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.

Details

Title
Methylthioadenosine Phosphorylase Genomic Loss in Advanced Gastrointestinal Cancers
Author
Ngoi, Natalie Y L 1   VIAFID ORCID Logo  ; Tin-Yun Tang 2   VIAFID ORCID Logo  ; Gaspar, Catia F 1 ; Pavlick, Dean C 3   VIAFID ORCID Logo  ; Buchold, Gregory M 1 ; Scholefield, Emma L 4 ; Parimi, Vamsi 3 ; Huang, Richard S P 3 ; Janovitz, Tyler 3 ; Danziger, Natalie 3 ; Levy, Mia A 3 ; Pant, Shubham 5 ; Anaemy Danner De Armas 5   VIAFID ORCID Logo  ; Kumpula, David 6 ; Ross, Jeffrey S 3   VIAFID ORCID Logo  ; Javle, Milind 5   VIAFID ORCID Logo  ; Jordi Rodon Ahnert 1   VIAFID ORCID Logo 

1  Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX , USA 
2  Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX , USA 
3  Foundation Medicine Inc. , Cambridge, MA , USA 
4  Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde Glasgow , Glasgow , UK 
5  Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX , USA 
6  Departments of Pathology, Urology and Medicine (Oncology), Upstate Medical University , Syracuse, NY , USA 
Pages
493-503
Publication year
2024
Publication date
Jun 2024
Publisher
Oxford University Press
ISSN
10837159
e-ISSN
1549490X
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1093/oncolo/oyae011
ProQuest document ID
3191889522
Copyright
© The Author(s) 2024. Published by Oxford University Press. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.