Disease relevance of Colorectal Neoplasms, Hereditary Nonpolyposis

• METHODS: We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer [1].
• We have identified the source of the genetic instability in one ovarian tumor as a point mutation (R524P) in the human mismatch-repair gene MSH2 (Salmonella MutS homologue), which has recently been shown to be involved in hereditary nonpolyposis colorectal cancer [2].
• Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b transcripts may modify the age at onset of colon cancer in hereditary nonpolyposis colorectal cancer [3].
• Limiting genetic evaluation to women with synchronous endometrial and ovarian cancer who have a family history suggestive of HNPCC may appropriately identify women with Lynch syndrome [4].
• We evaluated patients (i) with a history of sporadic CRC at least 3 months after surgery, (ii) who were hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers, and (iii) with familial adenomatous polyposis (FAP) [5].

High impact information on Colorectal Neoplasms, Hereditary Nonpolyposis

• A role for MLH3 in hereditary nonpolyposis colorectal cancer [6].
• We investigated a possible role of the mismatch-repair gene MLH3 in hereditary nonpolyposis colorectal cancer by scanning for mutations in 39 HNPCC families and in 288 patients suspected of having HNPCC [6].
• Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer [7].
• Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome) [8].
• Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms [9].

Chemical compound and disease context of Colorectal Neoplasms, Hereditary Nonpolyposis

• The purposes of this study were to determine the association, in 10 pedigrees, between adenomatous polyposis coli, hereditary nonpolyposis colorectal cancer, and occult radiopaque jaw lesions, and to assess whether these radiodensities are predictors for adenomatous polyposis [10].
• Surprisingly, three patients with the highest 5-methylcytosine content in their normal colon appear to have a germline predisposition to cancer (Lynch syndrome) [11].
• Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design [12].
• Although an increased inherent predisposition of the patient to exhibit those neoplasms, similar to Lynch syndrome II, is to be discussed, her previous treatments with cyclophosphamide and external radiotherapy are likely to explain at least the occurrence of urothelial cancer [13].

Biological context of Colorectal Neoplasms, Hereditary Nonpolyposis

• CONTEXT: Germline mutations of the DNA mismatch repair (MMR) genes hMLH1 and hMSH2 have been shown to cosegregate with the colorectal cancer phenotype in multiple hereditary nonpolyposis colorectal cancer (HNPCC) pedigrees [14].
• Two susceptibility loci for hereditary nonpolyposis colorectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p [15].
• We have used denaturing gradient gel electrophoresis to analyze the 19 exons and exon-intron borders of hMLH1 in 39 Swedish hereditary nonpolyposis colorectal cancer families [16].
• One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC [17].
• We exploited a fortuitous experiment of nature to directly test this hypothesis: the TGF-beta type II receptor gene is inactivated by mutation in nearly all colorectal carcinomas having microsatellite instability, as seen in hereditary nonpolyposis colorectal cancer (HNPCC) and in sporadic medullary colorectal cancers [18].

Anatomical context of Colorectal Neoplasms, Hereditary Nonpolyposis

• Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD) [19].
• BACKGROUND: Carcinomas of the small intestine are rare, but the risk is greatly increased in patients with hereditary nonpolyposis colorectal cancer (HNPCC) due to an inherited mismatch repair (MMR) gene mutation, most commonly affecting the genes MLH1 or MSH2 [20].

Gene context of Colorectal Neoplasms, Hereditary Nonpolyposis

• We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing [1].
• Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer [21].
• The MSH6 gene is one of the mismatch-repair genes involved in hereditary nonpolyposis colorectal cancer (HNPCC) [22].
• Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome [23].
• BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer [24].

Analytical, diagnostic and therapeutic context of Colorectal Neoplasms, Hereditary Nonpolyposis

• Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer [25].
• As a result, it has been difficult to develop rationally designed dietary intervention studies in first-degree relatives of patients with established familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and other familial colon cancer syndromes [26].

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