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Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057

Mohamed E Salem1, J Nicholas Bodor2, Alberto Puccini3,4

  • 1Levine Cancer Institute, Atrium Health, Charlotte, North Carolina, USA.

International Journal of Cancer
|May 26, 2020
PubMed

Insights

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) predict immune-checkpoint inhibitor (ICI) response. TMB varies by the specific cause of MSI and tumor type, impacting ICI effectiveness.

Area of Science:

  • Oncology
  • Genetics
  • Immunotherapy

Background:

  • Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are key biomarkers for predicting response to immune-checkpoint inhibitors (ICIs).
  • The precise relationship between the molecular drivers of MSI and TMB in various tumors is not fully understood.

Purpose of the Study:

  • To investigate the association between TMB and mismatch repair (MMR) protein expression patterns (via immunohistochemistry) and MMR gene mutations.
  • To explore how these associations differ based on the specific MMR protein/gene affected and the tumor's histology or primary site.

Main Methods:

  • Analyzed 1057 MSI-H tumors out of 32,932 tested, with MSI assessed by next-generation sequencing (NGS) of over 7000 microsatellite loci.
  • Calculated TMB using nonsynonymous missense mutations from a 592-gene panel; MMR protein expression was assessed by immunohistochemistry (IHC) in a subset of MSI-H tumors.
  • Examined TMB variations based on MMR protein heterodimer loss (MLH1/PMS2 vs. MSH2/MSH6) and specific MMR gene mutations, considering tumor histology.

Main Results:

  • Loss of MLH1/PMS2 co-expression (77.2%) was more frequent than MSH2/MSH6 loss (11.5%) and was associated with significantly lower TMB (25.03 mut/Mb vs. 46.83 mut/Mb).
  • TMB varied by tumor histology, with colorectal cancers showing MLH1/PMS2 loss having higher TMB (33.14 mut/Mb) compared to endometrial cancers (20.60 mut/Mb).
  • MMR gene mutations were found in 42.0% of tumors, with MSH6 mutations being the most common (25.7%); MSH6 mutation patterns also showed variability by histology and TMB.

Conclusions:

  • Tumor mutational burden (TMB) exhibits significant heterogeneity depending on the underlying cause of microsatellite instability (MSI) and the specific tumor histology.
  • This observed heterogeneity in TMB, driven by different MSI etiological factors and tumor types, may explain variations in patient responses to immune-checkpoint inhibitors (ICIs).
Keywords:
MSITMBimmune checkpoint inhibitorsmicrosatellite instabilitymismatch repairtumor mutational burden

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