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- Title
Methylthioadenosine Phosphorylase Genomic Loss in Advanced Gastrointestinal Cancers.
- Authors
Ngoi, Natalie Y L; Tang, Tin-Yun; Gaspar, Catia F; Pavlick, Dean C; Buchold, Gregory M; Scholefield, Emma L; Parimi, Vamsi; Huang, Richard S P; Janovitz, Tyler; Danziger, Natalie; Levy, Mia A; Pant, Shubham; Armas, Anaemy Danner De; Kumpula, David; Ross, Jeffrey S; Javle, Milind; Ahnert, Jordi Rodon
- 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.
- Subjects
GASTROINTESTINAL tumors; GENOMICS; ADENOSINES; ANTINEOPLASTIC agents; TUMOR markers; CANCER patients; MEDICAL genetics; DISEASE prevalence; TREATMENT effectiveness; RETROSPECTIVE studies; DESCRIPTIVE statistics; GENE expression; LONGITUDINAL method; MEDICAL records; ACQUISITION of data; TRANSFERASES; GENETIC mutation; COMPARATIVE studies; DRUG development; SEQUENCE analysis; PHARMACODYNAMICS
- Publication
Oncologist, 2024, Vol 29, Issue 6, p493
- ISSN
1083-7159
- Publication type
Article
- DOI
10.1093/oncolo/oyae011