Lynch syndrome (LS) is caused by germline mutations in mismatch repair (MMR) genes, resulting in microsatellite-unstable tumours. Approximately 35% of suspected LS (sLS) patients test negative for germline MMR gene mutations, hampering conclusive LS diagnosis. The aim of this study was to investigate somatic MMR gene aberrations in microsatellite-unstable colorectal and endometrial cancers of sLS patients negative for germline MMR gene mutations. Suspected LS cases were selected from a retrospective Clinical Genetics Department diagnostic cohort and from a prospective multicentre population-based study on LS in The Netherlands. In total, microsatellite-unstable tumours of 40 sLS patients (male/female 20/20, median age 57 years) were screened for somatic MMR gene mutations by next-generation sequencing. In addition, loss of heterozygosity (LOH) of the affected MMR genes in these tumours as well as in 68 LS-associated tumours and 27 microsatellite-unstable tumours with MLH1 promoter hypermethylation was studied. Of the sLS cases, 5/40 (13%) tumours had two pathogenic somatic mutations and 16/40 (40%) tumours had a (likely) pathogenic mutation and LOH. Overall, LOH of the affected MMR gene locus was observed in 24/39 (62%) tumours with informative LOH markers. Of the LS cases and the tumours with MLH1 promoter hypermethylation, 39/61 (64%) and 2/21 (10%) tumours, respectively, demonstrated LOH. Half of microsatellite-unstable tumours of sLS patients without germline MMR gene mutations had two (likely) deleterious somatic MMR gene aberrations, indicating their sporadic origin. Therefore, we advocate adding somatic mutation and LOH analysis of the MMR genes to the molecular diagnostic workflow of LS.
Routine LS screening by analysis of microsatellite instability, immunohistochemistry, and MLH1 hypermethylation in CRC patients ≤70 years of age is a cost-effective strategy with important clinical benefits for CRC patients and their relatives.Genet Med 18 10, 966-973.
Crohn's disease and ulcerative colitis, also called chronic inflammatory bowel diseases (IBD), affect up to 500 per 100,000 persons in the Western world. Recent studies in the etiology of IBD suggest that these diseases are caused by a combination of genetic, environmental, and immunological factors. Results from humans and especially animal models of colitis reported by our group and others have indicated that these diseases result from a lack of tolerance to resident intestinal bacteria in genetically susceptible hosts. Probiotic bacteria have health-promoting effects for the host when ingested and have also shown efficacy in ulcerative colitis and refractory pouchitis. In light of the efficacy of providing probiotic bacteria to patients with IBD, there has been interest in the prophylactic and therapeutic potential of inulin, oligofructose, and other prebiotics for patients with or at risk of IBD. Prebiotics are nondigestible dietary oligosaccharides that affect the host by selectively stimulating growth, activity, or both of selective intestinal (probiotic) bacteria. Prebiotics are easy to administer and, in contrast to probiotic therapy, do not require administration of large amounts of (live) bacteria and are therefore easier to administer. Studies using prebiotics, especially beta-fructan oligosaccharides, for the treatment of chronic intestinal inflammation have shown benefit in animal models of colitis. Studies using these prebiotics alone or in combination with probiotics are emerging and have shown promise. These dietary therapies could lead to novel treatments for these chronic debilitating diseases.
Although early detection of Lynch syndrome (LS) is important, a considerable proportion of patients with LS remains unrecognized. We aimed to study the yield of LS detection by routine molecular analyses in colorectal cancer (CRC) patients until 70 years of age. We prospectively included consecutive CRC patients ≤70 years. Tumour specimens were analysed for microsatellite instability (MSI), immunohistochemical mismatch-repair protein expression and MLH1-promoter methylation. Tumours were classified as either: (a) likely caused by LS; (b) sporadic microsatellite-unstable (MSI-H); or (c) microsatellite-stable (MSS). Predictors of LS were determined by multivariable logistic regression. A total of 1117 CRC patients (57% males, median age 61 years) were included. Fifty patients (4.5%, 95% CI 3.4-5.9) were likely to have LS, and 71 had a sporadic MSI-H tumour (6.4%, 95% CI 5.1-8.0). Thirty-five patients likely to have LS (70%) were aged > 50 years. A molecular profile compatible with LS was detected in 10% (15/144) of patients aged ≤50, in 4% (15/377) of those aged 51-60 and in 3% (20/596) of patients > 61 years. Compared to MSS cases, patients likely to have LS were significantly younger (OR 3.9, 95% CI 1.7-8.7) and more often had right-sided CRCs (OR 14, 95% CI 6.0-34). In conclusion, molecular screening for LS in CRC patients ≤70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age criterion (≤50 years) routinely used for LS assessment. Routine use of MSI testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients.
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