Genetics of early-onset colorectal cancer

University of South Carolina

Lay summary

Colon cancer is rare in young people, however sometimes unlucky individuals develop colon cancer at young ages (before 50), prior to onset of screening by colonoscopy. These individuals may have some past special circumstances that increased their risk of colorectal cancer. Cancer is caused by somatic mutations in specific cancer causing genes. Such mutations usually happen because of random DNA mistakes made during stem cell division (bad luck). However, bad luck can be made worse by carcinogens or by inherited gene mutations. Some young people with colon cancer may have been unknowingly exposed to radiation or an uncommon chemical that mutates DNA, and accumulated a lifetimes worth of DNA mutations a very short amount of time, favouring bad luck.

Alternatively, they may have inherited a mutation in a gene responsible for metabolizing some common cancer causing chemical, and therefore experience a higher effective dose than do normal individuals. We intend to study UK Biobank individuals with and without a diagnosis of colon cancer in order to look for reasonable molecular explanations for the unusual cases of colon cancer in young people. We will perform statistical association studies between lifestyle risk factors, dietary components, occupational/environmental exposures, medications given during adolescence, and age of diagnosis of colorectal cancer. We will use advanced machine learning / artificial intelligence /deep learning computational tools to augment biostatistical and epidemiological analysis methods to elucidate potential interactions that increase risk of an early cancer diagnosis. We will perform genome-wide association analysis of germline variants (SNPS) with exposome factors and early diagnosis of colorectal cancer.

Finally, it has recently become apparent that somatic mutations in non-important (passenger) genes accumulate in normal cells throughout life, and when such mutations happen in stem cells, they can persist at low, sub-clonal levels for decades. Such low level sub-clonal mutations can be unwittingly captured during standard whole exome / genome sequencing efforts that utilize normal blood, saliva or tissue as the source of the DNA. These low level variant reads are usually discarded. We will assemble the low level somatic mutations into "mutation signatures" and look for individuals who have higher than typical mutation burden of one or more signatures. We will associate somatic mutation signatures with exposome factors, germline variants, and age of diagnosis of colon cancer (including future cancer diagnosis) to extract DNA mutation footprints left by agents that contribute to cancer risk.