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

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A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of- Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2 Avinoam Nevler, MD, Alexander J. Muller, PhD, Joseph A. Cozzitorto, BA, Austin Goetz, MD, Jordan M. Winter, MD, FACS, Theresa P. Yeo, PhD, MPH, MSN, Harish Lavu, MD, FACS, Charles J. Yeo, MD, FACS, George C. Prendergast, PhD, Jonathan R. Brody, PhD Journal of the American College of Surgeons Volume 226, Issue 4, Pages 596-603 (April 2018) DOI: 10.1016/j.jamcollsurg.2017.12.052 Copyright © 2018 The Authors Terms and Conditions

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). Journal of the American College of Surgeons 2018 226, 596-603DOI: (10.1016/j.jamcollsurg.2017.12.052) Copyright © 2018 The Authors Terms and Conditions

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. Journal of the American College of Surgeons 2018 226, 596-603DOI: (10.1016/j.jamcollsurg.2017.12.052) Copyright © 2018 The Authors Terms and Conditions

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. Journal of the American College of Surgeons 2018 226, 596-603DOI: (10.1016/j.jamcollsurg.2017.12.052) Copyright © 2018 The Authors Terms and Conditions