Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies.
Monika Vyas, Canan Firat, Jaclyn F Hechtman, Martin R Weiser, Rona Yaeger, Chad Vanderbilt, Jamal K Benhamida, Ajaratu Keshinro, Liying Zhang, Peter Ntiamoah, Marco Gonzalez, Rebecca Andrade, Imane El Dika, Arnold J Markowitz, J Joshua Smith, Julio Garcia-Aguilar, Efsevia Vakiani, David S Klimstra, Zsofia K Stadler, Jinru Shia
Author Information
Monika Vyas: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Canan Firat: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Jaclyn F Hechtman: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Martin R Weiser: Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Rona Yaeger: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Chad Vanderbilt: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Jamal K Benhamida: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ajaratu Keshinro: Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Liying Zhang: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA, USA.
Peter Ntiamoah: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Marco Gonzalez: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Rebecca Andrade: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Imane El Dika: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Arnold J Markowitz: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J Joshua Smith: Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Julio Garcia-Aguilar: Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Efsevia Vakiani: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
David S Klimstra: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Zsofia K Stadler: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Stadlerz@mskcc.org.
Jinru Shia: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Shiaj@mskcc.org. ORCID
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.
