Skip to main content
SpringerLink
Log in

Genomic Applications in Colorectal Carcinomas

  • Chapter
  • First Online:
Genomic Applications in Pathology

Abstract

Genomic testing has become an integral part of the diagnostic workup of colorectal carcinoma, as it provides guidance for prognosis, therapy, and inherited susceptibility. Currently, the main targets of molecular diagnostic testing in colorectal cancer include evaluations for mismatch repair deficiency (dMMR) and EGFR pathway alterations. Next-generation sequencing is a major advance in this field and will likely replace the numerous single-gene assays used today. This technique can efficiently and cost-effectively evaluate microsatellite instability, tumor mutational burden, Lynch syndrome, EGFR biomarkers, and biomarkers for clinical trials and provide a mutational template for circulating tumor DNA (ctDNA). The new paradigm may eventually be “upfront” NGS testing of all colorectal cancers at the time of diagnosis or resection, followed by ctDNA for evaluating tumor heterogeneity, risk of recurrence, detection of progression (“liquid imaging”), and the development of resistance mutations.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Furtado LV, Samowitz WS. Colorectal cancer molecular profiling: from IHC to NGS in search of optimal algorithm. Virchows Arch. 2017;471:235.

    Article  Google Scholar 

  2. Niu B, Ye K, Zhang Q, Lu C, Xie M, McLellan MD, et al. MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics. 2014;30(7):1015–6.

    Article  CAS  Google Scholar 

  3. Salipante SJ, Scroggins SM, Hampel HL, Turner EH, Pritchard CC. Microsatellite instability detection by next generation sequencing. Clin Chem. 2014;60(9):1192–9.

    Article  CAS  Google Scholar 

  4. Kautto EA, Bonneville R, Miya J, Yu L, Krook MA, Reeser JW, et al. Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. Oncotarget. 2017;8(5):7452–63.

    Article  Google Scholar 

  5. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):1342–50.

    Article  CAS  Google Scholar 

  6. Nowak JA, Yurgelun MB, Bruce JL, Rojas-Rudilla V, Hall DL, Shivdasani P, et al. Detection of mismatch repair deficiency and microsatellite instability in colorectal adenocarcinoma by targeted next-generation sequencing. J Mol Diagn. 2017;19(1):84–91.

    Article  CAS  Google Scholar 

  7. Stadler ZK, Battaglin F, Middha S, Hechtman JF, Tran C, Cercek A, et al. Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels. J Clin Oncol. 2016;34(18):2141–7.

    Article  CAS  Google Scholar 

  8. Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, et al. DNA polymerase epsilon and delta exonuclease domain mutations in endometrial cancer. Hum Mol Genet. 2013;22(14):2820–8.

    Article  CAS  Google Scholar 

  9. Haraldsdottir S, Hampel H, Tomsic J, Frankel WL, Pearlman R, de la Chapelle A, et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014;147(6):1308–16. e1

    Article  Google Scholar 

  10. Garofalo A, Sholl L, Reardon B, Taylor-Weiner A, Amin-Mansour A, Miao D, et al. The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome Med. 2016;8(1):79.

    Article  Google Scholar 

  11. van der Klift HM, Mensenkamp AR, Drost M, Bik EC, Vos YJ, Gille HJ, et al. Comprehensive mutation analysis of PMS2 in a large cohort of Probands suspected of Lynch syndrome or constitutional mismatch repair deficiency syndrome. Hum Mutat. 2016;37(11):1162–79.

    Article  Google Scholar 

  12. Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology. 2015;149(3):604–13. e20

    Article  CAS  Google Scholar 

  13. Clendenning M, Hampel H, LaJeunesse J, Lindblom A, Lockman J, Nilbert M, et al. Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat. 2006;27(5):490–5.

    Article  CAS  Google Scholar 

  14. Vaughn CP, Robles J, Swensen JJ, Miller CE, Lyon E, Mao R, et al. Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Hum Mutat. 2010;31(5):588–93.

    CAS  PubMed  Google Scholar 

  15. Hansen MF, Neckmann U, Lavik LA, Vold T, Gilde B, Toft RK, et al. A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes. Mol Genet Genomic Med. 2014;2(2):186–200.

    Article  Google Scholar 

  16. Pritchard CC, Smith C, Salipante SJ, Lee MK, Thornton AM, Nord AS, et al. ColoSeq provides comprehensive lynch and polyposis syndrome mutational analysis using massively parallel sequencing. J Mol Diagn. 2012;14(4):357–66.

    Article  CAS  Google Scholar 

  17. Vaughn CP, Hart KJ, Samowitz WS, Swensen JJ. Avoidance of pseudogene interference in the detection of 3′ deletions in PMS2. Hum Mutat. 2011;32(9):1063–71.

    Article  CAS  Google Scholar 

  18. Hampel H, de la Chapelle A. How do we approach the goal of identifying everybody with Lynch syndrome? Familial Cancer. 2013;12(2):313–7.

    Article  Google Scholar 

  19. Pahlman LA, Hohenberger WM, Matzel K, Sugihara K, Quirke P, Glimelius B. Should the benefit of adjuvant chemotherapy in colon cancer be re-evaluated? J Clin Oncol. 2016;34(12):1297–9.

    Article  Google Scholar 

  20. Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29(28):3768–74.

    Article  CAS  Google Scholar 

  21. Lanza G, Gafa R, Santini A, Maestri I, Guerzoni L, Cavazzini L. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol. 2006;24(15):2359–67.

    Article  CAS  Google Scholar 

  22. Grant M, Haydon A, Au L, Wilkins S, Oliva K, Segelov E, et al. Immunohistochemistry testing for mismatch repair deficiency in Stage 2 colon cancer: a cohort study of two cancer centres. Int J Surg. 2018;51:71–5.

    Article  Google Scholar 

  23. Tougeron D, Mouillet G, Trouilloud I, Lecomte T, Coriat R, Aparicio T, et al. Efficacy of adjuvant chemotherapy in colon cancer with microsatellite instability: a large multicenter AGEO Study. J Natl Cancer Inst. 2016;108(7):1–9.

    Google Scholar 

  24. Yang L, He W, Yang Q, Kong P, Xie Q, Jiang C, et al. Combination of primary tumor location and mismatch repair status guides adjuvant chemotherapy in stage II colon cancer. Oncotarget. 2017;8(58):99136–49.

    PubMed  PubMed Central  Google Scholar 

  25. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.

    Article  CAS  Google Scholar 

  26. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.

    Article  CAS  Google Scholar 

  27. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99.

    Article  Google Scholar 

  28. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.

    Article  CAS  Google Scholar 

  29. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–608.

    Article  CAS  Google Scholar 

  30. Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34.

    Article  Google Scholar 

  31. George TJ, Frampton GM, Sun J, Gowen K, Kennedy M, Greenbowe JR, et al. Tumor mutational burden as a potential biomarker for PD1/PD-L1 therapy in colorectal cancer. J Clin Oncol. 2016;34(15_suppl):3587.

    Article  Google Scholar 

  32. Gong J, Wang C, Lee PP, Chu P, Fakih M. Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation. J Natl Compr Cancer Netw. 2017;15(2):142–7.

    Article  Google Scholar 

  33. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45.

    Article  CAS  Google Scholar 

  34. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658–64.

    Article  Google Scholar 

  35. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–75.

    Article  CAS  Google Scholar 

  36. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32(21):2240–7.

    Article  CAS  Google Scholar 

  37. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27(5):663–71.

    Article  CAS  Google Scholar 

  38. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72.

    Article  CAS  Google Scholar 

  39. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–705.

    Article  CAS  Google Scholar 

  40. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706–13.

    Article  CAS  Google Scholar 

  41. 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.

    Article  CAS  Google Scholar 

  42. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705–12.

    Article  Google Scholar 

  43. Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27(35):5924–30.

    Article  CAS  Google Scholar 

  44. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69(5):1851–7.

    Article  CAS  Google Scholar 

  45. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596–606.

    Article  CAS  Google Scholar 

  46. Gu M, Nishihara R, Chen Y, Li W, Shi Y, Masugi Y, et al. Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells. Oncotarget. 2017;8(50):87379–89.

    Article  Google Scholar 

  47. Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn. 2017;19(2):187–225.

    Article  CAS  Google Scholar 

  48. Morelli MP, Overman MJ, Dasari A, Kazmi SM, Mazard T, Vilar E, et al. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol. 2015;26(4):731–6.

    Article  CAS  Google Scholar 

  49. Diaz LA Jr, 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.

    Article  CAS  Google Scholar 

  50. Taly V, Pekin D, Benhaim L, Kotsopoulos SK, Le Corre D, Li X, et al. Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. Clin Chem. 2013;59(12):1722–31.

    Article  CAS  Google Scholar 

  51. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.

    Article  Google Scholar 

  52. Takegawa N, Yonesaka K, Sakai K, Ueda H, Watanabe S, Nonagase Y, et al. HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer. Oncotarget. 2016;7(3):3453–60.

    Article  Google Scholar 

  53. Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795–801.

    Article  CAS  Google Scholar 

  54. Tie J, Wang Y, Tomasetti C, Li L, Springer S, Kinde I, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra92.

    Article  Google Scholar 

  55. Scholer LV, Reinert T, Orntoft MW, Kassentoft CG, Arnadottir SS, Vang S, et al. Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer. Clin Cancer Res. 2017;23(18):5437–45.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Chicago, Chicago, IL, USA

    Lauren L. Ritterhouse

  2. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Wade S. Samowitz

Authors
  1. Lauren L. Ritterhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wade S. Samowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wade S. Samowitz .

Editor information

Editors and Affiliations

  1. Professor and Chair of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    George Jabboure Netto

  2. Department of Pathology and Laboratory Medicine, NorthShore University HealthSystem, Clinical Professor of Pathology, University of Chicago Pritzker School of Medicine, Evanston, IL, USA

    Karen L. Kaul

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ritterhouse, L.L., Samowitz, W.S. (2019). Genomic Applications in Colorectal Carcinomas. In: Netto, G., Kaul, K. (eds) Genomic Applications in Pathology. Springer, Cham. https://doi.org/10.1007/978-3-319-96830-8_28

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-96830-8_28

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-96829-2

  • Online ISBN: 978-3-319-96830-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation