Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers

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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Purpose: 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 þ / þ and Ido2/ mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (N ¼ 200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression, and clinical survival data. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)724-734
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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