TY - JOUR
T1 - Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers
AU - Nevler, Avinoam
AU - Muller, Alexander J.
AU - Sutanto-Ward, Erika
AU - DuHadaway, James B.
AU - Nagatomo, Kei
AU - Londin, Eric
AU - O'Hayer, Kevin
AU - Cozzitorto, Joseph A.
AU - Lavu, Harish
AU - Yeo, Theresa P.
AU - Curtis, Mark
AU - Villatoro, Tatiana
AU - Leiby, Benjamin E.
AU - Mandik-Nayak, Laura
AU - Winter, Jordan M.
AU - Yeo, Charles J.
AU - Prendergast, George C.
AU - Brody, Jonathan R.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-0814
DO - 10.1158/1078-0432.CCR-18-0814
M3 - Article
C2 - 30266763
AN - SCOPUS:85060064517
SN - 1078-0432
VL - 25
SP - 724
EP - 734
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -