Nature and distribution of methyl thioadenosine phosphorylase (MTAP) genomic loss in human tumors.

Abstract

3067 Background: MTAP genomic loss, often but not exclusively a bi-allelic homozygous deletion, has recently emerged as important biomarker guiding a novel synthetic lethality mechanism for drugs in the class of PRMT5 and MAT2A inhibitors. In the current study, we assessed the nature and distribution of MTAP complete and partial loss in a variety of tumor samples. Methods: A total of 291,391 tissue samples underwent comprehensive genomic profiling (CGP) using a hybrid-capture method to evaluate all classes of genomic alterations (GA), and determine the microsatellite instability (MSI) status, tumor mutational burden (TMB), homologous recombination deficiency (HRD) score and genomic ancestry. The distribution of both complete and partial loss of MTAP was also determined. Results: MTAP GA were found in 8.6% of total with 9.3% genomic loss and 0.1% each short variant mutations and rearrangements. Important (not rare) tumor types with the most frequent MTAP loss included: 42.6% of glioblastoma (GBM), 13.4% of non-small cell lung cancer (NSCLC), 22.3% of pancreatic ductal and 24.9% of bladder urothelial carcinomas. The most frequently co-altered GA included CDKN2A (99.7%), CDKN2B (95.1%), TP53 (55.4%), KRAS (30.1%), TERT(20.5%) and PIK3CA (12%). In tumor types with frequent known targetable driver GA including short variant mutations in EGFR, ERBB2, BRAF, FGFR2-3and MET and fusions involving ALK, RET, ROS1 and NTRK1-3, MTAP loss was not associated with decreased frequencies of GA in these genes. The frequencies of MSI-high status was 0.3% and of TMB≥10 mut/Mb was 17%. In total, 63.7% of the MTAP loss cases involved deletion of all 8 MTAP exons (complete loss) with partial loss accounting for 36.3% of cases. All partial loss cases involved loss of multiple exons (35.8%) except for loss of only exon 8 (0.5%). There was no impact of MTAP loss status on genomic ancestry, cosmic trinucleotide signature and HRD score. The multiple exon loss frequencies included exons 2-8 loss in 24.7%, exons 5-8 loss in 4.1%, exons 6-8 loss in 3.3%, exons 3-8 loss in 1.6%, exons 7-8 in 1.1%, exon 4-8, 1-5, 2-7,2-5, 1-4, 2-6, 3-7 and 5-7 all at less than 1% frequencies. Conclusions: MTAPloss is a frequent GA of emerging clinical importance as the trials using PRMT5 and MTA-2 inhibitors progress. MTAPloss is frequent in common cancers of the brain, lung, pancreas and bladder and not associated with diminishment of other targetable driver mutations. Although one-third of MTAP loss is a partial loss, the partial loss cases involve near total (exons 2-8) loss and may well also be indicative of PRMT5/MAT2A inhibitor benefit. This study strengthens the opportunity to consider a tumor-agnostic approach to targeted therapies. [Table: see text]