Common familial colorectal cancer linked to chromosome 7q31: a genome-wide analysis.
Present investigations suggest that approximately 30% of colorectal cancer cases arise on the basis of inherited factors. We hypothesize that the majority of inherited factors are moderately penetrant genes, common in the population. We use an affected sibling pair approach to identify genetic regions that are coinherited by siblings with colorectal cancer. Individuals from families with at least two siblings diagnosed with colorectal adenocarcinoma or high-grade dysplasia were enrolled. Known familial colorectal cancer syndromes were excluded. A genome-wide scan on 151 DNA samples from 70 kindreds was completed using deCODE 1100 short tandem repeat marker set at an average 4-cM density. Fine mapping on a total of 184 DNAs from 83 kindreds was done in regions suggesting linkage. Linkage analysis was accomplished with Merlin analysis package. Nonparametric linkage analysis revealed three genetic regions with logarithm of the odds (LOD) scores >or=2.0: Ch. 3q29, LOD 2.61 (P = 0.0003); Ch. 4q31.3, LOD 2.13 (P = 0.0009); and Ch. 7q31.31, LOD 3.08 (P = 0.00008). Affected siblings with increased sharing at the 7q31 locus have a 3.8-year (+/- 3.5) earlier age of colorectal cancer onset although this is not statistically significant (P = 0.11). No significant linkage was found near genes causing known syndromes or regions previously reported (8q24, 9q22, and 11q23). The chromosome 3q21-q24 region reported to be linked in colorectal cancer relative pairs is supported by our study, albeit a minor peak (LOD 0.9; P = 0.02). No known familial cancer genes reside in the 7q31 locus, and thus the identified region may contain a novel susceptibility gene responsible for common familial colorectal cancer.
Neklason
Deborah W
DW
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550, USA. Deb.neklason@hci.utah.edu
Kerber
Richard A
RA
Nilson
David B
DB
Anton-Culver
Hoda
H
Schwartz
Ann G
AG
Griffin
Constance A
CA
Lowery
Jan T
JT
Schildkraut
Joellen M
JM
Evans
James P
JP
Tomlinson
Gail E
GE
Strong
Louise C
LC
Miller
Alexander R
AR
Stopfer
Jill E
JE
Finkelstein
Dianne M
DM
Nadkarni
Prakash M
PM
Kasten
Carol H
CH
Mineau
Geraldine P
GP
Burt
Randall W
RW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002897:Chromosomes, Human, Pair 7; D015179:Colorectal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008126:Lod Score; D008875:Middle Aged