Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility.
Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).
Lascorz
Jesús
J
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. j.lascorz@dkfz.de
Försti
Asta
A
Chen
Bowang
B
Buch
Stephan
S
Steinke
Verena
V
Rahner
Nils
N
Holinski-Feder
Elke
E
Morak
Monika
M
Schackert
Hans K
HK
Görgens
Heike
H
Schulmann
Karsten
K
Goecke
Timm
T
Kloor
Matthias
M
Engel
Cristoph
C
Büttner
Reinhard
R
Kunkel
Nelli
N
Weires
Marianne
M
Hoffmeister
Michael
M
Pardini
Barbara
B
Naccarati
Alessio
A
Vodickova
Ludmila
L
Novotny
Jan
J
Schreiber
Stefan
S
Krawczak
Michael
M
Bröring
Clemens D
CD
Völzke
Henry
H
Schafmayer
Clemens
C
Vodicka
Pavel
P
Chang-Claude
Jenny
J
Brenner
Hermann
H
Burwinkel
Barbara
B
Propping
Peter
P
Hampe
Jochen
J
Hemminki
Kari
K
D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany / Q000453:epidemiology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D044465:White People / Q000235:genetics*
D020928:Mitogen-Activated Protein Kinases