Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers

Abstract

Chromosome deletions are the most common genetic events observed in cancer. These deletions are generally thought to reflect the existence of a tumour suppressor gene within the lost region. However, when the lost region does not precisely coincide with a hereditary cancer locus, identification of the putative tumour suppressor gene (target of the deletion) can be problematic. For example, previous studies have demonstrated that chromosome 18q is lost in over 60% of colorectal as well as in other cancers, but the lost region could not be precisely determined. Here we present a rigorous strategy for mapping and evaluating allelic deletions in sporadic tumours, and apply it to the evaluation of chromosome 18 in colorectal cancers. Using this approach, we define a minimally lost region (MLR) on chromosome 18q21, which contains at least two candidate tumour suppressor genes, DPC4 and DCC. The analysis further suggested genetic heterogeneity, with DPC4 the deletion target in up to a third of the cases and DCC or a neighbouring gene the target in the remaining tumours.

Blockade of Smad4 in transformed keratinocytes containing a Ras oncogene leads to hyperactivation of the Ras-dependent Erk signalling pathway associated with progression to undifferentiated carcinomas

“…Pancreatic adenocarcinomas exhibit the highest rate of activating Ras (K-Ras) mutations found in human tumours with a frequency above 90% (Almoguera et al, 1988;Rozenblum et al, 1997), and about 50% of carcinomas have inactivated Smad4 (DPC4) (Hahn and Schmiegel, Rozenblum et al, 1997). These frequencies are lower in colon carcinomas with approximately 50% of the tumours containing mutations in K-Ras (Bos et al, 1987;Burmer et al, 1990) and about 15% loss of Smad4 (DPC4) (MacGrogan et al, 1997;Thiagalingam et al, 1996). It would be of clinical interest to analyse whether the combination of an oncogenic Ras mutation (an early event in carcinogenesis) and inactivated Smad4 suppressor genes (a late event) is a prognostic factor for the development of more malignant undi erentiated carcinomas.…”

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

“…Mutation of this partially buried arginine residue may have an e ect on the local structure, but may leave the global structure of the amino-terminal domain intact . P130S in Smad4 was identi®ed in colorectal cancer (Thiagalingam et al, 1996). This proline residue is completely buried and found in all R-and Co-Smads; mutation of this residue to a polar serine residue may have a signi®cant e ect of amino-terminal domain global structure Figure 1).…”

Induction of apoptosis and G2/M cell cycle arrest by DCC

“…Deduced amino acid sequence shows a high homology with the neural cell adhesion molecule (N-CAM) and other related cell surface glycoproteins of the Ig superfamily (Fearon et al, 1990;Cho et al, 1994). Frequent loss of heterozygosity at the DCC locus and loss of DCC expression have been observed in human colon (Fearon et al, 1990;Thiagalingam et al, 1996) and prostate carcinomas (Gao et al, 1993) as well as in pancreatic, gastric, esophageal, bladder, breast, head and neck carcinomas and male germ cell tumors, neuroblastoma, glioma, hematologic malignancy (Fearon, 1996, references therein). These results suggest that inactivation of the DCC gene may be involved in the development of human cancers.…”

“…Because of this close proximity and the uncertainty of DCC function, there was a question whether DPC4 rather than DCC is the tumor suppressor gene that is inactivated in colon carcinoma cells. In order to address this question, the loss of heterozygosity at 18q has been re-evaluated in colon tumor samples (Thiagalingam et al, 1996). The results suggest that the DCC, but not the DPC4, is the most frequently altered gene on chromosome 18q13.…”