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

doi:10.1093/oncolo/oyae011

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

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	493-503
Number of pages	11
Journal	The Oncologist
Volume	29
Issue number	6
Early online date	8 Feb 2024
DOIs	https://doi.org/10.1093/oncolo/oyae011
Publication status	Published - Jun 2024

Keywords

cholangiocarcinoma
MTAP loss
9p21 loss
biomarkers
genomics
tumor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Ngoi, N. Y. L., Tang, T.-Y., Gaspar, C. F., Pavlick, D. C., Buchold, G. M., Scholefield, E. L., Parimi, V., Huang, R. S. P., Janovitz, T., Danziger, N., Levy, M. A., Pant, S., De Armas, A. D., Kumpula, D., Ross, J. S., Javle, M., & Rodon Ahnert, J. (2024). Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers. The Oncologist, 29(6), 493-503. https://doi.org/10.1093/oncolo/oyae011

@article{11ac4a15620f4b84a3218d24c4fef974,

title = "Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers",

abstract = "BackgroundOne 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 MethodsWe 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.ResultsThe 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).ConclusionIn 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 = "cholangiocarcinoma, MTAP loss, 9p21 loss, biomarkers, genomics, tumor",

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

year = "2024",

month = jun,

doi = "10.1093/oncolo/oyae011",

language = "English",

volume = "29",

pages = "493--503",

number = "6",

}

Ngoi, NYL, Tang, T-Y, Gaspar, CF, Pavlick, DC, Buchold, GM, Scholefield, EL, Parimi, V, Huang, RSP, Janovitz, T, Danziger, N, Levy, MA, Pant, S, De Armas, AD, Kumpula, D, Ross, JS, Javle, M & Rodon Ahnert, J 2024, 'Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers', The Oncologist, vol. 29, no. 6, pp. 493-503. https://doi.org/10.1093/oncolo/oyae011

TY - JOUR

T1 - Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers

AU - Ngoi, Natalie Y.L.

AU - Tang, Tin-Yun

AU - Gaspar, Catia F.

AU - Pavlick, Dean C.

AU - Buchold, Gregory M.

AU - Scholefield, Emma L.

AU - Parimi, Vamsi

AU - Huang, Richard S.P.

AU - Janovitz, Tyler

AU - Danziger, Natalie

AU - Levy, Mia A.

AU - Pant, Shubham

AU - De Armas, Anaemy Danner

AU - Kumpula, David

AU - Ross, Jeffrey S.

AU - Javle, Milind

AU - Rodon Ahnert, Jordi

PY - 2024/6

Y1 - 2024/6

N2 - BackgroundOne 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 MethodsWe 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.ResultsThe 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).ConclusionIn 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.

AB - BackgroundOne 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 MethodsWe 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.ResultsThe 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).ConclusionIn 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.

KW - cholangiocarcinoma

KW - MTAP loss

KW - 9p21 loss

KW - biomarkers

KW - genomics

KW - tumor

U2 - 10.1093/oncolo/oyae011

DO - 10.1093/oncolo/oyae011

M3 - Article

SN - 1083-7159

VL - 29

SP - 493

EP - 503

JO - The Oncologist

JF - The Oncologist

IS - 6

ER -

Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers

Abstract

Keywords

UN SDGs

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