Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 10% of all new cancers. The purpose of this thesis was to provide new insights into the genetic architecture of CRC susceptibility, as well as the identification of individuals with substantial genetic risk. The first aim was to study the diagnostic approach to hereditary cancer syndromes in early-onset CRC patients. We investigated a series of 38 CRC patients diagnosed before age 40 years. To assess the practical feasibility and added value of whole-exome sequencing (WES) as a diagnostic test, we performed WES on 23 early-onset CRC patients with unknown etiology. Ten high-penetrance CRC predisposition genes (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, SMAD4, BMPR1A, STK11 and PTEN) were analyzed for nonsynonymous variants, and family histories were acquired from national population registries. Hereditary CRC syndromes were diagnosed in 42% of the early-onset CRC patients (16/38; 95% CI, 26%-59%), but the diagnostic yield of WES was not superior to microsatellite instability testing and clinical assessment for gastrointestinal polyposis. The second aim was to study the contribution of rare germline variants to early-onset CRC. We analyzed WES data from 22 unexplained early-onset CRC patients and studied 95 familial CRC patients as a validation set. In this series of 22 early-onset CRC cases, we did not find any genes with recurrent loss-of-function (LoF) variants with minor allele frequency <0.1%. This observation, together with negative family history in 86% (19/22) of the unexplained young patients, suggests that the genetic background of these patients may be complex. Rare LoF variants in three genes - ADAMTS4, CYTL1 and SYNE1 - were shared between early-onset and familial CRC cases. Both INTS5 and ACSL5 harbored rare missense variants in two of the 22 patients, whereas ARHGAP12, ATM, DONSON, MCTP2 and ROS1 showed rare homozygous variants in single early-onset CRC cases. Further studies are needed to determine whether the identified variants are associated with CRC risk. The third aim was to study the genetic basis of common, complex CRC. We conducted a genome-wide association study (GWAS) of CRC in 1,701 cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 single-nucleotide variants were imputed and analyzed, and most promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. Thirteen previously published loci (2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33) were associated with CRC in the Finnish population, but new risk loci were not found. These results replicate multiple CRC susceptibility loci and underscore similarities in the genetic architecture of CRC susceptibility between the Finnish population isolate and outbred populations, which informs the design of future GWASs.
|Tilldelningsdatum||20 dec 2018|
|Status||Publicerad - 2018|
|MoE-publikationstyp||G5 Doktorsavhandling (artikel)|
- 3111 Biomedicinska vetenskaper
- 3122 Cancersjukdomar
- 1184 Genetik, utvecklingsbiologi, fysiologi