The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24.
Hereditary colorectal cancer accounts for approximately 30% of all colorectal cancers, but currently only 5% of these families can be explained by highly penetrant, inherited mutations. In the remaining 25% it is not possible to perform a gene test to identify the family members who would benefit from prophylactic screening. Consequently, all family members are asked to follow a screening program. The purpose of this study was to localize a new gene which causes colorectal cancer. We performed a linkage analysis using data from a SNP6.0 chip in one large family with 12 affected family members. We extended the linkage analysis with microsatellites (STS) and single nucleotide polymorphisms (SNP's) and looked for the loss of heterozygosity in tumour tissue. Furthermore, we performed the exome sequencing of one family member and we sequenced candidate genes by use of direct sequencing. Major rearrangements were excluded after karyotyping. The linkage analysis with SNP6 data revealed three candidate areas, on chromosome 2, 6 and 11 respectively, with a LOD score close to two and no negative LOD scores. After extended linkage analysis, the area on chromosome 6 was excluded, leaving areas on chromosome 2 and chromosome 11 with the highest possible LOD scores of 2.6. Two other studies have identified 11q24 as a candidate area for colorectal cancer susceptibility and this area is supported by our results.
Department of Cellular and Molecular Medicine, Faculty of Health, Panum Institute 24.4, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark.
Laura Aviaja
LA
Rudkjøbing
Hans
H
Eiberg
Hanne Birte
HB
Mikkelsen
Marie Louise Mølgaard
ML
Binderup
Marie Luise
ML
Bisgaard
D000236:Adenoma / Q000235:genetics*; D000071503:AlkB Homolog 8, tRNA Methyltransferase; D002880:Chromosomes, Human, Pair 11; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D012359:tRNA Methyltransferases / Q000235:genetics
C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; C549623:ALKBH8 protein, human; D000071503:AlkB Homolog 8, tRNA Methyltransferase; D012359:tRNA Methyltransferases