Deciphering the genetics of hereditary non-syndromic colorectal cancer.
Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.
Papaemmanuil
Eli
E
Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.
Carvajal-Carmona
Luis
L
Sellick
Gabrielle S
GS
Kemp
Zoe
Z
Webb
Emily
E
Spain
Sarah
S
Sullivan
Kate
K
Barclay
Ella
E
Lubbe
Steven
S
Jaeger
Emma
E
Vijayakrishnan
Jayaram
J
Broderick
Peter
P
Gorman
Maggie
M
Martin
Lynn
L
Lucassen
Anneke
A
Bishop
D Timothy
DT
Evans
D Gareth
DG
Maher
Eamonn R
ER
Steinke
Verena
V
Rahner
Nils
N
Schackert
Hans K
HK
Goecke
Timm O
TO
Holinski-Feder
Elke
E
Propping
Peter
P
Van Wezel
Tom
T
Wijnen
Juul
J
Cazier
Jean-Baptiste
JB
Thomas
Huw
H
Houlston
Richard S
RS
Tomlinson
Ian
I
D000236:Adenoma / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005192:Family Health; D018628:Gene Dosage; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008126:Lod Score; D020641:Polymorphism, Single Nucleotide