期刊
CLINICAL CANCER RESEARCH
卷 25, 期 2, 页码 724-734出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-0814
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资金
- NIH [R01 CA191191]
- Lankenau Medical Center Foundation
- Main Line Health
- American Cancer Society-IRG grant
- AACR Pancreatic Cancer Action Network
- Mary Halinski Fellowship
- SKCC Core Grant (TJU) [P30 CA056036]
- [R01 CA212600]
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(+/+) 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. 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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