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      Integrated Genomic Characterization of Endometrial Carcinoma

      The Cancer Genome Atlas Research Network

      Nature

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          Summary

          We performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors.

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          Most cited references 32

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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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              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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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                5 June 2013
                2 May 2013
                02 November 2013
                : 497
                : 7447
                : 67-73
                Author notes
                Correspondence and requests for materials should be addressed to D. Levine ( levine2@ 123456mskcc.org )
                Article
                NIHMS458933
                10.1038/nature12113
                3704730
                23636398

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U54 HG003273 || HG
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U54 HG003079 || HG
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U54 HG003067 || HG
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA144025 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143883 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143882 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143867 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143866 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143858 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143848 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143845 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143843 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143840 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143835 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA143799 || CA
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