Comparative molecular analysis between microsatellite instability-high (MSI-H) tumors with high tumor mutational burden (TMB-H) versus MSI-H tumors with TMB-intermediate/low

  • Salem M
  • Puccini A
  • Grothey A
  • et al.
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Abstract

Background: A strong correlation between MSI-H and TMB-H has been shown. Nevertheless, not all MSI-H tumors exhibit an increased TMB. Thus, we examined the molecular differences between MSH-H tumors with TMB-H and MSH-H tumors with TMB-intermediate/low. Methods: MSI-H was determined by examining altered microsatellite loci using NextGen sequencing (cutoff ≥46) on a 592-gene panel. TMB was calculated by enumerating somatic missense mutations. Mismatch Repair (MMR) proteins expression was evaluated by IHC. ANOVA and chi-square tests were used for comparisons. Results: A total of 1057 MSI-H tumors (283 colorectal cancer [CRC]; 449 endometrial cancer [EC]; and 325 others from 29 cancer types) were examined. Despite being MSIH, 26% of tumors exhibited low (< 6 mutations/megabase [mt/MB]) or intermediate (7 -16 mt/MB) TMB status, while 74% of MSI-H tumors were TMB-H (≥17 mt/MB). The prevalence of MSI-HTMB-intermediate/low significantly differed according to the tumor location. In MSI-H CRC, only 6.4% of tumors were TMB-intermediate/low, whereas in MSI-H EC, 38% of tumors were TMB-intermediate/low (P<0.001). Significant association between the microsatellite loci and the level of TMB was observed (Rho = 0.60, P

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Salem, M. E., Puccini, A., Grothey, A., Xiu, J., Goldberg, R., Kim, E. S., … Hall, M. J. (2018). Comparative molecular analysis between microsatellite instability-high (MSI-H) tumors with high tumor mutational burden (TMB-H) versus MSI-H tumors with TMB-intermediate/low. Annals of Oncology, 29, viii650–viii651. https://doi.org/10.1093/annonc/mdy303.005

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