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Early detection: the impact of genomics

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Abstract

The field of genomics has shifted our view on disease development by providing insights in the molecular and functional processes encoded in the genome. In the case of cancer, many alterations in the DNA accumulate that enable tumor growth or even metastatic dissemination. Identification of molecular signatures that define different stages of progression towards cancer can enable early tumor detection. In this review, the impact of genomics will be addressed using early detection of colorectal cancer (CRC) as an example. Increased understanding of the adenoma-to-carcinoma progression has led to the discovery of several diagnostic biomarkers. This combined with technical advancements, has facilitated the development of molecular tests for non-invasive early CRC detection in stool and blood samples. Even though several tests have already made it to clinical practice, sensitivity and specificity for the detection of precancerous lesions still need improvement. Besides the diagnostic qualities, also the accuracy of the intermediate endpoint is an important issue on how the effectiveness of a novel test is perceived. Here, progression biomarkers may provide a more precise measure than the currently used morphologically based features. Similar developments in biomarker use for early detection have taken place in other cancer types.

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References

  1. Forbes SA, Bhamra G, Bamford S et al (2008) The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet Chapter 10:10.11

    Google Scholar 

  2. Muzny DM, Bainbridge MN, Chang K et al (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337

    Article  CAS  Google Scholar 

  3. Hanahan D, Weinberg RA, Adams JM et al (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  4. Wilson JMG, Jungner G (1968) Principles and practice of screening for disease. WHO. Available from http://www.who.int/bulletin/volumes/86/4/07-050112bp.pdf, Geneva Accessed 25 January 2017

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

    Article  PubMed  Google Scholar 

  6. Gray JAM, Patnick J, Blanks RG (2008) Maximizing benefit and minimizing harm of screening. BMJ 336:480–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. IJspeert JEG, Vermeulen L, Meijer GA, Dekker E (2015) Serrated neoplasia-role in colorectal carcinogenesis and clinical implications. Nat Rev Gastroenterol Hepatol 12:401–409

    Article  CAS  PubMed  Google Scholar 

  8. Muto T, Bussey HJ, Morson BC (1975) The evolution of cancer of the colon and rectum. Cancer 36:2251–2270

    Article  CAS  PubMed  Google Scholar 

  9. Lieberman DA, Weiss DG, Bond JH et al (2000) Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 343:162–168

    Article  CAS  PubMed  Google Scholar 

  10. Imperiale TF, Wagner DR, Lin CY et al (2000) Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal findings. N Engl J Med 343:169–174

    Article  CAS  PubMed  Google Scholar 

  11. Shinya H, Wolff WI (1979) Morphology, anatomic distribution and cancer potential of colonic polyps. Ann Surg 190:679–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Groden J, Thliveris A, Samowitz W et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600

    Article  CAS  PubMed  Google Scholar 

  13. Drost J, van Jaarsveld RH, Ponsioen B et al (2015) Sequential cancer mutations in cultured human intestinal stem cells. Nature 521:43–47

    Article  CAS  PubMed  Google Scholar 

  14. Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol Mech Dis 6:479–507

    Article  CAS  Google Scholar 

  15. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Article  CAS  PubMed  Google Scholar 

  16. Derks S, Postma C, Moerkerk PTM et al (2006) Promoter methylation precedes chromosomal alterations in colorectal cancer development. Cell Oncol 28:247–257

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sook Kim M, Lee J, Sidransky D (2010) DNA methylation markers in colorectal cancer. Cancer Metastasis Rev 29:181–206

    Article  Google Scholar 

  18. Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386:623–627

    Article  CAS  PubMed  Google Scholar 

  19. Barber TD, McManus K, Yuen KWY et al (2008) Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci U S A 105:3443–3448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C (2003) The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer 3:695–701

    Article  CAS  PubMed  Google Scholar 

  21. Ried T, Knutzen R, Steinbeck R et al (1996) Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors. Genes Chromosom Cancer 15:234–245

    Article  CAS  PubMed  Google Scholar 

  22. Meijer GA, Hermsen MA, Baak JP et al Progression from colorectal adenoma to carcinoma is associated with non- random chromosomal gains as detected by comparative genomic hybridisation. J Clin Pathol 51:901–909

  23. Douglas EJ, Fiegler H, Rowan A et al (2004) Array comparative genomic hybridization analysis of colorectal cancer cell lines and primary carcinomas. Cancer Res 64:4817–4825

    Article  CAS  PubMed  Google Scholar 

  24. Hermsen M, Postma C, Baak J et al (2002) Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability. Gastroenterology 123:1109–1119

    Article  CAS  PubMed  Google Scholar 

  25. Carvalho B, Postma C, Mongera S et al (2009) Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression. Gut 58:79–89

    Article  CAS  PubMed  Google Scholar 

  26. de Groen FLM, Krijgsman O, Tijssen M et al (2014) Gene-dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression. Genes Chromosom Cancer 53:339–348

    Article  CAS  PubMed  Google Scholar 

  27. Camps J, Pitt JJ, Emons G et al (2013) Genetic amplification of the NOTCH modulator LNX2 upregulates the WNT/ -catenin pathway in colorectal cancer. Cancer Res 73:2003–2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Firestein R, Bass AJ, Kim SY et al (2008) CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature 455:547–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sillars-Hardebol AH, Carvalho B, Tijssen M et al (2012) TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression. Gut 61:1568–1575

    Article  CAS  PubMed  Google Scholar 

  30. Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269

    Article  CAS  PubMed  Google Scholar 

  31. Ivanovska I, Ball AS, Diaz RL et al (2008) MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol Cell Biol 28:2167–2174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Petrocca F, Visone R, Onelli MR et al (2008) E2F1-regulated microRNAs impair TGFβ-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13:272–286

    Article  CAS  PubMed  Google Scholar 

  33. Diosdado B, van de Wiel MA, Terhaar Sive Droste JS et al (2009) MiR-17-92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma to adenocarcinoma progression. Br J Cancer 101:707–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nagel R, le Sage C, Diosdado B et al (2008) Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res 68:5795–5802

    Article  CAS  PubMed  Google Scholar 

  35. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130

    Article  CAS  PubMed  Google Scholar 

  36. Guinney J, Dienstmann R, Wang X et al (2015) The consensus molecular subtypes of colorectal cancer. Nat Med 21:1350–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dienstmann R, Vermeulen L, Guinney J et al (2017) Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer 17:79–92

    Article  CAS  PubMed  Google Scholar 

  38. Ahlquist DA (2010) Molecular detection of colorectal neoplasia. Gastroenterology 138:2127–2139

    Article  CAS  PubMed  Google Scholar 

  39. Lee JK, Liles EG, Bent S, et al. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis

  40. Ahlquist DA, Harrington JJ, Burgart LJ, Roche PC (2000) Morphometric analysis of the “mucocellular layer” overlying colorectal cancer and normal mucosa: relevance to exfoliation and stool screening. Hum Pathol 31:51–57

    Article  CAS  PubMed  Google Scholar 

  41. Zou H, Taylor WR, Harrington JJ et al (2009) High detection rates of colorectal neoplasia by stool DNA testing with a novel digital melt curve assay. Gastroenterology 136:459–470

    Article  CAS  PubMed  Google Scholar 

  42. Sidransky D, Tokino T, Hamilton SR et al (1992) Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science 256:102–105

    Article  CAS  PubMed  Google Scholar 

  43. Deuter R, Müller O (1998) Detection of APC mutations in stool DNA of patients with colorectal cancer by HD-PCR. Hum Mutat 11:84–89

    Article  CAS  PubMed  Google Scholar 

  44. Eguchi S, Kohara N, Komuta K, Kanematsu T (1996) Mutations of the p53 gene in the stool of patients with resectable colorectal cancer. Cancer 77:1707–1710

    Article  CAS  PubMed  Google Scholar 

  45. Müller HM, Oberwalder M, Fiegl H et al (2004) Methylation changes in fecal DNA: a marker for colorectal cancer screening? Lancet 363:1283–1285

    Article  PubMed  Google Scholar 

  46. Bosch LJW, Carvalho B, Fijneman RJA et al (2011) Molecular tests for colorectal cancer screening. Clin Colorectal Cancer 10:8–23

    Article  CAS  PubMed  Google Scholar 

  47. Imperiale TF, Ransohoff DF, Itzkowitz SH et al (2014) Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 370:1287–1297

    Article  CAS  PubMed  Google Scholar 

  48. Heigh RI, Yab TC, Taylor WR et al (2014) Detection of colorectal serrated polyps by stool DNA testing: comparison with fecal immunochemical testing for occult blood (FIT). PLoS One 9:e85659

    Article  PubMed  PubMed Central  Google Scholar 

  49. de Wijkerslooth TR, Stoop EM, Bossuyt PM et al (2012) Immunochemical fecal occult blood testing is equally sensitive for proximal and distal advanced eoplasia. Am J Gastroenterol 107:1570–1578

    Article  PubMed  Google Scholar 

  50. Hoff G, Grotmol T, Thiis-Evensen E et al (2004) Testing for fecal calprotectin (PhiCal) in the Norwegian Colorectal Cancer Prevention trial on flexible sigmoidoscopy screening: comparison with an immunochemical test for occult blood (FlexSure OBT). Gut 53:1329–1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Uppara M, Adaba F, Askari A et al (2015) A systematic review and meta-analysis of the diagnostic accuracy of pyruvate kinase M2 isoenzymatic assay in diagnosing colorectal cancer. World J Surg Oncol 13:48

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yajima S, Ishii M, Matsushita H et al (2007) Expression profiling of fecal colonocytes for RNA-based screening of colorectal cancer. Int J Oncol 31:1029–1037

    CAS  PubMed  Google Scholar 

  53. Beaulieu J-F, Herring E, Kanaoka S, Tremblay É (2016) Use of integrin alpha 6 transcripts in a stool mRNA assay for the detection of colorectal cancers at curable stages. Oncotarget 7:14684–14692

    Article  PubMed  PubMed Central  Google Scholar 

  54. Link A, Balaguer F, Shen Y et al (2010) Fecal microRNAs as novel biomarkers for colon cancer screening. Cancer Epidemiol Biomark Prev 19:1766–1774

    Article  CAS  Google Scholar 

  55. Schwarzenbach H, Hoon DSB, Pantel K (2011) Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11:426–437

    Article  CAS  PubMed  Google Scholar 

  56. Kopreski MS, Benko FA, Kwee C et al (1997) Detection of mutant K-ras DNA in plasma or serum of patients with colorectal cancer. Br J Cancer 76:1293–1299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Church TR, Wandell M, Lofton-Day C et al (2014) Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut 63:317–325

    Article  CAS  PubMed  Google Scholar 

  58. FDA US Food & Drug Administration (2013) Letter of Approval Epi ProColon P130001 Available from: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_template.cfm?id=p130001. Accessed 31 Jan 2017

  59. Heichman KA (2014) Blood-based testing for colorectal cancer screening. Mol Diagn Ther 18:127–135

    Article  PubMed  Google Scholar 

  60. Thomson DM, Krupey J, Freedman SO, Gold P (1969) The radioimmunoassay of circulating carcinoembryonic antigen of the human digestive system. Proc Natl Acad Sci U S A 64:161–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ma H, Chen G, Guo M (2016) Mass spectrometry based translational proteomics for biomarker discovery and application in colorectal cancer. PROTEOMICS - Clin Appl 10:503–515. doi:10.1002/prca.201500082

    Article  CAS  PubMed  Google Scholar 

  62. Kraus S, Shapira S, Kazanov D, et al. (2015) Predictive levels of CD24 in peripheral blood leukocytes for the early detection of colorectal adenomas and adenocarcinomas. Dis Markers 2015:916098.

  63. García JM, García V, Peña C et al (2008) Extracellular plasma RNA from colon cancer patients is confined in a vesicle-like structure and is mRNA-enriched. RNA 14:1424–1432

    Article  PubMed  PubMed Central  Google Scholar 

  64. Chao S, Ying J, Liew G et al (2013) Blood RNA biomarker panel detects both left- and right-sided colorectal neoplasms: a case-control study. J Exp Clin Cancer Res 32:44

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ganepola GA, Nizin J, Rutledge JR, Chang DH (2014) Use of blood-based biomarkers for early diagnosis and surveillance of colorectal cancer. World J Gastrointest Oncol 6:83–97

    Article  PubMed  PubMed Central  Google Scholar 

  66. Young GP, Senore C, Mandel JS et al (2016) Recommendations for a step-wise comparative approach to the evaluation of new screening tests for colorectal cancer. Cancer 122:826–839

    Article  PubMed  PubMed Central  Google Scholar 

  67. Bailey VJ, Zhang Y, Keeley BP et al (2010) Single-tube analysis of DNA methylation with silica superparamagnetic beads. Clin Chem 56:1022–1025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Huttenhain R, Soste M, Selevsek N, et al. (2012) Reproducible quantification of cancer-associated proteins in body fluids using targeted proteomics. Sci Transl Med 4:142ra94-142ra94

  69. Schwenk JM, Igel U, Kato BS et al (2010) Comparative protein profiling of serum and plasma using an antibody suspension bead array approach. Proteomics 10:532–540

    Article  CAS  PubMed  Google Scholar 

  70. Winawer SJ, Zauber AG, Ho MN et al (1993) Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329:1977–1981

    Article  CAS  PubMed  Google Scholar 

  71. Sillars-Hardebol AH, Carvalho B, Van Engeland M et al (2012) The adenoma hunt in colorectal cancer screening: defining the target. J Pathol 226:1–6

    Article  CAS  PubMed  Google Scholar 

  72. Matano M, Date S, Shimokawa M et al (2015) Modeling colorectal cancer using CRISPR-Cas9–mediated engineering of human intestinal organoids. Nat Med 21:256

    CAS  PubMed  Google Scholar 

  73. Sahasrabuddhe VV, Luhn P, Wentzensen N (2011) Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts. Future Microbiol 6:1083–1098

    Article  PubMed  Google Scholar 

  74. Van Der Veen N Uitvoeringskader Bevolkingsonderzoek Baarmoederhalskanker

  75. Paulson TG, Maley CC, Li X et al (2009) Chromosomal instability and copy number alterations in Barrett’s esophagus and esophageal adenocarcinoma. Clin Cancer Res 15:3305–3314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors were supported by the Dutch Cancer Society (reference numbers: KWF Fellowship 2013-5885 and NKI 2013-6338) and a SU2C-DCS International Translational Cancer Research Dream Team Grant (MEDOCC). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.

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Authors and Affiliations

  1. Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, the Netherlands

    M. C. J. van Lanschot, L. J. W. Bosch, M. de Wit, B. Carvalho & G. A. Meijer

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  1. M. C. J. van Lanschot
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  2. L. J. W. Bosch
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  3. M. de Wit
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  5. G. A. Meijer
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Correspondence to G. A. Meijer.

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van Lanschot, M.C.J., Bosch, L.J.W., de Wit, M. et al. Early detection: the impact of genomics. Virchows Arch 471, 165–173 (2017). https://doi.org/10.1007/s00428-017-2159-2

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