MTAP as an emerging biomarker in thoracic malignancies

Magdalena M Brune; Spasenija Savic Prince; Tatjana Vlajnic; Obinna Chijioke; Luca Roma; David König; Lukas Bubendorf

doi:10.1016/j.lungcan.2024.107963

MTAP as an emerging biomarker in thoracic malignancies

Lung Cancer. 2024 Sep 29:197:107963. doi: 10.1016/j.lungcan.2024.107963. Online ahead of print.

Authors

Magdalena M Brune¹, Spasenija Savic Prince¹, Tatjana Vlajnic¹, Obinna Chijioke¹, Luca Roma¹, David König², Lukas Bubendorf³

Affiliations

¹ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland.
² Division of Medical Oncology, University Hospital Basel, Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
³ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland. Electronic address: lukas.bubendorf@usb.ch.

PMID: 39357262
DOI: 10.1016/j.lungcan.2024.107963

Abstract

S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency is an emerging biomarker in non-small cell lung cancer (NSCLC) and beyond. The MTAP gene is located in the chromosomal region 9p21.3, which shows one of the most common homozygous deletions across all human cancers (9p21 loss). Loss of 9p21 is found in the majority of pleural mesotheliomas, where it serves as an established diagnostic marker. Until recently, fluorescence in situ hybridization (FISH) was the gold standard for the detection of 9p21 losses, but loss of MTAP expression by immunohistochemistry (IHC) gains increasing importance as an easy to apply and cost-effective diagnostic surrogate marker. Besides, MTAP loss, which has been reported in 13% of NSCLC, is becoming an emerging predictive biomarker in two different scenarios in NSCLC and other cancer types: 1) MTAP loss seems to negatively predict the response to immune checkpoint inhibitor (ICI) treatment via silencing of the tumor microenvironment, and 2) MTAP loss serves as a predictive biomarker for novel targeted treatment strategies. MTAP deficiency leads to an impaired function of the protein arginine methyltransferase 5 (PRMT5) due to its partial inhibition by MTAP's accumulating substrate methylthioadenosine (MTA). This process leaves MTAP deficient tumor cells heavily dependent on the remaining function of PRMT5, making it a perfect target for synthetic lethality. Indeed, MTA-cooperative PRMT5-inhibitors are now tested in several clinical trials with promising early results in solid malignancies. With its emergence as a predictive biomarker, the implementation of MTAP IHC into diagnostic routine for NSCLC and other tumors is likely to take place soon. In this review article, we summarize the current literature on the role of MTAP in thoracic tumors and evaluate different testing methods, including IHC, FISH and next generation sequencing.

Keywords: FISH; Immunohistochemistry; MTAP; Next generation sequencing; Non-small cell lung cancer; PRMT5-inhibitors; Predictive marker.

Publication types

Review