Diet-gene interactions in sporadic and hereditary colorectal carcinogenesis : epidemiological perspectives

D. Voskuil

Research output: Thesisinternal PhD, WU

Abstract

<p>Colorectal cancer is known to develop by accumulation of alterations in regulatory genes. Both familial and environmental factors play a role in the etiology of colorectal cancer and its adenomatous precursor lesions. This thesis examines diet-gene interactions in sporadic and hereditary colorectal carcinogenesis, from two different epidemiological perspectives, as outlined in AIMS 1 and 2.</p><p>AIM 1: <em>to examine evidence for a role of dietary risk factors in the etiology of Hereditary Non-Polyposis Colorectal Cancer (HNPCC); are some aspects of the etiology similar to sporadic colorectal carcinogenesis?</em></p><p>In a descriptive epidemiological study of HNPCC first degree relatives, the cumulative incidence of colorectal cancer at age 75 increased from 19% in ancestors, to 32% in the first generation and 55% in the second generation, which is largely attributable to a birth cohort effect. The earlier age of onset in successive HNPCC generations thus appears not to be a biological feature of HNPCC but reflects a time trend in cancer occurrence which is similar to trends in the general population.</p><p>Subsequently, we assessed frequencies of mutations in the K-ras gene and overexpression of the p53 protein, in 48 HNPCC and 59 sporadic adenomas. Frequencies of these abnormalities were indeed similar in HNPCC (31% and 25% for K-ras and p53 respectively) and sporadic (32% and 25% for K-ras and p53 respectively) adenomas. This points towards similar molecular pathways to early stages of colorectal carcinogenesis with regard to K-ras and p53, and therefore suggests that environmental factors may play a similar role.</p><p>To study the association between risk of HNPCC colorectal adenomas and dietary factors related to meat consumption and preparation directly, we conducted a case control study of HNPCC and sporadic adenomas (n=62 and 57 respectively), and endoscopy control groups for both (n=83 and 65 for HNPCC and sporadic respectively). We observed red meat consumption and darkly browned meat surface to be positively associated with risk of adenomas in the sporadic group (Odds Ratio (OR) 4.1 and 3.0 respectively, 95% confidence interval (95% CI) 0.7-23.0 and 1.2-7.5 respectively), but not in the HNPCC group (OR 0.4 and 0.7, 95% CI 0.1-2.2 and 0.3-1.4 respectively). Although this may suggest that meat consumption and preparation are only relevant in the etiology of sporadic adenomas, it does not exclude that (other) dietary factors play a role in some phases of HNPCC colorectal carcinogenesis.</p><p>AIM 2: <em>to examine evidence for a differential effect of dietary risk factors on K-ras/p53 dependent and independent pathways to colorectal carcinogenesis.</em></p><p>In a case control study on dietary factors and the risk of sporadic colon cancer, we examined carcinoma tissue (n=185) for mutations in the K-ras and p53 genes. We found high intakes of animal protein and calcium to be positively associated with carcinomas harboring K-ras codon 12 mutations (OR 1.5 and 1.2, 95% CI 1.0-2.1 and 0.9-1.6 respectively), but inversely with carcinomas harboring codon 13 mutations (OR 0.4 and 0.6, 95% CI 0.2-1.0 and 0.3-1.2 respectively). Transition and transversion mutations were not differently associated with diet.</p><p>We examined both p53 mutations and p53 overexpression in relation to diet, and observed a positive association for (saturated) fat, only in the p53-independent pathway (for saturated fat, no overexpression OR 1.5, 95% CI 1.1-2.0) and not in the p53-dependent pathway (for saturated fat, with overexpression OR 1.1, 95% CI 0.8-1.5). This difference was more pronounced with p53 overexpression than with p53 mutation as endpoint. Interestingly, when examining specific mutations we found similar dietary factors only to be associated with transversion mutations (for saturated fat, OR 2.0, 95% CI 1.0-4.1), and not with mutations at CpG islands (for saturated fat, OR 0.9, 95% CI 0.6-1.6).</p><p>Both studies suggest that if diet is associated with K-ras and p53 mutations in colon cancer, very specific types of mutations may be involved. Our studies have been among the first to examine diet-gene interactions in colorectal carcinogenesis, using an epidemiological approach. Such "early" studies into a new area, tend to be of small size, and they are therefore not sufficient to provide "proof" of diet-gene interactions. However, these studies have served well to to suggest directions for future research, and to develop and expand the relevant research infrastructures.</p><p>Future studies on diet-gene interactions in colorectal carcinogenesis should continue to aim at disentangling the effects of diet in all molecular phases of the adenoma-carcinoma sequence, and additionally, clarifying the possible role of environmental factors in hereditary colorectal cancer.</p>
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Supervisors/Advisors
  • Kok, Frans, Promotor
  • van 't Veer, Pieter, Promotor
  • Nagengast, F.M., Promotor, External person
Award date12 May 1999
Place of PublicationS.l.
Print ISBNs9789058080325
Publication statusPublished - 1999

Keywords

  • diet
  • colorectal cancer
  • genetics
  • carcinogenesis
  • epidemiology

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