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

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Bibliographische Detailangaben
Zeitschriftentitel:	Clinical Cancer Research
Personen und Körperschaften:	Nevler, Avinoam, Muller, Alexander J., Sutanto-Ward, Erika, DuHadaway, James B., Nagatomo, Kei, Londin, Eric, O'Hayer, Kevin, Cozzitorto, Joseph A., Lavu, Harish, Yeo, Theresa P., Curtis, Mark, Villatoro, Tatiana, Leiby, Benjamin E., Mandik-Nayak, Laura, Winter, Jordan M., Yeo, Charles J., Prendergast, George C., Brody, Jonathan R.
In:	Clinical Cancer Research, 25, 2019, 2, S. 724-734
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Association for Cancer Research (AACR)
Schlagwörter:	Cancer Research Oncology

Details
Zusammenfassung:	<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>PDAC development was notably decreased in the Ido2−/− mice (30% vs. 10%, P &lt; 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 &lt; 0.01), a treatment modality that has been highly debated due to its variable efficacy.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>
Umfang:	724-734
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.ccr-18-0814