ABSTRACT
Colorectal cancer (CRC) is one of the major cancer types in the western world including Sweden. However, known genetic risk factors could only explain a limited part of heritability of the disease. Moreover, colon and rectal cancers are habitually discussed as one entity, colorectal cancer, although different carcinogenesis has been recognized. A genome-wide linkage scan in 32 colon- and 56 rectal cancer families from Sweden was performed based on 475 non-FAP/HNPCC patients genotyped using SNP arrays. A maximum HLOD of 2.50 at locus 6p21.1-p12.1 and a HLOD of 2.56 at 18p11.2 was obtained for colon and rectal cancer families, respectively. Exome sequencing over the regions of interest in 12 patients from six families identified 22 and 25 candidate risk variants for colon and rectal cancer, respectively. Haplotype association analysis in the two regions was carried out between additional 477 familial CRC cases and 4780 controls and suggested candidate haplotypes possibly associated with CRC risk. This study suggested two new linkage regions for colon cancer and rectal cancer with candidate predisposing variants. Further studies are required to elucidate the pathogenic mechanism of these regions and to pinpoint the causative genes.
Subject(s)
Chromosomes, Human, Pair 18/genetics , Chromosomes, Human, Pair 6/genetics , Colonic Neoplasms/genetics , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Rectal Neoplasms/genetics , Aged , Chromosome Mapping , Colonic Neoplasms/diagnosis , Family Health , Female , Genome-Wide Association Study/methods , Genotype , Haplotypes , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Rectal Neoplasms/diagnosis , SwedenABSTRACT
Genome-wide association studies (GWAS) have identified dozens of common genetic variants associated with risk of colorectal cancer (CRC). However, the majority of CRC heritability remains unclear. In order to discover low-frequency, high-risk CRC susceptibility variants in Swedish population, we genotyped 1 515 CRC patients enriched for familial cases, and 12 108 controls. Case/control association analysis suggested eight novel variants associated with CRC risk (OR 2.0-17.6, p-value < 2.0E-07), comprised of seven coding variants in genes RAB11FIP5, POTEA, COL27A1, MUC5B, PSMA8, MYH7B, and PABPC1L as well as one variant downstream of NEU1 gene. We also confirmed 27 out of 30 risk variants previously reported from GWAS in CRC with a mixed European population background. This study identified rare, coding sequence variants associated with CRC risk through analysis in a relatively homogeneous population. The segregation data suggest a complex mode of inheritance in seemingly dominant pedigrees.
