DNA Damage Response and Repair (DDR) Gene Mutations and Correlation with Tumor Mutation Burden (TMB) in Non-Small Cell Lung Cancer (NSCLC)

Authors:

Hirva Mamdani , Jerry Chen , Seongho Kim , Yahya Ibrahim , Rebecca Feldman , Jorge J Nieva, Abdul Rafeh Naqash , Stephen V Liu , Patrick C Ma, David C Portnoy , Hossein Borghaei , Nagla Abdel Karim , Yanis Boumber , Ari M Vanderwalde , Alexander I Spira , Shadia I Jalal

BACKGROUND

  • Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution.
  • DNA repair deficiency has emerged as a predictive biomarker of response to platinum based chemotherapy and PARP
    inhibition.
  • More recently, DNA repair defects have been shown to predict response to immune checkpoint inhibitors.
  • Data on the relationship between DNA repair defects and TMB in NSCLC is limited.

STUDY OBJECTIVES

  • Characterize the landscape of DNA damage response and repair (DDR) genes mutations in NSCLC
  • Correlate DDR gene mutations with immune biomarkers (TMB and PD-L1)
  • Identify mutations with the strongest association with high TMB

METHODS

  • We retrospectively analyzed biomarker profiles of 5,667 NSCLC tumors that had undergone molecular profiling between 01/16 – 06/18 (Caris Life Sciences, Phoenix, AZ).
  • Profiling included next-generation sequencing of 592 genes, TMB, and PD-L1 expression by immunohistochemistry (22c3).
  • Genes of interest: ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, ERCC2, ERCC3, FANCA, FANCC, FANCD2, FANCE, FANCG, FANCL, MLH1, MSH2, MSH6, MRE11, NBN, PALB2, POLE, PTEN, RAD50, RAD51, WRN
  • Samples harboring mutation in at least one of the 29 genes representing several DDR pathways were included in the analysis.
  • Available clinical information: Age, gender, histology

CONCLUSION

  • DDR genes mutations are common in NSCLC, with RAD50, WRN, CHEK2, ATM, ATR, and MRE11 being the most commonly mutated genes.
  • Over half of the DDR mutated NSCLC tumors have high TMB and one-third have high PD-L1.
  • DDR genes mutations are not mutually exclusive.
  • BRCA1, PALB2, and POLE mutations are most likely to be associated with high TMB.

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