Confirmation of linkage to and localization of familial colon cancer risk haplotype on chromosome 9q22.
Genetic risk factors are important contributors to the development of colorectal cancer. Following the definition of a linkage signal at 9q22-31, we fine mapped this region in an independent collection of colon cancer families. We used a custom array of single-nucleotide polymorphisms (SNP) densely spaced across the candidate region, performing both single-SNP and moving-window association analyses to identify a colon neoplasia risk haplotype. Through this approach, we isolated the association effect to a five-SNP haplotype centered at 98.15 Mb on chromosome 9q. This haplotype is in strong linkage disequilibrium with the haplotype block containing HABP4 and may be a surrogate for the effect of this CD30 Ki-1 antigen. It is also in close proximity to GALNT12, also recently shown to be altered in colon tumors. We used a predictive modeling algorithm to show the contribution of this risk haplotype and surrounding candidate genes in distinguishing between colon cancer cases and healthy controls. The ability to replicate this finding, the strength of the haplotype association (odds ratio, 3.68), and the accuracy of our prediction model (approximately 60%) all strongly support the presence of a locus for familial colon cancer on chromosome 9q.
Gray-McGuire
Courtney
C
Department of Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Guda
Kishore
K
Adrianto
Indra
I
Lin
Chee Paul
CP
Natale
Leanna
L
Potter
John D
JD
Newcomb
Polly
P
Poole
Elizabeth M
EM
Ulrich
Cornelia M
CM
Lindor
Noralane
N
Goode
Ellen L
EL
Fridley
Brooke L
BL
Jenkins
Robert
R
Le Marchand
Loic
L
Casey
Graham
G
Haile
Robert
R
Hopper
John
J
Jenkins
Mark
M
Young
Joanne
J
Buchanan
Daniel
D
Gallinger
Steve
S
Adams
Mark
M
Lewis
Susan
S
Willis
Joseph
J
Elston
Robert
R
Markowitz
Sanford D
SD
Wiesner
Georgia L
GL
D002899:Chromosomes, Human, Pair 9; D003110:Colonic Neoplasms / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide