Host <i>IDO2</i> Gene Status Influences Tumor Progression and Radiotherapy Response in <i>KRAS</i>-Driven Sporadic Pancreatic Cancers.

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 <i>IDO2</i> 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.<b>Experimental Design:</b> Transgenic <i>Ido2</i> ^+/+ and <i>Ido2</i> ^-/- mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (<i>N</i> = 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 <i>Ido2</i> ^-/- mice (30% vs. 10%, <i>P</i> < 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 (<i>P</i> < 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 <i>IDO2</i> 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.