Landscape Of Genetic Characterization Of Ulcerative Colitis Associated Colorectal Cancer Base On Next-generation Sequencing

Ulcerative colitis (UC), a kind of chronic relapsing intestinal inflammatory disorder of the colon, is caused by a complex interaction of environmental, genetic, and immunoregulatory factors, associated with high risk of colorectal cancer (CRC). UC may be accompany with ankylosing spondylitis (AS). Patients with long-standing of UC have an increased risk of developing CRC. Genetic alterations are associated with the susceptibility of UC and AS, and also participate in the development of CRC. In recent years there has been an enormous increase in research involving UCCRC, but our knowledge is still limited in whole genome characteristics of different pathological tissues of UCCRC patients, which plays a very important part in explaining the strength of the genetic effects in UCCRC.A 39 years old male was diagnosed as sigmoid colonic adenocarcinoma with history of UC and AS. We applied whole genome sequencing and exome sequencing on his peripheral blood, inflammatory and cancer tissue from colon. Variants were analyzed and annotated by variant-level, gene-level and pathway-level based on databases. Genome mutation spectrum was also compared with general Chinese Han population to investigate individual characteristics. We also provided suggestion of potential drugs for future treatment by analyzing his pharmacogenomics.30X sequencing depth of whole genome sequencing and more than 120X whole exome sequencing rawdata were obtained.3,195,782 germ-line variants,18,016 inflammatory-specific variants, 27,117 cancer-specific variants,35,244 inflammatory and cancer shared variants were identified respectively. On one hand, germ-line and somatic variants were analyzed and annotated by variant-level, gene-level and pathway-level based on database. We found amount of germ-line mutations associated with UC、AS and CRC and somatic mutations associated with CRC. Lots of germ-line mutations were found in DNA replication and repair associated genes. Mutated FEN1 results in insufficient function of DNA repair system. On the other hand, genome mutation spectrum of our patient was compared to individuals of general Chinese Han population. We found that the number of variants was much higher than average of General Han population especially in rare variants. Additionally, lots of microsatellite mutations in our patient were found, some of which were also reported in microsatellite instable (MSI) CRC genome by other researches. Moreover, drug associated metaliziam and toxity mutations were annotated by pharmGKB database. One variant in ABCB1 suggested its resistance of cyclosporine; Homogenous mutations in CD14 and TLR2 indicated loss of efficiency from therapy using anti TNF-a drugs; Mutations in ABCC1, ADCY, AREG, EGF and XRCC1 illustrated that anti EGFR drugs like cetuximab and panitumumab are not fit for our patient, and oxaliplatin and carboplatin may be efficient.These results indicated a high genetic susceptibility to UC、AS and CRC due to his tremendous germline mutations. And a MSI or hypermutation phenotype may be caused by insufficient function of DNA replication and repair system, indicating DNA repair system may participate in the development of UCCRC.