Methylthioadenosine Phosphorylase Genomic Loss in Advanced Gastrointestinal Cancers

Authors

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

Publication Date

6-3-2024

Journal

Oncologist

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.

Keywords

Humans, Purine-Nucleoside Phsphorylase, Male, Female, Gastrointestinal Neoplasms, Middle Aged, Aged, Retrospective Studies, Biomarkers, Tumor, Adult, Prognosis, Genomics, MTAP loss, 9p21 loss, genomics, biomarkers, tumor, cholangiocarcinoma

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Supplementary Materials

PMID: 38330461