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. 2023 Jan;12(2):1157-1166.
doi: 10.1002/cam4.4971. Epub 2022 Jun 23.

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

Prashanth Ashok Kumar  1 , Stephen L Graziano  1 , Natalie Danziger  2 , Dean Pavlick  2 , Eric A Severson  2 , Shakti H Ramkissoon  2 , Richard S P Huang  2 , Brennan Decker  2 , Jeffrey S Ross  1   2
Affiliations

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

Prashanth Ashok Kumar et al. Cancer Med. 2023 Jan.

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.

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

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Conflict of interest statement

All Foundation Medicine co‐authors disclose that they are employees of Foundation Medicine and own shares in Roche Holdings. Authors affiliated with Upstate have no conflict of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Genomic alterations in MTAP intact and MTAP loss non‐small cell lung cancer
FIGURE 2
FIGURE 2
Clinically advanced NSCLC with sarcomatoid features in a 64‐year‐old man. Hematoxylin and eosin‐stained image of the tumor at low magnification (4X) and high magnification in the inset (20X) are shown (A). This tumor stained positively for TTF‐1 and Napsin A. PD‐L1 tumor cell expression was 40% using the DAKO 22C3 assay (B). On comprehensive genomic profiling, the tumor had co‐deletion of CDKN2A, CDKN2B, and MTAP, and was microsatellite stable and TMB‐Low (1 mutation/Mb of sequenced DNA) (C). There was an activating EGFR L858R mutation (D). Potential therapy options for this patient would include both anti‐EGFR targeted therapies and, despite the low TMB, immunotherapy given the strong anti‐PD‐L1 IHC staining
See this image and copyright information in PMC

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