Associations of sex, anthropometric and reproductive factors with clinicopathological and molecular characteristics of colorectal cancer

Abstract: Colorectal cancer (CRC) is the third most common cancer globally, with approximately 1.2 million new cases every year. The highest incidence rates are seen in developed countries, thereby imposing dietary and lifestyle factors in the etiology of CRC. Accumulating epidemiological evidence suggests that obesity is a risk factor for CRC in particular in men, as weak or no associations are seen in women. The reason for this sex difference is not fully understood, but hormonal factors are suggested to play an important role. CRC is a largely heterogenous disease, and colorectal carcinogenesis can be regarded as a complex process involving multiple genetic and epigenetic alterations engendering tumours with different clinicopathological features. The aims of this thesis were to investigate the associations between obesity, measured as different anthropometric factors, and risk of CRC according to clinocopathological and tumour biological characteristics in men and women, respectively. In addition, the relationship between use of postmenopausal homone therapy (HRT) and oral contraceptives (OC) with CRC risk was examined. All papers are based on tumours from incident CRC in the Malmö Diet and Cancer study, a large prospective population based cohort including 28098 individuals. Baseline examinations comprised anthropometric measurements, questionnaire on medications, socioeconomic- and lifestyle related factors. By the end of follow-up in 2008, 584 cases of incident CRC had been registered. Using the tissue microarray technique (TMA), immunohistochemical (IHC) expression of beta-catenin, cyclin D1, p53 and microsatellite instability (MSI) status of the tumours was investigated. KRAS/BRAF mutation status was assessed by pyrosequencing. Interestingly, we found that obesity was associated with an increased risk of more advanced CRC, i.e. tumour (T)-stage 3 and 4, lymph node positive and metastatic disease, predominantly in men. Further, obesity was associated with an overall increased risk of CRC in both sexes (Paper 1). Associations of anthropometric factors with the risk of various molecular subsets of CRC revealed that obesity was not related to risk of MSI tumours, indicating that obesity influences carcinogenesis through other pathways than the MSI pathway (Paper 2). Given the sex differences in the associations between obesity and CRC, and, that HRT has been shown to be a protective factor of CRC, we also examined the associations of HRT and OC use and CRC risk in the female cohort. The principle finding was that current use of HRT was not associated with a decreased overall CRC risk as expected, but with a decreased risk of T -stage 1 and 2 CRC. Further, HRT use was associated with a lower risk of lymph node negative-, non-metastatic disease and of p53 negative- and cyclin D1 negative tumours in the rectum, but not in the colon (Paper 3). Finally, we found that obesity was associated with an increased risk of both wild-type and KRAS-mutated colorectal tumours in men, and with an increased risk of BRAF wild-type tumours, but not with BRAF-mutated tumours, in both sexes (Paper 4).