Showing papers by "Eric R. Fearon published in 1995"

Molecular Genetics of Colorectal Cancer

Abstract: Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes—most prominently the APC, KRAS, and p53 genes—are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target protein...

Frequent alterations in e-cadherin and alpha - and beta -catenin expression in human breast cancer cell lines

Abstract: Alterations in intercellular junction and membrane cytoskeletal proteins may underlie some of the morphological, invasive and metastatic properties of cancer. E-cadherin, a transmembrane protein that functions in epithelial cell-cell interactions at adherens junctions, is linked to the membrane cytoskeletal matrix through interactions with alpha- and beta-catenin. We have carried out studies of E-cadherin and alpha- and beta-catenin in 18 breast cancer cell lines to determine the prevalence and nature of alterations in these genes in breast cancer. Ten lines failed to express E-cadherin protein at detectable levels and seven failed to produce detectable levels of E-cadherin transcripts. In a line lacking E-cadherin expression (SK-BR-3) a homozygous deletion of a large portion of the E-cadherin gene was noted. Localized sequence alterations in E-cadherin transcripts were not identified in any lines. In contrast to the results of a previous study, no relationship was identified between E-cadherin expression and HER-2/NEU expression. Two of the 18 lines had no detectable alpha-catenin protein and six others had reduced levels. The two lines lacking alpha-catenin protein had reduced or undetectable levels of alpha-catenin transcripts, while no consistent changes in alpha-catenin transcript levels were seen in the lines with reduced, but detectable, levels of alpha-catenin protein. Similarly, although two lines lacked beta-catenin protein, in most lines the levels of beta-catenin transcripts and protein were not well correlated with one another. Our findings suggest that alterations in E-cadherin and alpha- and beta-catenin expression are frequent in human breast cancer-derived cell lines, and that in some cases the decreased expression may result from mutations in the genes. Furthermore, the frequent alterations in the expression of these proteins argue that loss of function in the E-cadherin-catenin pathway may be critical in the development of many breast cancers.

DCC expression is altered by multiple mechanisms in brain tumours

Abstract: The DCC (deleted in colorectal cancer) candidate tumor suppressor gene spans greater than 1350 kilobases at chromosomes 18q21.1 and encodes a transmembrane protein of unknown function. Although DCC is expressed in a number of adult tissues, its expression is highest in the brain and we have, therefore, undertaken studies to determine if DCC inactivation might contribute to tumors arising there. Decreased or absent DCC protein expression was noted in more than 50% of the thirty brain tumors studied. Although specific mutations in the DCC gene were not identified, a variety of mechanisms appeared to contribute to the altered DCC expression, including allelic loss, aberrant splicing of transcripts and allele-specific loss of transcripts. In total, the data suggest that DCC inactivation may be important in brain tumor pathogenesis.

Diagnostic method detecting loss of wild-type p53

Abstract: Methods and kits are provided for assessing mutations and/or loss of the p53 gene in human tumors. Both deletion mutations and point mutations in p53 are observed in the same human tumor cells and these mutations are clonal within the cells of the tumor. Loss of wild-type p53 genes is responsible for neoplastic progression.