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Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies

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Abstract

The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one—and not all—PMS2-LS associated MMR-deficient carcinomas; (3) “compound LS” with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated.

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Acknowledgements

This study was supported in part by National Cancer Institute (US) Grant P30 C008748 and by the Romeo Milio Lynch Syndrome Foundation.

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  1. Monika Vyas

    Present address: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA

Authors and Affiliations

  1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Monika Vyas, Canan Firat, Jaclyn F. Hechtman, Chad Vanderbilt, Jamal K. Benhamida, Peter Ntiamoah, Marco Gonzalez, Rebecca Andrade, Efsevia Vakiani, David S. Klimstra & Jinru Shia

  2. Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Martin R. Weiser, Ajaratu Keshinro, J. Joshua Smith & Julio Garcia-Aguilar

  3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Rona Yaeger, Imane El Dika, Arnold J. Markowitz & Zsofia K. Stadler

  4. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA, USA

    Liying Zhang

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Vyas, M., Firat, C., Hechtman, J.F. et al. Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies. Familial Cancer 20, 201–213 (2021). https://doi.org/10.1007/s10689-020-00210-4

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