Diet, lifestyle, and molecular alterations that drive colorectal carcinogenesis

Environmental factors have been repeatedly implicated in the etiology of colorectal cancer, and much is known about the molecular events involved in colorectal carcinogenesis. The relationships between environmental risk factors and the molecular alterations that drive colorectal carcinogenesis are less dear. Further insight into these relationships may prove useful for the development of etfective colorectal cancer prevention and/or treatment strategies. In this thesis, we examine associations between dietary and lifestyle factors previously reported to be associated with colorectal cancer risk and the molecular alterations known to play important roles in colorectal carcinogenesis.Data from a case-control study of sporadic colorectal polyps (278 cases; 414 polyp-free controls) were used to evaluate associations between dietary factors and truncating APC mutations in adenomas. High intake of red meat and fat seemed to increase the risk of polyps without truncating APC mutation (APC-) in particular, whereas high intake of carbohydrates seemed to especially decrease the risk of APC.polyps.Associations between dietary factors and truncating APC mutations in colorectal carcinomas were investigated in a population-based case-control study (184 cases; 259 controls) of sporadic colon cancer. Consumption of vegetables lowered the risk of tumors with truncating APC mutation (APC+) asweilas APC- tumors, most explicitly of the last. Alcohol intake was associated with an increased risk of APC.tumorsonly, whereas meat, fish and fat seemed to especially increase the risk of APC+ tumors. The same study population was used to evaluate associations between dietary factors and MSI, hMLH I expression and hMLH J hypermethylation. Intake of red meat seemed to increase the risk of MSI-LIMSS carcinomas in particular, whereas alcohol intake appeared to increase the risk of MSI-H tumors. Fruit consumption seemed to especially decrease the risk of MSI-H tumors with hypermethylated hMLHJ. Associations between cigarette smoking and mutations in the APC, K-ras and p53 genes, p53 overexpression, and MSI were also assessed in this study population. Our data suggest that smokingrelated colon carcinomas develop through a p53 overexpression-negative pathway and that smoking results in colon tumor cells with transversion mutations in particular.Finally, we used data from a case-control study of HNPCC-associated colorectal tumors (145 cases; 103 tumor-free controls) to gain insight into the etfects of environmental factors on colorectal tumor risk in individuals with HNPCC. Fruit consumption and dietary fiber intake lowered the risk of ever developing HNPCC-associated colorectal tumors, whereas cigarette smoking and alcohol consumption seemed to increase this risk. This suggests that also HNPCC-associated outcomes may be modified by environmental factors.

Bibliographic Details

Main Author:	Diergaarde, B.
Other Authors:	Kok, Frans
Format:	Doctoral thesis biblioteca
Language:	English
Subjects:	carcinoma, consumption patterns, environmental factors, food hygiene, gastrointestinal diseases, genetic disorders, health, intestinal diseases, lifestyle, neoplasms, nutritional state, carcinoom, consumptiepatronen, darmziekten, genetische stoornissen, gezondheid, levensstijl, maagdarmziekten, milieufactoren, neoplasma's, voedingstoestand, voedselhygiëne,
Online Access:	https://research.wur.nl/en/publications/diet-lifestyle-and-molecular-alterations-that-drive-colorectal-ca
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