Open AccessDiscordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies
Author(s) -
Monika Vyas,
Canan Fırat,
Jaclyn F. Hechtman,
Martin R. Weiser,
Rona Yaeger,
Chad Vanderbilt,
Jamal Benhamida,
Ajaratu Keshinro,
Liying Zhang,
Peter Ntiamoah,
Marco Antonio Robles González,
Rebecca Andrade,
Imane El Dika,
Arnold J. Markowitz,
J. Joshua Smith,
Julio GarciaAguilar,
Efsevia Vakiani,
David S. Klimstra,
Zsofia K. Stadler,
Jinru Shia
Publication year - 2020
Publication title -
familial cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.946
H-Index - 57
eISSN - 1573-7292
pISSN - 1389-9600
DOI - 10.1007/s10689-020-00210-4
Subject(s) - pms2 , lynch syndrome , msh6 , microsatellite instability , familial adenomatous polyposis , dna mismatch repair , msh2 , medicine , mlh1 , germline mutation , cancer , oncology , colorectal cancer , adenomatous polyposis coli , cancer research , biology , genetics , mutation , gene , microsatellite , allele
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.