MTAP as an emerging biomarker in thoracic malignancies.

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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lukas Bubendorf reports a relationship with Astra Zeneca that includes: consulting or advisory and speaking and lecture fees. Lukas Bubendorf reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Bayer AG that includes: consulting or advisory and speaking and lecture fees. Lukas Bubendorf reports a relationship with Eli Lilly and Company that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Amgen Inc that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Takeda Oncology that includes: consulting or advisory and speaking and lecture fees. Lukas Bubendorf reports a relationship with Thermo Fisher Scientific Inc that includes: funding grants and speaking and lecture fees. Lukas Bubendorf reports a relationship with Novartis that includes: funding grants. Lukas Bubendorf reports a relationship with Systems Oncology that includes: board membership and consulting or advisory. David Koenig reports a relationship with Astra Zeneca that includes:. David Koenig reports a relationship with MSD that includes: consulting or advisory. David Koenig reports a relationship with Novartis Pharmaceuticals Corporation that includes: consulting or advisory. David Koenig reports a relationship with Mirati Therapeutics Inc that includes: consulting or advisory. David Koenig reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. David Koenig reports a relationship with PharmaMar SA that includes: consulting or advisory. David Koenig reports a relationship with Amgen Inc that includes: consulting or advisory. David Koenig reports a relationship with Sanofi that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory and speaking and lecture fees. Spasenija Savic Prince reports a relationship with Merck & Co Inc that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Astra Zeneca that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Pfizer that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Thermo Fisher Scientific Inc that includes: consulting or advisory. Lukas Bubendorf reports a relationship with F Hoffmann-La Roche Ltd that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)