Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22.
A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
Mine S
MS
Cicek
Julie M
JM
Cunningham
Brooke L
BL
Fridley
Daniel J
DJ
Serie
William R
WR
Bamlet
Brenda
B
Diergaarde
Robert W
RW
Haile
Loic
L
Le Marchand
Theodore G
TG
Krontiris
H Banfield
HB
Younghusband
Steven
S
Gallinger
Polly A
PA
Newcomb
John L
JL
Hopper
Mark A
MA
Jenkins
Graham
G
Casey
Fredrick
F
Schumacher
Zhu
Z
Chen
Melissa S
MS
DeRycke
Allyson S
AS
Templeton
Ingrid
I
Winship
Roger C
RC
Green
Jane S
JS
Green
Finlay A
FA
Macrae
Susan
S
Parry
Graeme P
GP
Young
Joanne P
JP
Young
Daniel
D
Buchanan
Duncan C
DC
Thomas
D Timothy
DT
Bishop
Noralane M
NM
Lindor
Stephen N
SN
Thibodeau
John D
JD
Potter
Ellen L
EL
Goode
D000328:Adult; D000368:Aged; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D002884:Chromosomes, Human, Pair 15; D002894:Chromosomes, Human, Pair 4; D002898:Chromosomes, Human, Pair 8; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair; D005190:Family; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide