Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: Frequency, patterns, and molecular etiologies Journal Article
| Authors: | Vyas, M.; Firat, C.; Hechtman, J. F.; Weiser, M. R.; Yaeger, R.; Vanderbilt, C.; Benhamida, J. K.; Keshinro, A.; Zhang, L.; Ntiamoah, P.; Gonzalez, M.; Andrade, R.; El Dika, I.; Markowitz, A. J.; Smith, J. J.; Garcia-Aguilar, J.; Vakiani, E.; Klimstra, D. S.; Stadler, Z. K.; Shia, J. |
| Article Title: | Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: Frequency, patterns, and molecular etiologies |
| 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. © 2020, Springer Nature B.V. |
| Keywords: | colorectal cancer; lynch syndrome; mismatch repair deficiency; hereditary cancer; mmr ihc; mutational testing; gastrointestinal tract cancer |
| Journal Title: | Familial Cancer |
| Volume: | 20 |
| Issue: | 3 |
| ISSN: | 1389-9600 |
| Publisher: | Springer |
| Date Published: | 2021-07-01 |
| Start Page: | 201 |
| End Page: | 213 |
| Language: | English |
| DOI: | 10.1007/s10689-020-00210-4 |
| PUBMED: | 33033905 |
| PROVIDER: | scopus |
| PMCID: | PMC8032798 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2021 -- Source: Scopus |
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