Common molecular markers related to obesity and colorectal cancer
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Overweight and obesity is a risk factor for diseases like diabetes, heart conditions and cancer. A major cause of obesity is an imbalance between energy intake and consumption. However, a large part of the population has normal weight although living in an obesogenic environment. This is an indication of non-environmental factors making some individuals more predisposed to obesity than others. Colorectal cancer (CRC) is the second most common cancer in Norway, after prostate cancer in men and breast cancer in women. Diet, physical activity and family history are all identified as risk factors in this heterogeneous disease. There is increasing evidence for obesity and CRC being associated whereof fat distribution, gender and genetics may be common influential factors. Adipose tissue has traditionally been seen as a non-functional tissue for energy storage. Recent research shows that it is an important endocrine and metabolic organ as well, with impact in immunity and inflammation. These secondary effects of obesity may be involved in the development of various cancers. Epigenetics is the study of heritable changes in gene expression that occurs in absence of a change in the DNA sequence, and is an evolving research field. One epigenetic mechanism is DNA methylation, which more specifically consists of adding a methyl group to the 5´cytosine of C-G dinucleotides. Changes in DNA methylation can be essential for normal development, and environmental exposures can affect this mechanism. Within the subject of obesity, epigenetics is an interesting research field that should receive attention. When it comes to cancer, epigenetics has for a quite long time been shown to influence cancer risk and development. When it comes to both obesity and CRC, diet and lifestyle are important elements. Most of the material in this master thesis derives from the HUNT study; “Helseundersøkelsen i Nord-Trøndelag”. In addition we had material from CRC-patients and relevant cancer cell lines. Our main aim was to explore the possibility of common molecular mechanisms for obesity and CRC. A key aspect was to investigate the association between relevant polymorphisms related to obesity and CRC, and to study the effects on CRC and overweight/obesity as outcome. Single nucleotide polymorphisms (SNPs) within the FTO gene, the most common gene in the context of obesity, were tested for association to CRC, but we did not find any associations. Further, polymorphisms within the APC, DCC and H19, iii genes previously associated to CRC, were tested against overweight and obesity both at adolescence and adulthood as outcome. We found that the G-variant in the APC gene had a protective effect of overweight at adolescence. We observed tendencies of associations in the DCC gene variant, however with the opposite effects in men and women. To study the context between epigenetics and obesity, we performed a methylation analysis in fifty lean and fifty obese women using a kit targeting eight genes. The analysis resulted in differential methylation patterns with four women from the lean group showing methylation in one or several genes, and one woman from the obese group. In conclusion, we found some interesting genetic associations between obesity and CRC, especially in genes associated with CRC.