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The Molecular Taxonomy of Colorectal Cancer: What’s New?

  • Therapeutic Approaches to Metastatic Colorectal Cancers (L Vecchione, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

Colorectal cancer is a highly complex and heterogeneous disease. Since Vogelstein’s description of a colorectal cancer model almost 30 years ago, significant advances have been made to better characterize and classify colorectal tumors. The technological advances in the past few years have favored a deeper analysis of the genetic and epigenetic features that characterize colorectal tumors, leading to several molecular classifications. Although not always consistent, these analyses have shed light on the molecular features that shape colorectal tumors. In recent times, consensus groups and collaborations are joining forces to provide a single comprehensive colorectal cancer molecular classification that includes genetic, epigenetic, and clinical features. Here, we review what is new in the molecular taxonomy of colorectal cancers and the clinical implications of these classifications.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.

    Article  PubMed  Google Scholar 

  2. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.

    Article  CAS  PubMed  Google Scholar 

  3. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525–32.

    Article  CAS  PubMed  Google Scholar 

  4. Krausova M, Korinek V. Wnt signaling in adult intestinal stem cells and cancer. Cell Signal. 2013;26(3):570–9.

    Article  PubMed  Google Scholar 

  5. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the apc/beta-catenin/tcf pathway in colorectal cancer. Cancer Res. 1998;58(6):1130–4.

    CAS  PubMed  Google Scholar 

  6. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. Comprehensive evaluation of genetic alterations in colorectal cancers.

    Article  Google Scholar 

  7. Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260(5109):816–9.

    Article  CAS  PubMed  Google Scholar 

  9. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363(6429):558–61.

    Article  CAS  PubMed  Google Scholar 

  10. Buhard O, Suraweera N, Lectard A, Duval A, Hamelin R. Quasimonomorphic mononucleotide repeats for high-level microsatellite instability analysis. Dis Markers. 2004;20(4–5):251–7.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Rudzki Z, Zazula M, Okon K, Stachura J. Low-level microsatellite instability colorectal carcinomas: do they really belong to a "gray zone" between high-level microsatellite instability and microsatellite-stable cancers? Int J Color Dis. 2003;18(3):216–21.

    Google Scholar 

  12. Wright CM, Dent OF, Newland RC, Barker M, Chapuis PH, Bokey EL, et al. Low level microsatellite instability may be associated with reduced cancer specific survival in sporadic stage C colorectal carcinoma. Gut. 2005;54(1):103–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Poulogiannis G, Frayling IM, Arends MJ. DNA mismatch repair deficiency in sporadic colorectal cancer and lynch syndrome. Histopathology. 2010;56(2):167–79.

    Article  PubMed  Google Scholar 

  14. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, et al. Methylation of the hmlh1 promoter correlates with lack of expression of hmlh1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997;57(5):808–11.

    CAS  PubMed  Google Scholar 

  15. Whitehall VL, Wynter CV, Walsh MD, Simms LA, Purdie D, Pandeya N, et al. Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res. 2002;62(21):6011–4.

    CAS  PubMed  Google Scholar 

  16. Issa JP. Cpg island methylator phenotype in cancer. Nat Rev Cancer. 2004;4(12):988–93.

    Article  CAS  PubMed  Google Scholar 

  17. Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M, et al. Identification of differentially methylated sequences in colorectal cancer by methylated cpg island amplification. Cancer Res. 1999;59(10):2307–12.

    CAS  PubMed  Google Scholar 

  18. Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS. Cpg island methylator phenotype-low (cimp-low) in colorectal cancer: possible associations with male sex and kras mutations. J Mol Diagn JMD. 2006;8(5):582–8.

    Article  CAS  Google Scholar 

  19. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. Cpg island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with braf mutation in colorectal cancer. Nat Genet. 2006;38(7):787–93.

    Article  CAS  PubMed  Google Scholar 

  20. Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A. 2007;104(47):18654–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Theodoratou E, Campbell H, Tenesa A, Houlston R, Webb E, Lubbe S, et al. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer. 2010;103(12):1875–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. van Lier MG, Westerman AM, Wagner A, Looman CW, Wilson JH, de Rooij FW, et al. High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome. Gut. 2011;60(2):141–7.

    Article  PubMed  Google Scholar 

  23. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50(1):113–30.

    Article  CAS  PubMed  Google Scholar 

  24. Yagi K, Akagi K, Hayashi H, Nagae G, Tsuji S, Isagawa T, et al. Three DNA methylation epigenotypes in human colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(1):21–33.

    Article  CAS  Google Scholar 

  25. Hinoue T, Weisenberger DJ, Lange CP, Shen H, Byun HM, Van Den Berg D, et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 2012;22(2):271–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(3):609–18.

    Article  CAS  Google Scholar 

  27. Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, Labianca R, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103(11):863–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(20):3219–26.

    Article  CAS  Google Scholar 

  30. Sinicrope FA, Mahoney MR, Smyrk TC, Thibodeau SN, Warren RS, Bertagnolli MM, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of Folfox-based adjuvant chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(29):3664–72.

    Article  CAS  Google Scholar 

  31. Klingbiel D, Saridaki Z, Roth AD, Bosman FT, Delorenzi M, Tejpar S. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or folfiri in relation to microsatellite status: results of the petacc-3 trialdagger. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2015;26(1):126–32.

    Article  CAS  Google Scholar 

  32. Pogue-Geile K, Yothers G, Taniyama Y, Tanaka N, Gavin P, Colangelo L, et al. Defective mismatch repair and benefit from bevacizumab for colon cancer: Findings from nsabp c-08. J Natl Cancer Inst. 2013;105(13):989–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Van Rijnsoever M, Elsaleh H, Joseph D, McCaul K, Iacopetta B. Cpg island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2003;9(8):2898–903.

    Google Scholar 

  34. Iacopetta B, Kawakami K, Watanabe T. Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the cpg island methylator phenotype the 5-fluorouracil-responsive subgroup? Int J Clin Oncol. 2008;13(6):498–503.

    Article  CAS  PubMed  Google Scholar 

  35. Shen L, Catalano PJ, Benson 3rd AB, O'Dwyer P, Hamilton SR, Issa JP. Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13(20):6093–8.

    Article  CAS  Google Scholar 

  36. Eschrich S, Yang I, Bloom G, Kwong KY, Boulware D, Cantor A, et al. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(15):3526–35.

    Article  CAS  Google Scholar 

  37. Wang Y, Jatkoe T, Zhang Y, Mutch MG, Talantov D, Jiang J, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes' B colon cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(9):1564–71.

    Article  CAS  Google Scholar 

  38. Salazar R, Roepman P, Capella G, Moreno V, Simon I, Dreezen C, et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(1):17–24.

    Article  Google Scholar 

  39. Salazar R, de Waard JW, Glimelius B, Marshall J, Klaase J, Hoeven JVD, et al. The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (cc) patients using Coloprint. J Clin Oncol. 2012;30(suppl 4; abstr 678).

  40. O'Connell MJ, Lavery I, Yothers G, Paik S, Clark-Langone KM, Lopatin M, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(25):3937–44.

    Article  Google Scholar 

  41. Gray RG, Quirke P, Handley K, Lopatin M, Magill L, Baehner FL, et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(35):4611–9.

    Article  Google Scholar 

  42. Yothers G, O'Connell MJ, Lee M, Lopatin M, Clark-Langone KM, Millward C, et al. Validation of the 12-gene colon cancer recurrence score in nsabp c-07 as a predictor of recurrence in patients with stage ii and iii colon cancer treated with fluorouracil and leucovorin (fu/lv) and fu/lv plus oxaliplatin. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(36):4512–9.

    Article  CAS  Google Scholar 

  43. De Sousa EMF, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LP, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013;19(5):614–8.

    Article  Google Scholar 

  44. Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19(5):619–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Sadanandam A, Wang X, de Sousa EMF, Gray JW, Vermeulen L, Hanahan D, et al. Reconciliation of classification systems defining molecular subtypes of colorectal cancer: interrelationships and clinical implications. Cell Cycle. 2014;13(3):353–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10(5):e1001453.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Roepman P, Schlicker A, Tabernero J, Majewski I, Tian S, Moreno V, et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer J Int Cancer. 2014;134(3):552–62.

    Article  CAS  Google Scholar 

  48. Budinska E, Popovici V, Tejpar S, D'Ario G, Lapique N, Sikora KO, et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol. 2013;231(1):63–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Schlicker A, Beran G, Chresta CM, McWalter G, Pritchard A, Weston S, et al. Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med Genet. 2012;5:66.

    CAS  Google Scholar 

  50. Dienstmann R, Guinney J, Delorenzi M, De Reynies A, Roepman P, Sadanandam A, et al. Colorectal cancer subtyping consortium (CRCSC) identification of a consensus of molecular subtypes. J Clin Oncol. 2014;32:5s. suppl; abstr 3511.

    Article  Google Scholar 

  51. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    Article  CAS  PubMed  Google Scholar 

  52. Diaz Jr LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–40.

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of kras mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532–6. Proof of principle showing how colorectal cancer can adapt and evolve influenced by the administered treatment.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546–58. Excellent review on cancer genomics.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Hiley C, de Bruin EC, McGranahan N, Swanton C. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biol. 2014;15(8):453.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Kopetz S, Overman MJCK, et al. Mutation and copy number discordance in primary versus metastatic colorectal cancer (MCRC). J Clin Oncol. 2014;32:5s (suppl; abstr 3509).

    Article  Google Scholar 

  57. Pelizzola M, Ecker JR. The DNA methylome. FEBS Lett. 2011;585(13):1994–2000.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

Ana Sebio is a recipient of a Juan Rodés contract from Instituto de Salud Carlos III, Spain (JR00006).

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Ana Sebio and Heinz-Josef Lenz declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Heinz-Josef Lenz.

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This article is part of the Topical Collection on Therapeutic Approaches to Metastatic Colorectal Cancers

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Sebio, A., Lenz, HJ. The Molecular Taxonomy of Colorectal Cancer: What’s New?. Curr Colorectal Cancer Rep 11, 118–124 (2015). https://doi.org/10.1007/s11888-015-0267-4

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