Genotyping and Expression Analysis of IDO2 in Human Pancreatic Cancer: A Novel, Active Target

Agnieszka K. Witkiewicz, Christina L. Costantino, Richard Metz, Alexander J. Muller, George C. Prendergast, Charles J. Yeo, Jonathan R. Brody

Research output: Contribution to journalArticle

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Abstract

Background: The recently discovered indoleamine 2,3-dioxygenase-2 (IDO2) gene has 2 functional polymorphisms that abolish its enzymatic activity. We hypothesize that expression of the IDO2 enzyme in primary pancreatic ductal adenocarcinomas (PDA) can help cancer cells evade immune detection. Study Design: Because the IDO2 enzyme might be the preferential target of d-1-methyl-tryptophan, a clinical lead inhibitor of IDO currently being evaluated in phase I trials, we sequenced IDO2 in 36 pancreatic specimens and evaluated its expression. Results: We found that 58% (21 of 36) of cases were heterozygous for the R248W polymorphism; 28% (10 of 36) were homozygous wild-type; and only 14% (5 of 36) were homozygous for the functionally inactive polymorphism. As for the Y359STOP polymorphism, we found that 27% (10 of 36) of cases were heterozygous, 62% (22 of 36) were homozygous wild-type, and only 11% (4 of 36) were homozygous for this functionally inactive allele. Ruling out the possibility of compound polymorphic variants, we estimated 75% of our resected patient cohort had an active IDO2 enzyme, with a conservative estimate that 58% of the patients had at least 1 functional allele. IDO2 was expressed in PDA tissue from each genetically polymorphic subgroup. We also detected IDO2 protein expression in the genetically distinct pancreatic cancer cell lines after exposure with interferon-γ. Conclusions: This is the first study to report IDO2 expression in PDA and related cancers indicating that IDO2 genetic polymorphisms do not negate interferon-γ-inducible protein expression. Taken together, our data strongly suggest that the clinical lead compound d-1-methyl-tryptophan might be useful in treatment of PDA.

Original languageEnglish (US)
Pages (from-to)781-787
Number of pages7
JournalJournal of the American College of Surgeons
Volume208
Issue number5
DOIs
StatePublished - May 2009

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Pancreatic Neoplasms
Adenocarcinoma
Interferons
Enzymes
Alleles
human indoleamine 2,3-dioxygenase 2
Genetic Polymorphisms
Neoplasms
Proteins
Cell Line

ASJC Scopus subject areas

  • Surgery

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Genotyping and Expression Analysis of IDO2 in Human Pancreatic Cancer : A Novel, Active Target. / Witkiewicz, Agnieszka K.; Costantino, Christina L.; Metz, Richard; Muller, Alexander J.; Prendergast, George C.; Yeo, Charles J.; Brody, Jonathan R.

In: Journal of the American College of Surgeons, Vol. 208, No. 5, 05.2009, p. 781-787.

Research output: Contribution to journalArticle

Witkiewicz, Agnieszka K. ; Costantino, Christina L. ; Metz, Richard ; Muller, Alexander J. ; Prendergast, George C. ; Yeo, Charles J. ; Brody, Jonathan R. / Genotyping and Expression Analysis of IDO2 in Human Pancreatic Cancer : A Novel, Active Target. In: Journal of the American College of Surgeons. 2009 ; Vol. 208, No. 5. pp. 781-787.
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abstract = "Background: The recently discovered indoleamine 2,3-dioxygenase-2 (IDO2) gene has 2 functional polymorphisms that abolish its enzymatic activity. We hypothesize that expression of the IDO2 enzyme in primary pancreatic ductal adenocarcinomas (PDA) can help cancer cells evade immune detection. Study Design: Because the IDO2 enzyme might be the preferential target of d-1-methyl-tryptophan, a clinical lead inhibitor of IDO currently being evaluated in phase I trials, we sequenced IDO2 in 36 pancreatic specimens and evaluated its expression. Results: We found that 58{\%} (21 of 36) of cases were heterozygous for the R248W polymorphism; 28{\%} (10 of 36) were homozygous wild-type; and only 14{\%} (5 of 36) were homozygous for the functionally inactive polymorphism. As for the Y359STOP polymorphism, we found that 27{\%} (10 of 36) of cases were heterozygous, 62{\%} (22 of 36) were homozygous wild-type, and only 11{\%} (4 of 36) were homozygous for this functionally inactive allele. Ruling out the possibility of compound polymorphic variants, we estimated 75{\%} of our resected patient cohort had an active IDO2 enzyme, with a conservative estimate that 58{\%} of the patients had at least 1 functional allele. IDO2 was expressed in PDA tissue from each genetically polymorphic subgroup. We also detected IDO2 protein expression in the genetically distinct pancreatic cancer cell lines after exposure with interferon-γ. Conclusions: This is the first study to report IDO2 expression in PDA and related cancers indicating that IDO2 genetic polymorphisms do not negate interferon-γ-inducible protein expression. Taken together, our data strongly suggest that the clinical lead compound d-1-methyl-tryptophan might be useful in treatment of PDA.",
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AU - Witkiewicz, Agnieszka K.

AU - Costantino, Christina L.

AU - Metz, Richard

AU - Muller, Alexander J.

AU - Prendergast, George C.

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AU - Brody, Jonathan R.

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N2 - Background: The recently discovered indoleamine 2,3-dioxygenase-2 (IDO2) gene has 2 functional polymorphisms that abolish its enzymatic activity. We hypothesize that expression of the IDO2 enzyme in primary pancreatic ductal adenocarcinomas (PDA) can help cancer cells evade immune detection. Study Design: Because the IDO2 enzyme might be the preferential target of d-1-methyl-tryptophan, a clinical lead inhibitor of IDO currently being evaluated in phase I trials, we sequenced IDO2 in 36 pancreatic specimens and evaluated its expression. Results: We found that 58% (21 of 36) of cases were heterozygous for the R248W polymorphism; 28% (10 of 36) were homozygous wild-type; and only 14% (5 of 36) were homozygous for the functionally inactive polymorphism. As for the Y359STOP polymorphism, we found that 27% (10 of 36) of cases were heterozygous, 62% (22 of 36) were homozygous wild-type, and only 11% (4 of 36) were homozygous for this functionally inactive allele. Ruling out the possibility of compound polymorphic variants, we estimated 75% of our resected patient cohort had an active IDO2 enzyme, with a conservative estimate that 58% of the patients had at least 1 functional allele. IDO2 was expressed in PDA tissue from each genetically polymorphic subgroup. We also detected IDO2 protein expression in the genetically distinct pancreatic cancer cell lines after exposure with interferon-γ. Conclusions: This is the first study to report IDO2 expression in PDA and related cancers indicating that IDO2 genetic polymorphisms do not negate interferon-γ-inducible protein expression. Taken together, our data strongly suggest that the clinical lead compound d-1-methyl-tryptophan might be useful in treatment of PDA.

AB - Background: The recently discovered indoleamine 2,3-dioxygenase-2 (IDO2) gene has 2 functional polymorphisms that abolish its enzymatic activity. We hypothesize that expression of the IDO2 enzyme in primary pancreatic ductal adenocarcinomas (PDA) can help cancer cells evade immune detection. Study Design: Because the IDO2 enzyme might be the preferential target of d-1-methyl-tryptophan, a clinical lead inhibitor of IDO currently being evaluated in phase I trials, we sequenced IDO2 in 36 pancreatic specimens and evaluated its expression. Results: We found that 58% (21 of 36) of cases were heterozygous for the R248W polymorphism; 28% (10 of 36) were homozygous wild-type; and only 14% (5 of 36) were homozygous for the functionally inactive polymorphism. As for the Y359STOP polymorphism, we found that 27% (10 of 36) of cases were heterozygous, 62% (22 of 36) were homozygous wild-type, and only 11% (4 of 36) were homozygous for this functionally inactive allele. Ruling out the possibility of compound polymorphic variants, we estimated 75% of our resected patient cohort had an active IDO2 enzyme, with a conservative estimate that 58% of the patients had at least 1 functional allele. IDO2 was expressed in PDA tissue from each genetically polymorphic subgroup. We also detected IDO2 protein expression in the genetically distinct pancreatic cancer cell lines after exposure with interferon-γ. Conclusions: This is the first study to report IDO2 expression in PDA and related cancers indicating that IDO2 genetic polymorphisms do not negate interferon-γ-inducible protein expression. Taken together, our data strongly suggest that the clinical lead compound d-1-methyl-tryptophan might be useful in treatment of PDA.

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