Abstract
Purpose
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).
Conclusion
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.
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References
Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249
Barrett JC, Fry B, Maller J et al (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Barton NH (2000) Genetic hitchhiking. Philos Trans R Soc Lond B Biol Sci 355:1553–1562
Bernstein CN, Blanchard JF, Kliewer E et al (2001) Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 91:854–862
Biswas S, Trobridge P, Romero-Gallo J et al (2008) Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor beta resistant cells. Genes Chromosom Cancer 47:95–106
Brokx RD, Revers L, Zhang Q et al (2003) Nuclear magnetic resonance-based dissection of a glycosyltransferase specificity for the mucin MUC1 tandem repeat. Biochemistry 42:13817–13825
Carlson CS, Thomas DJ, Eberle MA et al (2005) Genomic regions exhibiting positive selection identified from dense genotype data. Genome Res 15:1553–1565
Coop G, Pickrell JK, Novembre J et al (2009) The role of geography in human adaptation. PLoS Genet 5:e1000500
NCBI dbSNP. http://www.ncbi.nlm.nih.gov/
De La Chapelle A (2004) Genetic predisposition to colorectal cancer. Nat Rev Cancer 4:769–780
Duffy MJ, Lamerz R, Haglund C et al (2014) Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. Int J Cancer 134:2513–2522
Fay JC, Wu CI (2000) Hitchhiking under positive Darwinian selection. Genetics 155:1405–1413
Fearnhead NS, Wilding JL, Bodmer WF (2002) Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull 64:27–43
Forbes SA, Bindal N, Bamford S et al (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39:D945–D950
Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709
Guo C, Chang CC, Wortham M et al (2012) Global identification of MLL2-targeted loci reveals MLL2’s role in diverse signaling pathways. Proc Natl Acad Sci USA 109:17603–17608
Haber DA, Fearon ER (1998) The promise of cancer genetics. Lancet 351(Suppl 2):SII1–SII8
HaploReg v2. http://www.broadinstitute.org/mammals/haploreg/haploreg.php
Hemminki K, Forsti A, Lorenzo Bermejo J (2009) Surveying the genomic landscape of colorectal cancer. Am J Gastroenterol 104:789–790
Huxley RR, Ansary-Moghaddam A, Clifton P et al (2009) The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer 125:171–180
Jasperson KW, Tuohy TM, Neklason DW et al (2010) Hereditary and familial colon cancer. Gastroenterology 138:2044–2058
Kandoth C, Mclellan MD, Vandin F et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339
Kawashima H (2012) Roles of the gel-forming MUC2 mucin and its O-glycosylation in the protection against colitis and colorectal cancer. Biol Pharm Bull 35:1637–1641
Kloosterman WP, Hoogstraat M, Paling O et al (2011) Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biol 12:R103
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081
Lee J, Kim DH, Lee S et al (2009) A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4. Proc Natl Acad Sci USA 106:8513–8518
Markowitz S, Wang J, Myeroff L et al (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338
Matsuoka H, Iwata N, Ito M et al (1997) Expression of a kinase-defective Eph-like receptor in the normal human brain. Biochem Biophys Res Commun 235:487–492
Naccarati A, Pardini B, Stefano L et al (2012) Polymorphisms in miRNA-binding sites of nucleotide excision repair genes and colorectal cancer risk. Carcinogenesis 33:1346–1351
Oleksyk TK, Smith MW, O’brien SJ (2010) Genome-wide scans for footprints of natural selection. Philos Trans R Soc Lond B Biol Sci 365:185–205
Peng JB, Brown EM, Hediger MA (2001) Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Genomics 76:99–109
PolyPhen-2. http://genetics.bwh.harvard.edu/pph2/
Quanto. http://hydra.usc.edu/gxe/
Sabeti PC, Reich DE, Higgins JM et al (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837
Savas S, Younghusband HB (2010) dbCPCO: a database of genetic markers tested for their predictive and prognostic value in colorectal cancer. Hum Mutat 31:901–907
Shin N, You KT, Lee H et al (2011) Identification of frequently mutated genes with relevance to nonsense mediated mRNA decay in the high microsatellite instability cancers. Int J Cancer 128:2872–2880
SIFT. http://sift.jcvi.org/
Sjöblom T, Jones S, Wood LD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274
SNPnexus. http://snp-nexus.org/citation.html
Sobin LH, Gospodarowicz MK, Wittekind C et al (2010) TNM classification of malignant tumours. Wiley-Blackwell, Hoboken
Southam L, Soranzo N, Montgomery SB et al (2009) Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants? Diabetologia 52:1846–1851
Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595
The Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337
The International Hapmap3 Consortium (2010) Integrating common and rare genetic variation in diverse human populations. Nature 467:52–58
The International Hapmap Consortium (2003) The international HapMap project. Nature 426:789–796
Tomlinson I (2012) Colorectal cancer genetics: from candidate genes to GWAS and back again. Mutagenesis 27:141–142
Tomlinson IP, Dunlop M, Campbell H et al (2010) COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. Br J Cancer 102:447–454
Vasen HF, Watson P, Mecklin JP et al (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456
Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799
Voight BF, Kudaravalli S, Wen X et al (2006) A map of recent positive selection in the human genome. PLoS Biol 4:e72
Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934
Watanabe Y, Castoro RJ, Kim HS et al (2011) Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer. PLoS ONE 6:e23320
Williams JR, World Medical Association (2009) Medical ethics manual. WMA, Ferney-Voltaire Cedex
Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113
Wright S (1978) Evolution and the genetics of populations: variability within and among natural populations. University of Chicago Press, Chicago
Acknowledgments
We would like to thank all patients and blood donors for their participation in this research study on CRC susceptibility and prognosis. This work has been supported by the Grant Agency of the Czech Republic (GACR) and the Ministry of Education, Youth and Sport of the Czech Republic. [Grant Numbers: CZ:GA CR:GA304/12/1585, CZ:GA CR:GA304/10/1286, and Prvouk-P27/LF1/1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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The authors declare no conflict of interest.
Ethical standard
According to the Helsinki declaration, all patients and blood donors provided a written informed consent and approved the use of their biological samples for genetic studies (Medical ethics manual; WMA) [54]. The study was approved by the Ethics Committees of the Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague (Czech Republic); Institute for Clinical and Experimental Medicine and Faculty Thomayer Hospital, Prague (Czech Republic).
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Huhn, S., Bevier, M., Pardini, B. et al. Colorectal cancer risk and patients’ survival: influence of polymorphisms in genes somatically mutated in colorectal tumors. Cancer Causes Control 25, 759–769 (2014). https://doi.org/10.1007/s10552-014-0379-1
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DOI: https://doi.org/10.1007/s10552-014-0379-1