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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

Published on: September 20, 2016

Genomic landscape of non-small-cell lung cancer with methylthioadenosine phosphorylase (MTAP) deficiency

Prashanth Ashok Kumar¹, Stephen L Graziano¹, Natalie Danziger²

¹Upstate Cancer Center, Upstate Medical University, Syracuse, New York, USA.

Cancer Medicine

|June 24, 2022

Abstract

Introduction:

New treatment strategies for advanced non-small-cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP).

Methods:

Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid-capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD-L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay).

Results:

13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large-cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP-intact versus MTAP-lost (12% vs. 10%, p = 0.0003) and fewer EGFR short variant mutations in MTAP-intact versus MTAP-lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP-intact compared to MTAP-lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP-intact versus MTAP-lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP-intact versus MTAP-lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p = 0.001) and low (30% vs. 28%, p = 0.01) and high PD-L1 (32% vs. 30%, p = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups.

Conclusions:

MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper-dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies.

Insights

Methylthioadenosine phosphorylase (MTAP) loss occurs in 13% of advanced non-small-cell lung carcinoma (NSCLC) cases. This finding supports developing new therapies targeting PRMT5 to exploit MTAP loss in NSCLC treatment strategies.

Area of Science:

Oncology
Genomics
Pharmacology

Background:

Advanced non-small-cell lung carcinoma (NSCLC) treatment is evolving with synthetic lethality approaches.
Protein arginine methyl transferase 5 (PRMT5) is a target for synthetic lethality, particularly in tumors with methylthioadenosine phosphorylase (MTAP) loss.

Purpose of the Study:

To investigate the frequency of MTAP loss in advanced NSCLC.
To analyze genomic alterations and immunotherapy predictors associated with MTAP loss in NSCLC.

Main Methods:

Comprehensive genomic profiling of 29,379 advanced NSCLC cases.
Analysis of PD-L1 expression via immunohistochemistry.
Statistical analysis to compare genomic alterations and immunotherapy markers between MTAP-intact and MTAP-lost NSCLC cohorts.

Main Results:

MTAP loss was observed in 13.4% of advanced NSCLC cases.
Significant differences in KRAS, EGFR, TP53, RB1, and SMARCA4 alterations were noted between MTAP-intact and MTAP-lost NSCLC.
Tumor mutational burden and PD-L1 expression, predictors of immunotherapy efficacy, were higher in MTAP-intact NSCLC.

Conclusions:

MTAP loss is a significant genomic event in 13% of NSCLC, highlighting its potential as a target for PRMT5-based synthetic lethality therapies.
MTAP loss is associated with subtle but potentially impactful differences in targeted and immunotherapy options, influencing future combination treatment strategies in NSCLC.

Read full analysis

Keywords:

comprehensive genomic profiling methylthioadenosine phosphorylase (MTAP)non-small-cell lung cancer protein arginine methyl transferase synthetic lethality

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