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Poster Discussion session - Translational research 2

3857 - 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

Date

21 Oct 2018

Session

Poster Discussion session - Translational research 2

Topics

Targeted Therapy

Tumour Site

Presenters

Mohamed Salem

Citation

Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303

Authors

M.E. Salem1, A. Puccini2, A. Grothey3, J. Xiu4, R. Goldberg5, E.S. Kim6, W.M. Korn4, H.J. Lenz7, D. Raghavan8, J.L. Marshall9, M.J. Hall10

Author affiliations

  • 1 Medical Oncology, Levine Cancer Institute, Atrium Health, 28204 - Charlotte/US
  • 2 Medical Oncology 1, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, 16132 - Genova/IT
  • 3 Medical Oncology, Mayo Clinic, 55905 - Rochester/US
  • 4 Molecular Biology, Caris Life Sciences, 85054 - Phoenix/US
  • 5 Division Of Medical Oncology, West Virginia University Cancer Institute, 26506 - Morgantown/US
  • 6 Medical Oncology, Levine Cancer Institute, Atrium Health, Charlotte/US
  • 7 Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 8 Medical Oncology, Carolinas HealthCare System, 28204 - Charlotte/US
  • 9 Lombardi Cancer Center, Georgetown University Hospital, 20007 - Washington DC/US
  • 10 Clinical Genetics, Fox Chase Cancer Center, 19111-2497 - Philadelphia/US
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Abstract 3857

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 MSI-H, 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-H TMB-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 < .0001), where a significant difference was seen in the mean of altered microsatellite loci between TMB-H (81.5) vs. TMB-intermediate (60.2) vs. TMB-low (49.7) tumors, P < .0001. Compared to TMB-H tumors, TMB-intermediated/low exhibited significantly lower mutational rates in Homologous Recombination (HR) genes (BRCA1, BRCA2, ATM, PALB2), in histone modifiers genes (KMT2A, KMT2D, KMD5C) and several others (APC, BRAF, FBXW7, RFN43) (P < .001 for all comparisons).

Conclusions

Other mechanisms may be responsible for the increased TMB, such as HR and histone modifiers genes. Significant association between the mean of altered microsatellite loci and the level of TMB was observed. The association between MSI-H, TMB status and microsatellite loci was tumor type specific. MSI-H tumors with TMB-intermediate/low maybe a different disease entity from MSI-H TMB-H and their response to immunotherapy warrant further exploration.

Clinical trial identification

Legal entity responsible for the study

Mohamed E. Salem.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

J. Xiu, W.M. Korn: Employee: Caris Life Sciences. J.L. Marshall: Consultant: Caris Life Sciences. All other authors have declared no conflicts of interest.

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