A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2

Abstract

Background: Variation in an individual's genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of-function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC.

Study design: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, and the other genotypes were grouped as wild-type or heterozygous. Genotype distributions of each SNP were analyzed for Hardy-Weinberg deviation. A genotype frequency set from the 1000 Genomes Project (n = 99) was used as a genetic control for genotype distribution comparisons.

Results: A significant 2-fold increase in the overall prevalence of the Y359Stop homozygous genotype compared with the expected Hardy-Weinberg equilibrium was noted (p < 0.05). Familial pancreatic cancer was noted in 15 cases (19%) and comparison of the FPC cohort set to the genetic control set showed a 3-fold increase in Y359Stop homozygous rates (p = 0.054). Overall in our cohort, the homozygous genotype group was associated with increased risk of FPC (odds ratio 5.4; 95% CI 1.6 to 17.6; p < 0.01). Sex, age at diagnosis, and history of tobacco use were not found to be significantly associated with FPC.

Conclusions: Our preliminary data suggest a strong association between the IDO2 inactivating Y359Stop SNP and an increased risk of FPC when compared with the control group. Future studies will evaluate the value of IDO2 genotyping as a prognostic, early detection marker for pancreatic ductal adenocarcinoma and a predictive marker for novel immune checkpoint therapies.

Figure 1

Representative chromatograms of direct sequencing of patient constitutional genomic DNA showing the 3 possible sequences of homozygous, heterozygous, or wild-type sequence: R248W polymorphism (left) and Y359STOP (right).

Figure 2

Functionally inactive indoleamine-2,3-dioxygenase-2 (IDO2) alleles are frequently found in familial pancreatic cancer (FPC) patients. (A) Prevalence of FPC in various Y359Stop genotypes (wild-type, heterozygous, and homozygous) in the entire Thomas Jefferson University Hospital (TJUH) cohort (FPCs and sporadic pancreatic ductal adenocarcinoma [PDA]). Spearman’s correlation test (ρ = 0.229, p < 0.05). (B) Y359Stop genotype distribution in FPC as compared with CEU (Utah residents with northern and western European ancestry) control cases. chi-square test, 2 × 3 comparison, p = 0.054. WT, wild type. (C) Rates of FPC in various R248W genotypes. Spearman’s correlation test (ρ = 0.028, p = NS) in the entire TJUH cohort (FPCs and sporadic PDA). (D) R248W genotype distribution in FPC compared with CEU control cases. Chi-square test, 2 × 3 comparison, p = NS.

Figure 3

Indoleamine-2,3-dioxygenase-2 (IDO2) genotype variations in familial pancreatic cancer (FPC) compared with sporadic pancreatic ductal adenocarcinoma (PDA) cases and CEU (Utah residents with northern and western European ancestry) control cases. Chi-square/Fisher’s exact comparisons. OR, odds ratio.