Colorectal cancer risk and patients' survival: influence of polymorphisms in genes somatically mutated in colorectal tumors.
OBJECTIVE
The first two studies aiming for the high-throughput identification of the somatic mutation spectrum of colorectal cancer (CRC) tumors were published in 2006 and 2007. Using exome sequencing, they described 69 and 140 candidate cancer genes (CAN genes), respectively. We hypothesized that germline variants in these genes may influence CRC risk, similar to APC, which is causing CRC through germline and somatic mutations.


METHODS
After excluding the well-established CRC genes APC, KRAS, TP53, and ABCA1, we analyzed 35 potentially functional single-nucleotide polymorphisms (SNPs) in 10 CAN genes (OBSCN, MLL3, PKHD1, SYNE1, ERCC6, FBXW7, EPHB6/TRPV6, ELAC1/SMAD4, EPHA3, and ADAMTSL3) using KBiosciences Competitive Allele-Specific PCR™ genotyping assays. In addition to CRC risk (1,399 CRC cases, 838 controls), we also considered the influence of the SNPs on patients' survival (406 cases).


RESULTS
In spite of the fact that our in silico analyses suggested functional relevance for the studied genes and SNPs, our data did not support a strong influence of the studied germline variants on CRC risk and survival. The strongest association with CRC risk and survival was found for MLL3 (rs6464211, OR 1.50, p = 0.002, dominant model; HR 2.12, p = 0.020, recessive model). Two SNPs in EPHB6/TRPV6 (dominant model) showed marginal associations with survival (rs4987622 HR 0.58 p = 0.028 and rs6947538 HR 0.64, p = 0.036, respectively).


CONCLUSIONS
Although somatic mutations in the CAN genes have been related to the development and progression of various types of cancers in several next-generation sequencing or expression analyses, our study suggests that the studied potentially functional germline variants are not likely to affect CRC risk or survival.
Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany, s.huhn@dkfz.de.
Stefanie
S
Huhn
Melanie
M
Bevier
Barbara
B
Pardini
Alessio
A
Naccarati
Ludmila
L
Vodickova
Jan
J
Novotny
Pavel
P
Vodicka
Kari
K
Hemminki
Asta
A
Försti
D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality*; D018153:Czech Republic / Q000453:epidemiology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016019:Survival Analysis