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Colorectal cancer risk and patients' survival: influence of polymorphisms in genes somatically mutated in colorectal tumors

Huhn, Stefanie; Bevier, Melanie; Pardini, Barbara; Naccarati, Alessio; Vodickova, Ludmila; Novotny, Jan; Vodicka, Pavel; Hemminki, Kari LU and Försti, Asta LU (2014) In Cancer Causes and Control 25(6). p.759-769
Abstract
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. 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 AlleleaEuroSpecific PCR (TM)... (More)
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. 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 AlleleaEuroSpecific PCR (TM) 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). 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). 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Colorectal cancer, Risk, Survival, SNP, CAN genes
in
Cancer Causes and Control
volume
25
issue
6
pages
759 - 769
publisher
Springer
external identifiers
  • wos:000336023600011
  • scopus:84901197287
ISSN
1573-7225
DOI
10.1007/s10552-014-0379-1
language
English
LU publication?
yes
id
f8e42597-4ca5-432e-aab5-4211593b5d9e (old id 4469806)
date added to LUP
2014-07-01 07:42:17
date last changed
2017-11-12 03:12:02
@article{f8e42597-4ca5-432e-aab5-4211593b5d9e,
  abstract     = {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. 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 AlleleaEuroSpecific PCR (TM) 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). 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). 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.},
  author       = {Huhn, Stefanie and Bevier, Melanie and Pardini, Barbara and Naccarati, Alessio and Vodickova, Ludmila and Novotny, Jan and Vodicka, Pavel and Hemminki, Kari and Försti, Asta},
  issn         = {1573-7225},
  keyword      = {Colorectal cancer,Risk,Survival,SNP,CAN genes},
  language     = {eng},
  number       = {6},
  pages        = {759--769},
  publisher    = {Springer},
  series       = {Cancer Causes and Control},
  title        = {Colorectal cancer risk and patients' survival: influence of polymorphisms in genes somatically mutated in colorectal tumors},
  url          = {http://dx.doi.org/10.1007/s10552-014-0379-1},
  volume       = {25},
  year         = {2014},
}