Digestive Diseases and Sciences

, Volume 59, Issue 9, pp 2255–2263

Genetic Mechanisms in Interval Colon Cancers

  • James M. Richter
  • Maria Simona Pino
  • Thomas R. Austin
  • Emily Campbell
  • Jackie Szymonifka
  • Andrea L. Russo
  • Theodore S. Hong
  • Darrell Borger
  • A. John Iafrate
  • Daniel C. Chung
Original Article

DOI: 10.1007/s10620-014-3134-2

Cite this article as:
Richter, J.M., Pino, M.S., Austin, T.R. et al. Dig Dis Sci (2014) 59: 2255. doi:10.1007/s10620-014-3134-2

Abstract

Background and Aim

The factors underlying the development of interval colon cancers are not well defined and are likely heterogeneous. We sought to determine whether there are distinct molecular properties associated with interval colon cancers.

Methods

Colon cancers diagnosed within 5 years of a complete and well-prepped colonoscopic examination were identified over a 7-year period at a single institution. The clinical and pathological features of the tumors were defined. Analysis of DNA mismatch repair (MMR) and genotyping of a panel of oncogenes associated with colon cancer were performed.

Results

Forty-two interval colon cancers were diagnosed at an average age of 70 years. 69 % of tumors were located in the right colon. 41 % of tumors exhibited DNA microsatellite instability (MSI). Loss of staining of DNA MMR proteins by immunohistochemistry (IHC) was confirmed in 82 % of the MSI-positive tumors. Among tumors with abnormal MSI and IHC, 54 % exhibited somatic methylation of the MLH1 promoter, but the remaining 43 % exhibited molecular features indicative of underlying Lynch syndrome (LS). The frequency of somatic mutations in the KRAS, BRAF, NRAS, and PIK3CA oncogenes was similar between interval cancer cases and controls.

Conclusions

Interval colon cancers are not distinguished by the activation of the KRAS, NRAS, BRAF, or PIK3CA oncogenic pathways. However, MSI pathway defects are present in a significant proportion of interval colon cancers. Underlying LS may explain nearly half of these MSI-positive cases, and the remaining cases appear to represent sporadic serrated pathway tumors.

Keywords

Colon cancer MSI Colonoscopy Lynch syndrome 

Abbreviations

CRC

Colorectal cancer

MSI

Microsatellite instability

MSS

Microsatellite stability

LS

Lynch syndrome

Supplementary material

10620_2014_3134_MOESM1_ESM.doc (3 mb)
Supplementary material 1 (DOC 3027 kb)
10620_2014_3134_MOESM2_ESM.doc (54 kb)
Supplementary material 2 (DOC 54 kb)

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • James M. Richter
    • 1
  • Maria Simona Pino
    • 1
    • 6
  • Thomas R. Austin
    • 1
  • Emily Campbell
    • 1
  • Jackie Szymonifka
    • 2
  • Andrea L. Russo
    • 5
  • Theodore S. Hong
    • 3
  • Darrell Borger
    • 4
  • A. John Iafrate
    • 4
  • Daniel C. Chung
    • 1
  1. 1.GRJ 704, Gastrointestinal UnitMassachusetts General HospitalBostonUSA
  2. 2.Biostatistics CenterBostonUSA
  3. 3.Radiation Oncology DepartmentClark Center for Radiation Oncology, Massachusetts General HospitalBostonUSA
  4. 4.Molecular Pathology LaboratoryMassachusetts General HospitalBostonUSA
  5. 5.Harvard Radiation Oncology ProgramBrigham and Womens HospitalBostonUSA
  6. 6.Medical Oncology Unit, Department of OncologyAzienda Sanitaria FirenzeBagno a RipoliItaly

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