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ABSTRACT

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.

Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study Boparai, K.S.; Mathus-Vliegen, E.M.H.; Koornstra, J.J.; Nagengast, F.M.; van Leerdam, M.; van Noesel, C.J.M.; Houben, M.; Cats, A.; van Hest, L.P.; Fockens, P.; Dekker, E. General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.

Dietary factors are considered important environmental risk determinants for colorectal cancer development. Epidemiological studies have shown that a high fat (or meat) intake is associated positively and a high starch, fibre (non-starch polysaccharide), vegetable and fruit intake negatively with colorectal cancer incidence. One mechanism by which these effects are possibly exerted is through the metabolism of secondary bile acids. Secondary bile acids are formed after enzymatic deconjugation and dehydroxylation of primary bile acids in the large bowel by anaerobic bacteria. It has been shown that these compounds can have tumour-promoting capacities in animal experiments. In epidemiological studies, colonic cancer risk is related to the faecal bile acid concentration. In serum and bile of patients with colonic adenomas, more deoxycholic acid was detected than in healthy controls. Secondary bile acids are toxic to several cell systems at physiological concentrations. The exact mechanism by which these amphiphilic molecules exert their action is not well understood. It might act through membrane damage, intracellular mitochondrial action or genotoxic effects. So far the evidence that bile acids are involved in colonic carcinogenesis is largely circumstantial. It is, however, well accepted that environmental factors, such as dietary habits influence genetic susceptibility. Bile acids could play a promoting role in this process.

Resistant starch is by definition that part of starch that escapes digestion in the small bowel. Cecal fermentation of resistant starch into short-chain fatty acids will result subsequently in a decrease in pH. Thus, resistant starch may have the same effect on colonic luminal contents and mucosa as some fiber components. We studied the effects of adding 45 g native amylomaize (Hylon-VII) to a standardized diet in 14 healthy volunteers on fermentation and colonic mucosal proliferation. Hylon-VII is a high amylose maize starch, containing 62% resistant starch. During amylomaize consumption, breath hydrogen excretion rose 85% and fecal short chain fatty acid output increased 35% (P < 0.01). Excretion of primary bile acids increased and the soluble deoxycholic acid concentration decreased by 50% (P = 0.002). Subsequently, cytotoxicity of the aqueous phase of feces--as measured on a colon cancer cell line--decreased (P = 0.007). Colonic mucosal proliferation in rectal biopsies (proliferating cell nuclear antigen immunostaining) decreased from 6.7 to 5.4% (P = 0.05). We speculate that resistant starch consumption decreases colonic mucosal proliferation as a result of the decreased formation of cytotoxic secondary bile acids, which is possibly mediated through acidification of the large bowel by production of short-chain fatty acids.

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