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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary colorectal cancer syndromes are classified according to the presence of unusually large number of adenomatous or hamartomatous polyps, or their absence. The latter category includes hereditary non-polyposis colorectal cancer (Lynch syndrome) and its variants Muir-Torre and Turcot's syndromes. Adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and its variants, and the recently identified MYH- (mutY homolog)-associated polyposis. Hamartomatous polyposis syndromes include juvenile polyposis, Peutz-Jeghers syndrome, and Cowden syndrome, which is now included within the broader category 'PTEN (phosphatase and tensin homolog) hamartoma tumour syndrome'. Other syndromes such as the 'hereditary breast and colon cancer' and 'familial colorectal cancer' are not yet fully characterized. This review addresses the molecular basis of these syndromes with particular reference to the recent advances in this rapidly progressive field and the applications of such knowledge in diagnosis and management.
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PMID:Molecular basis and diagnostics of hereditary colorectal cancers. 1547 12

Genetic instability is known to drive colorectal carcinogenesis. Generally, a distinction is made between two types of genetic instability: chromosomal instability (CIN) and microsatellite instability (MIN or MSI). Most CIN tumours are aneuploid, whereas MSI tumours are considered near-diploid. However, for MUTYH-associated polyposis (MAP) the genetic instability involved in the carcinogenesis remains unclear, as near-diploid adenomas, aneuploid adenomas and near-diploid carcinomas have been reported. Remarkably, our analysis of 26 MAP carcinomas, using SNP arrays and flow sorting, showed that these tumours are often near-diploid (52%) and mainly contain chromosomal regions of copy-neutral loss of heterozygosity (LOH) (71%). This is in contrast to sporadic colon cancer, where physical loss is the main characteristic. The percentage of chromosomal gains (24%) is comparable to sporadic colorectal cancers with CIN. Furthermore, we verified our scoring of copy-neutral LOH versus physical loss in MAP carcinomas by two methods: fluorescence in situ hybridization, and LOH analysis using polymorphic markers on carcinoma fractions purified by flow sorting. The results presented in this study suggest that copy-neutral LOH is an important mechanism in the tumorigenesis of MAP.
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PMID:High frequency of copy-neutral LOH in MUTYH-associated polyposis carcinomas. 1850 5

Between 2% to 5% of all colon cancers arise in the setting of well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines.
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PMID:Hereditary and familial colon cancer. 2042 Sep 45

We describe a patient with MUTYH-associated polyposis diagnosed with colon cancer at 33 years of age, as well as gastric polyps at a later age. She was also diagnosed with papillary thyroid cancer at age 35. MUTYH-associated polyposis is an autosomal recessively inherited disease which has clinical overlap with Familial adenomatous polyposis and its attenuated form, in that it is associated with risk of colon cancer at a young age. Extra-intestinal cancers have also been reported in patients with MUTYH-associated polyposis; however the tumor spectrum is still evolving. National Comprehensive Cancer Network guidelines recommend screening for colon, duodenal and gastric polyps in individuals with MUTYH-associated polyposis. Screening for extra-intestinal cancers i.e. thyroid cancer is presently not part of these recommendations. These will likely continue to evolve as the MUTYH-associated polyposis tumor spectrum is better understood as a result of future case reports and research.
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PMID:Papillary thyroid cancer in a patient with MUTYH-associated polyposis (MAP). 2062 37

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.
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PMID:Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. 2117 Oct 15

Advances in molecular biology have defined the molecular basis for colorectal cancer (CRC). Though only a fraction of CRC has been determined to have a hereditary component, the discovery of genetic alterations in these clinical syndromes has permitted definition of similar discoveries in sporadic CRC. Here we will delineate the molecular basis for the most common of these defined syndromes, including familial adenomatous polyposis, hereditary non-polyposis colon cancer, MUTYH associated polyposis, Juvenile polyposis, Peutz-Jeghers syndrome, and Cowden's syndrome. The newest paradigm with implications for the pathogenesis of sporadic CRC is called the cancer stem cell hypothesis. As this paradigm also implicates aberrations in molecular pathways, a brief discussion of this hypothesis is included.
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PMID:MOLECULAR BASIS OF HEREDITARY COLORECTAL CANCER. 2177 43

Colon cancer is associated with a family history in up to 25% of cases. As many as 5% are associated with an established hereditary syndrome, demonstrating the profound influence of inheritable genetic mechanisms in the development of this disease. These syndromes confer a diverse spectrum of risk, age of presentation, endoscopic and histological findings, extracolonic manifestations, and modes of inheritance. As the molecular characteristics of these disorders become better described, enhanced genotype-phenotype correlations may offer a more targeted approach to diagnosis, screening, and surveillance. While the strategies for diagnosis and management of familial adenomatous polyposis (FAP) and Lynch syndrome are more established, the approach to newly recognized syndromes such as MUTYH-associated polyposis (MAP) and hyperplastic polyposis syndromes continues to evolve. Effective cancer prevention in affected individuals and at-risk family members first requires timely recognition of these hereditary colon cancer syndromes followed by integration of genetic testing and clinical examinations.
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PMID:Hereditary colon cancer syndromes. 2181 May 8

Base excision repair is the system used from bacteria to man to remove the tens of thousands of endogenous DNA damages produced daily in each human cell. Base excision repair is required for normal mammalian development and defects have been associated with neurological disorders and cancer. In this paper we provide an overview of short patch base excision repair in humans and summarize current knowledge of defects in base excision repair in mouse models and functional studies on short patch base excision repair germ line polymorphisms and their relationship to cancer. The biallelic germ line mutations that result in MUTYH-associated colon cancer are also discussed.
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PMID:Base excision repair and cancer. 2225 18

Mutational loss of the human DNA repair gene MUTYH in the germline predisposes for colorectal polyposis and cancer, a recessively heritable disease called MUTYH-associated polyposis. The MUTYH gene shows heavy alternative splicing, but the transcripts relevant for biological function and cancer prevention have not been determined. This knowledge is required to assess the consequences that germline variants of unknown functional significance may have. We therefore quantified expression and investigated patterns of alternative splicing in control individuals, tissue samples, and carriers of two frequent germline alterations. MUTYH expression differed organ dependently, correlating with proliferative activity. Alternative first exons were used tissue specifically; transcripts for mitochondrial proteins predominated in muscle tissues, while ascending colon and testes showed the highest fractions of transcripts for nuclear proteins. Colon cancer cell lines produced predominant transcripts for nuclear protein. Exon skipping was frequent and governed by splice-site quality. Five transcripts were found to encode the biologically relevant products of the MUTYH gene. Carriers of the disease-causing mutation c.1187G>A (p.Gly396Asp) showed normal transcript composition, but the frequent single-nucleotide polymorphism rs3219468:G>C largely reduced one transcript species of MUTYH. Since this alteration decreases protein production of the gene, an increased cancer risk for compound heterozygous carriers is possible.
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PMID:MUTYH gene expression and alternative splicing in controls and polyposis patients. 2247 53

Lynch syndrome (hereditary nonpolyposis colon cancer) and adenomatous polyposis syndromes frequently have overlapping clinical features. Current approaches for molecular genetic testing are often stepwise, taking a best-candidate gene approach with testing of additional genes if initial results are negative. We report a comprehensive assay called ColoSeq that detects all classes of mutations in Lynch and polyposis syndrome genes using targeted capture and massively parallel next-generation sequencing on the Illumina HiSeq2000 instrument. In blinded specimens and colon cancer cell lines with defined mutations, ColoSeq correctly identified 28/28 (100%) pathogenic mutations in MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH, including single nucleotide variants (SNVs), small insertions and deletions, and large copy number variants. There was 100% reproducibility of detection mutation between independent runs. The assay correctly identified 222 of 224 heterozygous SNVs (99.4%) in HapMap samples, demonstrating high sensitivity of calling all variants across each captured gene. Average coverage was greater than 320 reads per base pair when the maximum of 96 index samples with barcodes were pooled. In a specificity study of 19 control patients without cancer from different ethnic backgrounds, we did not find any pathogenic mutations but detected two variants of uncertain significance. ColoSeq offers a powerful, cost-effective means of genetic testing for Lynch and polyposis syndromes that eliminates the need for stepwise testing and multiple follow-up clinical visits.
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PMID:ColoSeq provides comprehensive lynch and polyposis syndrome mutational analysis using massively parallel sequencing. 2265 18


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