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Published on: April 11, 2016
Genomics of MTAP Loss in >500,000 Solid Tumor Specimens Profiled Using Comprehensive Genomic Profiling Platforms
Dean C Pavlick1, Shruthi Rengarajan1, Jessica K Lee2
1Department of Computational Discovery, Foundation Medicine, Inc, Boston, MA.
Purpose:
Methylthioadenosine phosphorylase (MTAP) genomic loss is an emerging biomarker for PRMT5 and MAT2A inhibitors based on synthetic lethality. The MTAP gene is located on chromosome 9p21.3 near CDKN2A/B. MTAP homozygous loss across tumor types, specific exons lost, MTAP expression, and the landscape of coalterations were assessed.
Methods:
409,755 tissue biopsies (TBx) and 85,801 liquid biopsies (LBx) were sequenced using hybrid capture-based NGS (FoundationOne CDx or FoundationOne Liquid CDx), evaluating all classes of genomic alterations and circulating tumor DNA (ctDNA) tumor fraction (TF). Additionally, 6,740 TBx were subjected to both RNA and DNA sequencing to compare MTAP gene expression with genomic MTAPloss.
Results:
The prevalence of pan-tumor MTAPloss was 11.4% using TBx, with the highest prevalence observed in mesothelioma (32.8%), glioma (32.7%), pancreatic (28.9%), and bladder cancers (26.4%). Prevalence of MTAPloss on LBx approximated that of TBx when ctDNA TF ≥20% (positive percent agreement [PPA] = 86.2%). CDKN2Aloss was not a reliable proxy for MTAPloss; 33.7% of CDKN2Aloss cases did not have MTAPloss. MTAPloss was enriched with CDKN2A/B losses pan-tumor, EGFR in NSCLC, ERBB2 in colorectal cancer, and PTEN in prostate cancer, while MTAPno_loss was enriched for RB1 pan-tumor, APC in colorectal cancer, CCNE1 in breast and ovarian cancer, and SPOP in prostate cancer. Complete loss (exons 1-8) was observed in 82.9%, multiple exons in 16.5% and exon 8 alone in <1%. MTAPloss, specifically the number of exons lost, was correlated with reduced RNA expression.
Conclusion:
MTAPloss is a frequent pan-tumor alteration that predicts potential sensitivity to PRMT5 or MAT2A inhibitors. Although most tumors exhibit complete MTAPloss, 16.5% are characterized by partial MTAPloss where clinical benefit remains uncertain. The genomic coalteration landscape reported here may inform future PRMT5 or MAT2A clinical trials, potentially in combination with other agents.
Insights
Methylthioadenosine phosphorylase (MTAP) loss is a common cancer alteration, indicating potential sensitivity to specific inhibitors. Further research is needed for partial MTAP loss cases to clarify clinical benefit.
Area of Science:
- Oncology
- Genomics
- Biomarker Discovery
Background:
- Methylthioadenosine phosphorylase (MTAP) genomic loss is an emerging biomarker for PRMT5 and MAT2A inhibitors.
- The MTAP gene is located on chromosome 9p21.3 near CDKN2A/B.
Purpose of the Study:
- Assess MTAP homozygous loss across tumor types, specific exons lost, MTAP expression, and associated co-alterations.
- Evaluate MTAP loss as a predictive biomarker for targeted therapies.
Main Methods:
- Sequenced 409,755 tissue biopsies and 85,801 liquid biopsies using hybrid capture-based NGS.
- Analyzed genomic alterations, ctDNA tumor fraction, and MTAP gene expression via RNA and DNA sequencing.
Main Results:
- Pan-tumor MTAP loss prevalence was 11.4%, highest in mesothelioma (32.8%), glioma (32.7%), pancreatic (28.9%), and bladder cancers (26.4%).
- Liquid biopsy detection approximated tissue biopsy results with ctDNA TF ≥20%.
- CDKN2A loss was not a reliable proxy for MTAP loss; 33.7% of CDKN2A loss cases lacked MTAP loss.
Conclusions:
- MTAP loss is a frequent pan-tumor alteration predicting potential sensitivity to PRMT5 or MAT2A inhibitors.
- Complete MTAP loss was observed in 82.9%, while 16.5% had partial loss with uncertain clinical benefit.
- The identified co-alteration landscape can inform future clinical trials for MTAP-targeted therapies.
