Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A subset of genetic susceptibility variants for colorectal cancer also has prognostic value

The Pharmacogenomics Journal volume 16, pages 173–179 (2016)Cite this article

Subjects

Abstract

We investigated the possible influence of 86 single-nucleotide polymorphisms (SNPs), known to associate with the risk of colorectal cancer (CRC), on overall survival and time to recurrence (TTR) in 733 Italian CRC patients followed up for up to 84 months after surgery. In the Cox multivariate analysis, adjusted for gender, age, pathological stage and adjuvant chemotherapy (yes/no), the risk of death significantly increased by rare allele count (P<0.05) for rs1801133 (MTHFR), rs4939827 (SMAD7), rs2306283 (SLCO1B1) and rs12898159 (BMP4), whereas for rs736775 (GPX3) the opposite was observed. Two additional SNPs associated with TTR, namely rs16892766 (downstream of EIF3H) and rs10749971 (COLCA2). Our findings show that some genetic variants previously found to associate with CRC risk are also associated with survival after treatment. The identification of alleles defining subgroups of patients with worse clinical outcome may have application in developing pharmacogenetic strategies aimed at personalizing CRC treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM . Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893–2917.

    Article  CAS  Google Scholar 

  2. Huxley RR, Ansary-Moghaddam A, Clifton P, Czernichow S, Parr CL, Woodward M . The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer 2009; 125: 171–180.

    Article  CAS  PubMed  Google Scholar 

  3. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78–85.

    Article  CAS  PubMed  Google Scholar 

  4. Houlston RS, Webb E, Broderick P, Pittman AM, Di Bernardo MC, Lubbe S et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 2008; 40: 1426–1435.

    Article  CAS  PubMed  Google Scholar 

  5. Houlston RS, Cheadle J, Dobbins SE, Tenesa A, Jones AM, Howarth K et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet 2010; 42: 973–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lascorz J, Forsti A, Chen B, Buch S, Steinke V, Rahner N et al. Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility. Carcinogenesis 2010; 31: 1612–1619.

    Article  CAS  PubMed  Google Scholar 

  7. Tomlinson IP, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 2008; 40: 623–630.

    Article  CAS  PubMed  Google Scholar 

  8. Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, Tenesa A, Jones AM, Howarth K et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet 2011; 7: e1002105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Peters U, Hutter CM, Hsu L, Schumacher FR, Conti DV, Carlson CS et al. Meta-analysis of new genome-wide association studies of colorectal cancer risk. Hum Genet 2012; 131: 217–234.

    Article  PubMed  Google Scholar 

  10. Tenesa A, Farrington SM, Prendergast JG, Porteous ME, Walker M, Haq N et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 2008; 40: 631–637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 2007; 39: 989–994.

    Article  CAS  PubMed  Google Scholar 

  12. Lubbe SJ, Pittman AM, Olver B, Lloyd A, Vijayakrishnan J, Naranjo S et al. The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4. Oncogene 2012; 31: 3777–3784.

    Article  CAS  PubMed  Google Scholar 

  13. Dai J, Gu J, Huang M, Eng C, Kopetz ES, Ellis LM et al. GWAS-identified colorectal cancer susceptibility loci associated with clinical outcomes. Carcinogenesis 2012; 33: 1327–1331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cicek MS, Slager SL, Achenbach SJ, French AJ, Blair HE, Fink SR et al. Functional and clinical significance of variants localized to 8q24 in colon cancer. Cancer Epidemiol Biomark Prev 2009; 18: 2492–2500.

    Article  CAS  Google Scholar 

  15. Tenesa A, Theodoratou E, Din FV, Farrington SM, Cetnarskyj R, Barnetson RA et al. Ten common genetic variants associated with colorectal cancer risk are not associated with survival after diagnosis. Clin Cancer Res 2010; 16: 3754–3759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abuli A, Lozano JJ, Rodriguez-Soler M, Jover R, Bessa X, Munoz J et al. Genetic susceptibility variants associated with colorectal cancer prognosis. Carcinogenesis 2013; 34: 2286–2291.

    Article  CAS  PubMed  Google Scholar 

  17. Xing J, Myers RE, He X, Qu F, Zhou F, Ma X et al. GWAS-identified colorectal cancer susceptibility locus associates with disease prognosis. Eur J Cancer 2011; 47: 1699–1707.

    Article  CAS  PubMed  Google Scholar 

  18. Sargent D, Sobrero A, Grothey A, O'Connell MJ, Buyse M, Andre T et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20 898 patients on 18 randomized trials. J Clin Oncol 2009; 27: 872–877.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27: 3109–3116.

    Article  CAS  PubMed  Google Scholar 

  20. Marcuello E, Altes A, del Rio E, Cesar A, Menoyo A, Baiget M . Single nucleotide polymorphism in the 5' tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 2004; 112: 733–737.

    Article  CAS  PubMed  Google Scholar 

  21. Thomas F, Motsinger-Reif AA, Hoskins JM, Dvorak A, Roy S, Alyasiri A et al. Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer. Br J Cancer 2011; 105: 1654–1662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Braun MS, Richman SD, Thompson L, Daly CL, Meade AM, Adlard JW et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 2009; 27: 5519–5528.

    Article  CAS  PubMed  Google Scholar 

  23. Pelucchi S, Mariani R, Calza S, Fracanzani AL, Modignani GL, Bertola F et al. CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients. Haematologica 2012; 97: 1818–1825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clarke GM, Anderson CA, Pettersson FH, Cardon LR, Morris AP, Zondervan KT . Basic statistical analysis in genetic case-control studies. Nat Protoc 2011; 6: 121–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. De Mattia E, Toffoli G . C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer 2009; 45: 1333–1351.

    Article  CAS  PubMed  Google Scholar 

  26. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.

    Article  CAS  PubMed  Google Scholar 

  27. Niemi M, Pasanen MK, Neuvonen PJ . Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 2011; 63: 157–181.

    Article  CAS  PubMed  Google Scholar 

  28. Innocenti F, Kroetz DL, Schuetz E, Dolan ME, Ramirez J, Relling M et al. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 2009; 27: 2604–2614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Phipps AI, Newcomb PA, Garcia-Albeniz X, Hutter CM, White E, Fuchs CS et al. Association between colorectal cancer susceptibility loci and survival time after diagnosis with colorectal cancer. Gastroenterology 2012; 143: 51–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tenesa A, Dunlop MG . New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 2009; 10: 353–358.

    Article  CAS  PubMed  Google Scholar 

  31. Xu Y, Pasche B . TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet 2007; 16: R14–R20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pittman AM, Naranjo S, Jalava SE, Twiss P, Ma Y, Olver B et al. Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H. PLoS Genet 2010; 6: e1001126.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Mahmood SF, Gruel N, Chapeaublanc E, Lescure A, Jones T, Reyal F et al. A siRNA screen identifies RAD21, EIF3H, CHRAC1 and TANC2 as driver genes within the 8q23, 8q24.3 and 17q23 amplicons in breast cancer with effects on cell growth, survival and transformation. Carcinogenesis 2014; 35: 670–682.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Valerie Matarese for scientific editing and writing support. This work was supported in part by a grant from the Italian Association for Cancer Research (AIRC, grant no. 12162). The funder had no role in the design and conduct of the study, in the collection, analysis or interpretation of the data, or in the preparation, review or approval of the manuscript.

Author information

Author notes

  1. F Melotti

    Present address: 6Present address: Pathology Service, Azienda Ospedaliera di Desenzano del Garda, Manerbio, Italy.,

  2. A Vannelli

    Present address: 7Present address: Division of Oncologic and Gastrointestinal Surgery, Valduce Hospital, Como, Italy.,

Authors and Affiliations

  1. Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    S Noci, T A Dragani & A Galvan

  2. Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    M Dugo

  3. Consortium for Human Molecular Genetics, University of Milano-Bicocca, Monza, Italy

    F Bertola

  4. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    F Melotti

  5. Division of General Surgery B, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    A Vannelli

Authors
  1. S Noci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Dugo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Bertola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Melotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Vannelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T A Dragani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Galvan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T A Dragani.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Noci, S., Dugo, M., Bertola, F. et al. A subset of genetic susceptibility variants for colorectal cancer also has prognostic value. Pharmacogenomics J 16, 173–179 (2016). https://doi.org/10.1038/tpj.2015.35

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.35

This article is cited by

Search

Advanced search

Quick links