 1987); and mutations in the p53 and 'deleted in colon carcinoma' (DCC) oncosuppressor genes are found in 70-80% of carcinomas (Vogelstein et al, 1988;Baker et al, 1989;Vogelstein et al, 1989;Baker et al, 1990;Fearon et al, 1990;Hollsetein et al, 1991). Moreover, although most cancers arise in patients over the age of 50 years, some are diagnosed substantially earlier, and in such younger patients there is often evidence for inherited susceptibility to the disease.…”