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      Integrated genomic characterization of endometrial carcinoma

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          Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

          Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations.
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            Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death.

            The t(14; 18) chromosomal translocation of human follicular B-cell lymphoma juxtaposes the bcl-2 gene with the immunoglobulin heavy chain locus. The bcl-2 immunoglobulin fusion gene is markedly deregulated resulting in inappropriately elevated levels of bcl-2 RNA and protein. Transgenic mice bearing a bcl-2 immunoglobulin minigene demonstrate a polyclonal expansion of resting yet responsive IgM-IgD B cells which display prolonged cell survival but no increase in cell cycling. Moreover, deregulated bcl-2 extends the survival of certain haematopoietic cell lines following growth-factor deprivation. By using immunolocalization studies we now demonstrate that Bcl-2 is an integral inner mitochondrial membrane protein of relative molecular mass 25,000 (25k). Overexpression of Bcl-2 blocks the apoptotic death of a pro-B-lymphocyte cell line. Thus, Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and interfering with programmed cell death independent of promoting cell division.
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              CpG island methylator phenotype in colorectal cancer.

              Aberrant methylation of promoter region CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia. To understand global patterns of CpG island methylation in colorectal cancer, we have used a recently developed technique called methylated CpG island amplification to examine 30 newly cloned differentially methylated DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-dependent manner in normal colon, 7 (23%) were methylated in a cancer-specific manner, and 4 (13%) were methylated only in cell lines. Thus, a majority of CpG islands methylated in colon cancer are also methylated in a subset of normal colonic cells during the process of aging. In contrast, methylation of the cancer-specific clones was found exclusively in a subset of colorectal cancers, which appear to display a CpG island methylator phenotype (CIMP). CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation. We thus define a pathway in colorectal cancer that appears to be responsible for the majority of sporadic tumors with mismatch repair deficiency.
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                10.1038/nature12113

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