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The heritability of colorectal cancer (CRC) is incompletely understood, and the contribution of undiscovered rare variants may be important. In search of rare disease-causing variants, we exome sequenced 22 CRC patients who were diagnosed before the age of 40 years. Exome sequencing data from 95 familial CRC patients were available as a validation set. Cases with known CRC syndromes were excluded. All patients were from Finland, a country known for its genetically homogenous population. We searched for rare nonsynonymous variants with allele frequencies below 0.1% in 3,374 Finnish and 58,112 non-Finnish controls. In addition, homozygous and compound heterozygous variants were studied. No genes with rare loss-of-function variants were present in more than one early-onset CRC patient. Three genes (ADAMTS4, CYTL1, and SYNE1) harbored rare loss-of-function variants in both early-onset and familial CRC cases. Five genes with homozygous variants in early-onset CRC cases were found (MCTP2, ARHGAP12, ATM, DONSON, and ROS1), including one gene (MCTP2) with a homozygous splice site variant. All discovered homozygous variants were exclusive to one early-onset CRC case. Independent replication is required to associate the discovered variants with CRC. These findings, together with a lack of family history in 19 of 22 (86%) early-onset patients, suggest genetic heterogeneity in unexplained early-onset CRC patients, thus emphasizing the requirement for large sample sizes and careful study designs to elucidate the role of rare variants in CRC susceptibility., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A common single nucleotide polymorphism (SNP), rs6983267, at 8q24.21 has recently been shown to associate with colorectal cancer (CRC). Three independent SNP association studies showed that rs6983267 contributes to CRC with odds ratios (OR) of 1.17 to 1.22. Here, we genotyped a population-based series of 1,042 patients with CRC and 1,012 healthy controls for rs6983267 and determined the contribution of SNP to CRC in Finland, using germ line DNA, as well as the respective cancer DNA in heterozygous patients. The comprehensive clinical data available from the 1,042 patients and their first-degree relatives enabled us to thoroughly examine the possible association of this variant with different clinical features. As expected, a significant association between the G allele of rs6983267 and CRC [OR, 1.22; 95% confidence interval (CI), 1.08-1.38; P = 0.0018] was found, confirming the previous observations. A trend towards association of the G allele with microsatellite-stable cancer (OR, 1.37; 95% CI, 1.02-1.85; P = 0.04) and family history of cancers other than CRC was seen (OR, 1.20; 95% CI, 1-1.43; P = 0.05). Four hundred and sixty-six GT heterozygotes identified in this study were analyzed for allelic imbalance at rs6983267 in the respective cancer DNA. One hundred and one tumors showed allelic imbalance (22%). The risk allele G was favored in 67 versus 34 tumors (P = 0.0007). This finding implicates that the underlying germ line genetic defect in 8q24.21 is a target in the somatic evolution of CRC.

Polymorphisms in nucleotide oligomerization domain 2 gene (NOD2) have been associated with increased susceptibility to Crohn's disease. Recently, possible association of the NOD2 variants R702W, G908R and 3020insC with colorectal cancer (CRC) has been studied among Polish, Greek, Finnish and New Zealand Caucasian CRC patients, but the results have been controversial. In the Polish study, 3020insC alone, and in the Greek study all the 3 variants, showed association with CRC. In a study from New Zealand, R702W appeared to increase CRC risk. In addition, the combined frequencies of the 3 variants were significantly elevated in CRC patients compared with healthy controls. We have previously shown that NOD2 3020insC is not associated with increased CRC risk in Finland. In the current study, we have genotyped the R702W and G908R in a population-based series of 1,042 CRC patients and in 508 healthy controls to study the possible contribution of these variants to CRC predisposition. Of the CRC patients, 953 were successfully analyzed. R702W and G908R were equally, frequently seen in CRC patients and controls (R702W: 2.2% vs. 2.1%; G908R: 0.3% vs. 0.2%). No associations between NOD2 variants and clinical characteristics were observed. Our results indicate that NOD2 variants R702W, G908R and 3020insC do not predispose to CRC in Finland. Environmental or additional genetic factors may play a role in CRC development in NOD2 variant carriers. Further work is necessary to establish the possible role of NOD2 variants in CRC predisposition.

Purpose: The estimated world-wide prevalence of keratoconus is 50 to 230 per 100,000 in the general population. Sporadic keratoconus is the leading cause of corneal transplantation surgery in Western countries. Positive family history has been reported in 6% to 8% of patients. The purpose of this study was to map the disease locus in 20 Finnish families with autosomal dominant keratoconus, each family having two or more affected members and with no other associated genetic disease., Methods: DNA was extracted from blood samples, collected from 42 affected and 34 unaffected family members. Genomic DNA from patients and their parents, was typed for alleles of 292 polymorphic markers. A genome-wide screening was performed to localize the disease gene. Fluorescent markers were amplified by polymerase chain reaction and separated on an automated sequencer. Allele sizes were assigned to each family member, after which LOD scores were calculated., Results: The disease locus was mapped to chromosome 16q, between the markers D16S2624 and D16S3090, with a maximum parametric multipoint LOD score of 4.10 and corresponding nonparametric score of 3.27 (NPL, P = 0.00006). Evidence from 20 families provided support for the linkage, consistent with a single locus for familial autosomal dominant keratoconus without heterogeneity., Conclusions: This study is the first genome-wide linkage study to map the keratoconus gene. The results suggest that the causative gene in keratoconus is located within the 16q22.3-q23.1 chromosomal region.