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Figure S2 from Host IDO2 Gene Status Influences Tumor Progression and Radiotherapy Response in KRAS-Driven Sporadic Pancreatic Cancers

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posted on 2023-03-31, 21:30 authored by Avinoam Nevler, Alexander J. Muller, Erika Sutanto-Ward, James B. DuHadaway, Kei Nagatomo, Eric Londin, Kevin O'Hayer, Joseph A. Cozzitorto, Harish Lavu, Theresa P. Yeo, Mark Curtis, Tatiana Villatoro, Benjamin E. Leiby, Laura Mandik-Nayak, Jordan M. Winter, Charles J. Yeo, George C. Prendergast, Jonathan R. Brody

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ARTICLE ABSTRACT

Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately affect cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2 in humans is the high prevalence of two inactivating single-nucleotide polymorphisms (SNP), which affords the opportunity to carry out loss-of-function studies directly in humans. In this study, we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment.Experimental Design: Transgenic Ido2+/+ and Ido2−/− mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (N = 200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression, and clinical survival data. PDAC development was notably decreased in the Ido2−/− mice (30% vs. 10%, P < 0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P < 0.01), a treatment modality that has been highly debated due to its variable efficacy. The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2 genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.

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