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Genetic Mechanisms in Interval Colon Cancers

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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.

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Abbreviations

CRC:

Colorectal cancer

MSI:

Microsatellite instability

MSS:

Microsatellite stability

LS:

Lynch syndrome

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Acknowledgments

Authors received grant support from Kate J. and Dorothy L. Clapp Fund (DCC), Oliver S., and Jennie R. Donaldson Charitable Trust (JMR).

Conflict of interest

None.

Author information

Author notes

  1. Maria Simona Pino

    Present address: Medical Oncology Unit, Department of Oncology, Azienda Sanitaria Firenze, Ospedale S. Maria Annunziata, Via dell’Antella 58, 50012, Bagno a Ripoli, FI, Italy

Authors and Affiliations

  1. GRJ 704, Gastrointestinal Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, MA, 02114, USA

    James M. Richter, Maria Simona Pino, Thomas R. Austin, Emily Campbell & Daniel C. Chung

  2. Biostatistics Center, 50 Staniford St., Suite 560, Boston, MA, 02114, USA

    Jackie Szymonifka

  3. Radiation Oncology Department, Clark Center for Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA, 02114, USA

    Theodore S. Hong

  4. Molecular Pathology Laboratory, Massachusetts General Hospital, GRJ 1028, 55 Fruit Street, Boston, MA, 02114, USA

    Darrell Borger & A. John Iafrate

  5. Harvard Radiation Oncology Program, Brigham and Womens Hospital, Rad Onc, 75 Francis St, Boston, MA, 02115, USA

    Andrea L. Russo

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  1. James M. Richter
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Corresponding author

Correspondence to Daniel C. Chung.

Additional information

James M. Richter and Maria Simona Pino contributed equally.

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Richter, J.M., Pino, M.S., Austin, T.R. et al. Genetic Mechanisms in Interval Colon Cancers. Dig Dis Sci 59, 2255–2263 (2014). https://doi.org/10.1007/s10620-014-3134-2

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  • DOI: https://doi.org/10.1007/s10620-014-3134-2

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