Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers

Natalie Y.L. Ngoi*, Tin-Yun Tang, Catia F. Gaspar, Dean C. Pavlick, Gregory M. Buchold, Emma L. Scholefield, Vamsi Parimi, Richard S.P. Huang, Tyler Janovitz, Natalie Danziger, Mia A. Levy, Shubham Pant, Anaemy Danner De Armas, David Kumpula, Jeffrey S. Ross, Milind Javle, Jordi Rodon Ahnert

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
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Abstract

Background
One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker.

Materials and Methods
We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP-loss and MTAP-intact tumors in a retrospective study.

Results
The prevalence of MTAP-loss in GI cancers is 8.30%. MTAP-loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP-loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN) were observed in MTAP-loss tumors and varied according to tumor type. MTAP-loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP-loss versus MTAP-intact IHCC tumors (23.2% vs 31.2%, P = .017).

Conclusion
In GI cancers, MTAP-loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP-loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations.
Original languageEnglish
Pages (from-to)493-503
Number of pages11
JournalThe Oncologist
Volume29
Issue number6
Early online date8 Feb 2024
DOIs
Publication statusPublished - Jun 2024

Keywords

  • cholangiocarcinoma
  • MTAP loss
  • 9p21 loss
  • biomarkers
  • genomics
  • tumor

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