Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes Journal Article


Authors: Hechtman, J. F.; Rana, S.; Middha, S.; Stadler, Z. K.; Latham, A.; Benayed, R.; Soslow, R.; Ladanyi, M.; Yaeger, R.; Zehir, A.; Shia, J.
Article Title: Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes
Abstract: Immunohistochemistry for mismatch repair protein expression is widely used as a surrogate for microsatellite instability status—an important signature for immunotherapy and germline testing. There are no systematic analyses examining the sensitivity of immunohistochemistry for microsatellite instability-high status. Mismatch repair immunohistochemistry and microsatellite instability testing were performed routinely as clinically validated assays. We classified germline/somatic mutation types as truncating (nonsense, frameshift, and in/del) versus missense and predicted pathogenicity of the latter. Discordant cases were compared with concordant groups: microsatellite instability-high/mismatch repair-deficient for mutation comparison and microsatellite stable/mismatch repair-proficient for immunohistochemical comparison. 32 of 443 (7%) microsatellite instability-high cases had immunohistochemistry. Four additional microsatellite instability-high research cases had discordant immunohistochemistry. Of 36 microsatellite instability-high cases with discordant immunohistochemistry, 30 were mismatch repair-proficient, while six (five MLH1 and one MSH2) retained expression of the defective mismatch repair protein and lost its partner. In microsatellite instability-high tumors with discordant immunohistochemistry, we observed an enrichment in deleterious missense mutations over truncating mutations, with 69% (25/36) of cases having pathogenic germline or somatic missense mutations, as opposed to only 19% (7/36) in a matched microsatellite instability-high group with concordant immunohistochemistry (p = 0.0007). In microsatellite instability-high cases with discordant immunohistochemistry and MLH1 or PMS2 abnormalities, less cells showed expression (p = 0.015 and p = 0.00095, respectively) compared with microsatellite stable/mismatch repair-proficient cases. Tumor mutation burden, MSIsensor score, and truncating mismatch repair gene mutations were similar between microsatellite instability-high cases with concordant versus discordant immunohistochemical expression. Approximately 6% of microsatellite instability-high cases have retained mismatch repair protein expression and would be missed by immunohistochemistry-based testing, hindering patient access to immunotherapy. Another 1% of microsatellite instability-high cases show isolated loss of the defective gene’s dimerization partner, which may lead to germline testing of the wrong gene. These cases are enriched for pathogenic mismatch repair missense mutations. © 2019, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
Keywords: immunohistochemistry; clinical article; protein expression; treatment response; gene mutation; promoter region; somatic mutation; frameshift mutation; missense mutation; sensitivity analysis; cancer immunotherapy; dna methylation; colorectal carcinoma; mismatch repair; microsatellite instability; mismatch repair protein; nonsense mutation; germline mutation; indel mutation; high throughput sequencing; human; priority journal; article; pembrolizumab; malignant neoplasm; mutl protein homolog 1; dna mismatch repair protein msh2
Journal Title: Modern Pathology
Volume: 33
Issue: 5
ISSN: 0893-3952
Publisher: Nature Research  
Date Published: 2020-05-01
Start Page: 871
End Page: 879
Language: English
DOI: 10.1038/s41379-019-0414-6
PUBMED: 31857677
PROVIDER: scopus
PMCID: PMC7195218
DOI/URL:
Notes: Article -- Export Date: 1 June 2020 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Zsofia Kinga Stadler
    391 Stadler
  2. Marc Ladanyi
    1328 Ladanyi
  3. Jinru Shia
    720 Shia
  4. Rona Denit Yaeger
    316 Yaeger
  5. Robert Soslow
    793 Soslow
  6. Ahmet Zehir
    343 Zehir
  7. Jaclyn Frances Hechtman
    212 Hechtman
  8. Rym Benayed
    188 Benayed
  9. Sumit   Middha
    83 Middha
  10. Satshil Rana
    37 Rana
  11. Alicia Latham
    59 Latham