MTAP Biomarker Testing for Precision Oncology Research

MTAP is an enzyme involved in the salvage pathway of adenine and methionine metabolism [2]. It catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate (MTR), which is subsequently converted through several steps into methionine (Figure 2). Methionine is needed to synthesize S-adenosylmethionine (SAM), the key methyl donor in various cellular processes and substrate of the protein arginine N-methyltransferase (PRMT5). PRMT5 is a type II arginine methyltransferase involved in cell-cycle regulation, cell differentiation, DNA repair, proliferation, and apoptosis. Loss of MTAP results in the accumulation of MTA, leading to the partial inhibition of PRMT5. Because MTAP-deficient tumors are dependent on the remaining function of PRMT5, these tumors are emerging as an ideal target for synthetic lethality [2].

MTAP is emerging as a predictive biomarker in two different scenarios for solid tumors. In the first scenario, MTAP loss seems to negatively predict the response to immune checkpoint inhibitors by immune silencing of the tumor microenvironment through the accumulation of MTA [3,4].

In the second scenario, MTAP-deficient malignancies are an ideal target for synthetic lethality with new MTA-cooperative PRMT5 inhibitors, which selectively inhibit PRMT5 in the presence of elevated MTA, while sparing MTAP-proficient cells [5-7]. There are several clinical studies ongoing that are currently evaluating these promising new PRMT5 inhibitors across a range of advanced solid malignancies [8]. Additionally, methionine adenosyltransferase II alpha (MAT2A), which is essential for the synthesis of SAM, the substrate for PRMT5, has been identified as another potential target for synthetic lethality in MTAP-deficient cells and is actively being investigated [9].

MTAP is an emerging biomarker for future therapeutics that may necessitate effective testing strategies to study this important biomarker. Fluorescence in situ hybridization (FISH) is considered the gold standard to detect homozygous 9p21 deletions, but its use is limited due to cost, turnaround time, and technical expertise requirements [2].

Because of these limitations, detecting the loss of MTAP production by immunohistochemistry (IHC) is a widely accepted surrogate for identifying 9p21 deletions [10]. Recently, a next-generation sequencing (NGS) approach using comprehensive genomic profiling (CGP) revealed MTAP loss in 13.4% of ~30,000 cases of advanced non-small cell lung cancer (NSCLC) [11]. While IHC may be more sensitive in cases with sparse tumor cells (i.e., tumor content is insufficient for molecular analysis), CGP makes it possible to comprehensively evaluate the tumor for genomic alterations across hundreds of genes and for genomic signatures to obtain more insights.

The Oncomine Comprehensive Assay Plus, available on the Ion Torrent Genexus and Ion GeneStudio S5 systems, offers a complete, end-to-end CGP solution. The assay detects a broad range of genomic alterations in 517 genes, including single-nucleotide variants (SNVs), insertions and deletions (indels), copy number variations (CNVs), and fusions (Table 1). CNVs include detection of copy number losses in MTAP, CDKN2A, and CDKN2B, which are important for MTAP research (Figure 3).

Of note, CDKN2A loss alone should not be used as a surrogate for MTAP loss if the NGS panel does not specifically cover the MTAP gene because it has been reported that only 73% of NSCLC samples with CDKN2A loss have co-deletion of MTAP [2]. Additionally, the assay detects genomic signatures such as homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI). Leveraging proven Ion Torrent NGS technology, the Oncomine Comprehensive Assay Plus offers a complete, easy, fast, and robust solution to help you meet your laboratory research needs.