Skip to main content

Advertisement

SpringerLink
Log in

Genetic Landscape of Primary Versus Metastatic Colorectal Cancer: to What Extent Are They Concordant?

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

Abstract

Recent developments in genomic technologies have led an unprecedented view of the profound molecular complexity of colorectal cancer (CRC) and its evolution. The genomic landscape of CRC is characterized by a high heterogeneous landscape both at an intratumoral and at an inter-metastatic and intrametastatic level. In the era of personalized cancer medicine, the challenge is the definition of predictive biomarkers in respect of a such complex scenario. Despite the robust differences occurring between primary tumor and metastatic sites, the biomarkers currently validated in clinical practice have high concordance. The purpose of this review is to explore differences existing in genetic landscape of primary tumor and metastatic sites in CRC, in order to assess concordance and discordance rates of biologic events between different tumor lesions in CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  2. Malvezzi M, Bertuccio P, Rosso T, Rota M, Levi F, La Vecchia C, et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann Oncol. 2015. doi:10.1093/annonc/mdv001.

    PubMed  Google Scholar 

  3. Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, on behalf of the ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Supplement 3):iii1–9. doi:10.1093/annonc/mdu260.

    Article  PubMed  Google Scholar 

  4. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.

    Article  PubMed  Google Scholar 

  5. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.

    Article  CAS  PubMed  Google Scholar 

  6. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041–7. Cross Ref Medline Web of Science Google Scholar.

    Article  CAS  PubMed  Google Scholar 

  7. Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007;370(9582):135–42.

    Article  CAS  PubMed  Google Scholar 

  8. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  9. Van Cutsem E, Ohtsu A, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Phase III RECOURSE trial of TAS-102 vs. placebo, with best supportive care (BSC), in patients (PTS) with metastatic colorectal cancer (MCRC) refractory to standard therapies. ESMO Abstract LBA13. Ann Oncol. 2014;25(Supplement 5):v1–41. doi:10.1093/annonc/mdu438.11.

    Article  Google Scholar 

  10. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12. doi:10.1016/S0140-6736(12)61900-X.

    Article  CAS  PubMed  Google Scholar 

  11. Qing-Yang F, Ye W, Jing-Wen C, Wen-Ju C, Le-Chi Y, De-Xiang Z, et al. Anti-EGFR and anti-VEGF agents: important targeted therapies of colorectal liver metastases. World J Gastroenterol. 2014;20(15):4263–75.

    Article  Google Scholar 

  12. Schilsky RL. Personalized medicine in oncology: the future is now. Nat Rev Drug Discov. 2010;9:363–6. doi:10.1038/nrd3181.

    Article  CAS  PubMed  Google Scholar 

  13. Marte B. Tumour heterogeneity. Nature. 2013;501:327. doi:10.1038/501327a.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. Author manuscript; available in PMC 2013 August 22. Science. 2013;339(6127): 1546–1558. doi: 10.1126/science.1235122. This paper is of high importance, it represents a general background to understand genome landscape in solid tumors .

  16. Tomasetti C, Marchionni L, Nowak MA, Parmigiani G, Vogelstein B. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci U S A. 2015;112(1):118–23. doi:10.1073/pnas.1421839112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361(25):2449–60. doi:10.1056/NEJMra0804588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Perea J, Lomas M, Hidalgo M. Molecular basis of colorectal cancer: towards an individualized management? Rev Esp Enferm Dig. 2011;103(1):29–35.

    Article  CAS  PubMed  Google Scholar 

  20. Kanthan R, Senger JL, Kanthan SC. Molecular events in primary and metastatic colorectal carcinoma: a review. Pathol Res Int. 2012;2012:597497.

    Article  Google Scholar 

  21. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999;96(15):8681–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059–72. doi:10.1053/j.gastro.2009.12.065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.

    Article  CAS  PubMed  Google Scholar 

  24. Santos C, Sanz-Pamplona R, Nadal E, Grasselli J, Pernas S, Dienstmann R, et al. Intrinsic cancer subtypes-next steps into personalized medicine. Cell Oncol. 2015;38(1):3–16. doi:10.1007/s13402-014-0203-7. This paper explains the importance of CRC subtypes for personalized medicine.

    Article  Google Scholar 

  25. De Sousa E, Melo F, Wang X, Jansen M, Fessler E, Trinh A, 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. doi:10.1038/nm.3174.

    Article  Google Scholar 

  26. 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. doi:10.1002/path.4212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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. ASCO Meet Abstr. 2014;32:3511. This paper represents all the efforts done to understand CRC subtypes.

    Google Scholar 

  28. Xie T, Cho YB, Wang K, Huang D, Hong HK, Choi YL, et al. Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing. Genomics. 2014;104(4):234–41. doi:10.1016/j.ygeno.2014.07.012.

    Article  CAS  PubMed  Google Scholar 

  29. Mekenkamp LJ, Haan JC, Israeli D, van Essen HF, Dijkstra JR, van Cleef P, et al. Chromosomal copy number aberrations in colorectal metastases resemble their primary counterparts and differences are typically non-recurrent. PLoS One. 2014;9(2):e86833. doi:10.1371/journal.pone.0086833. eCollection 2014.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Haan JC, Labots M, Rausch C, Koopman M, Tol J, Mekenkamp LJ, et al. Genomic landscape of metastatic colorectal cancer. Nat Commun. 2014;5:5457. doi:10.1038/ncomms6457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mao C, Wu XY, Yang ZY, Threapleton DE, Yuan JQ, Yu YY, et al. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep. 2015;5:8065. doi:10.1038/srep08065. This brilliant meta-analysis gives an insight into differences between primary tumors and metastasis in CRC according with KRAS, BRAF, PI3KCA and PTEN.

    Article  CAS  PubMed  Google Scholar 

  32. Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J, et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol. 2012;30(24):2956–62. doi:10.1200/ JCO.2011.38.2994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 2009;27(16):2622–9. doi:10.1200/JCO.2008.20.2796.

    Article  CAS  PubMed  Google Scholar 

  34. Atreya CE, Sangale Z, Xu N, Matli MR, Tikishvili E, Welbourn W, et al. PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival. Cancer Med. 2013;2(4):496–506. doi:10.1002/cam4.97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ren B, Zakharov V, Yang Q, McMahon L, Yu J, Cao W. MACC1 is related to colorectal cancer initiation and early-stage invasive growth. Am J Clin Pathol. 2013;140(5):701–7. doi:10.1309/AJCPRH1H5RWWSXRB.

    Article  PubMed  Google Scholar 

  36. Zhen T, Dai S, Li H, Yang Y, Kang L, Shi H, et al. MACC1 promotes carcinogenesis of colorectal cancer via β-catenin signaling pathway. Oncotarget. 2014;5(11):3756–69.

    PubMed  PubMed Central  Google Scholar 

  37. Li N, Lorenzi F, Kalakouti E, Normatova M, Babaei-Jadidi R, Tomlinson I, Nateri AS. FBXW7-mutated colorectal cancer cells exhibit aberrant expression of phosphorylated-p53 at serine-15. Oncotarget. 2015 Mar 16.

  38. Tomasetti C, Vogelstein B, Parmigiani G. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc Natl Acad Sci U S A. 2013;110(6):1999–2004. doi:10.1073/pnas.1221068110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Arriba M, García JL, Inglada-Pérez L, Rueda D, Osorio I, Rodríguez Y, et al. DNA copy number profiling reveals different patterns of chromosomal instability within colorectal cancer according to the age of onset. Mol Carcinog. 2015. doi:10.1002/mc.22315.

    PubMed  Google Scholar 

  40. Chen L, Zhou W, Zhang L, Zhang F. Genome architecture and its roles in human copy number variation. Genomics Inform. 2014;12(4):136–44. doi:10.5808/GI.2014.12.4.136.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Fisher R, Pusztai L, Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer. 2013;108(3):479–85. doi:10.1038/bjc.2012.581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. doi:10.1038/nature11252Cancer.

    Article  Google Scholar 

  43. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011;39(Database issue):D945–50. doi:10.1093/nar/gkq929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H, Forbes S, et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 2013;41(Database issue):D955–61. doi:10.1093/nar/gks1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.

    Article  PubMed  Google Scholar 

  46. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48(10):1466–75. doi:10.1016/j.ejca.2012.02.057.

    Article  CAS  PubMed  Google Scholar 

  47. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34. doi:10.1056/NEJMoa1305275.

    Article  CAS  PubMed  Google Scholar 

  48. Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010;28(7):1254–61. doi:10.1200/JCO.2009.24.6116.

    Article  CAS  PubMed  Google Scholar 

  49. Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013;3(6):658–73. doi:10.1158/2159-8290.CD-12-0558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1(6):508–23. doi:10.1158/2159-8290.CD-11-0109.

    Article  CAS  PubMed  Google Scholar 

  51. Ingold Heppner B, Behrens H-M, Balschun K, Haag J, Krüger S, Becker T, et al. HER2/neu testing in primary colorectal carcinoma. Br J Cancer. 2014;111:1977–84. doi:10.1038/bjc.2014.483.

    Article  CAS  PubMed  Google Scholar 

  52. Kaneko Y, Kuramochi H, Nakajima G, Inoue Y, Yamamoto M. Degraded DNA may induce discordance of KRAS status between primary colorectal cancer and corresponding liver metastases. Int J Clin Oncol. 2014;19(1):113–20. doi:10.1007/s10147-012-0507-4.

    Article  CAS  PubMed  Google Scholar 

  53. Kopetz S, Overman MJ, Chen K, Lucio-Eterovic AK, Kee BK, Fogelman DR, 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 

  54. Li XL, Zhou J, Chen ZR, Chng WJ. P53 mutations in colorectal cancer—molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 2015;21(1):84–93. doi:10.3748/wjg.v21.i1.84.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell. 2000;100:387–90.

    Article  PubMed  Google Scholar 

  56. Molinari F, Frattini M. Functions and Regulation of the PTEN gene in colorectal cancer. Front Oncol. 2013;3:326.

    PubMed  PubMed Central  Google Scholar 

  57. Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97(8):1139–45. doi:10.1038/sj.bjc.6604009. Published online 2007 October 16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I, et al. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med. 2009;15(1):59–67. doi:10.1038/nm.1889.

    Article  CAS  PubMed  Google Scholar 

  59. Davis H, Tomlinson I. CDC4/FBXW7 and the ‘just enough’ model of tumourigenesis. J Pathol. 2012;227(2):131–5. doi:10.1002/path.4004.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Claudia Cardone, Giulia Martini, Teresa Troiani, Stefania Napolitano, Francesco Selvaggi, Fortunato Ciardiello, and Erika Martinelli declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

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

Author information

Author notes

    Authors and Affiliations

    1. Second University of Naples, Via Pansini 5, 80131, Naples, Italy

      Claudia Cardone, Giulia Martini, Teresa Troiani, Stefania Napolitano, Fortunato Ciardiello & Erika Martinelli

    2. Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy

      Francesco Selvaggi

    Authors
    1. Claudia Cardone
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Giulia Martini
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Teresa Troiani
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Stefania Napolitano
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Francesco Selvaggi
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Fortunato Ciardiello
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Erika Martinelli
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Erika Martinelli.

    Additional information

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

    Claudia Cardone and Giulia Martini contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Cardone, C., Martini, G., Troiani, T. et al. Genetic Landscape of Primary Versus Metastatic Colorectal Cancer: to What Extent Are They Concordant?. Curr Colorectal Cancer Rep 11, 217–224 (2015). https://doi.org/10.1007/s11888-015-0278-1

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11888-015-0278-1

    Keywords

    Search

    Navigation