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: 13899600
Publisher: 2020, Springer Nature B.v  
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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MSK Authors
  1. Arnold J Markowitz
    120 Markowitz
  2. Zsofia Kinga Stadler
    254 Stadler
  3. David S Klimstra
    948 Klimstra
  4. Jinru Shia
    583 Shia
  5. Martin R Weiser
    409 Weiser
  6. Rona Denit Yaeger
    164 Yaeger
  7. Efsevia Vakiani
    208 Vakiani
  8. Jaclyn Frances Hechtman
    196 Hechtman
  9. Jesse Joshua Smith
    97 Smith
  10. Imane El Dika
    38 El Dika
  11. Monika Vyas
    11 Vyas
  12. Canan Firat
    13 Firat