PMID- 29426021
OWN - NLM
STAT- MEDLINE
DCOM- 20190715
LR  - 20211108
IS  - 1879-1190 (Electronic)
IS  - 1072-7515 (Print)
IS  - 1072-7515 (Linking)
VI  - 226
IP  - 4
DP  - 2018 Apr
TI  - A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of 
      Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2.
PG  - 596-603
LID - S1072-7515(18)30062-0 [pii]
LID - 10.1016/j.jamcollsurg.2017.12.052 [doi]
AB  - 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.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Nevler, Avinoam
AU  - Nevler A
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA.
FAU - Muller, Alexander J
AU  - Muller AJ
AD  - Department of Microbiology and Immunology, Thomas Jefferson University, 
      Philadelphia, PA; Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, 
      Thomas Jefferson University, Philadelphia, PA; Lankenau Institute for Medical 
      Research, Wynnewood, PA.
FAU - Cozzitorto, Joseph A
AU  - Cozzitorto JA
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA.
FAU - Goetz, Austin
AU  - Goetz A
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA.
FAU - Winter, Jordan M
AU  - Winter JM
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA; Sidney Kimmel Medical College and 
      Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
FAU - Yeo, Theresa P
AU  - Yeo TP
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA; Sidney Kimmel Medical College and 
      Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
FAU - Lavu, Harish
AU  - Lavu H
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA; Sidney Kimmel Medical College and 
      Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
FAU - Yeo, Charles J
AU  - Yeo CJ
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA; Sidney Kimmel Medical College and 
      Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
FAU - Prendergast, George C
AU  - Prendergast GC
AD  - Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 
      Philadelphia, PA; Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, 
      Thomas Jefferson University, Philadelphia, PA; Lankenau Institute for Medical 
      Research, Wynnewood, PA.
FAU - Brody, Jonathan R
AU  - Brody JR
AD  - Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, 
      Thomas Jefferson University, Philadelphia, PA; Sidney Kimmel Medical College and 
      Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA. 
      Electronic address: jonathan.brody@jefferson.edu.
LA  - eng
GR  - P30 CA056036/CA/NCI NIH HHS/United States
GR  - R01 CA191191/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180207
PL  - United States
TA  - J Am Coll Surg
JT  - Journal of the American College of Surgeons
JID - 9431305
RN  - 0 (IDO2 protein, human)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
SB  - IM
CIN - J Am Coll Surg. 2018 Apr;226(4):603-604. PMID: 29576161
MH  - Carcinoma, Pancreatic Ductal/*genetics
MH  - Case-Control Studies
MH  - Female
MH  - Humans
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/*genetics
MH  - Loss of Function Mutation/*genetics
MH  - Male
MH  - Pancreatic Neoplasms/*genetics
MH  - Polymorphism, Single Nucleotide/*genetics
PMC - PMC6047862
MID - NIHMS955609
EDAT- 2018/02/10 06:00
MHDA- 2019/07/16 06:00
PMCR- 2018/07/16
CRDT- 2018/02/10 06:00
PHST- 2017/12/18 00:00 [received]
PHST- 2017/12/19 00:00 [accepted]
PHST- 2018/02/10 06:00 [pubmed]
PHST- 2019/07/16 06:00 [medline]
PHST- 2018/02/10 06:00 [entrez]
PHST- 2018/07/16 00:00 [pmc-release]
AID - S1072-7515(18)30062-0 [pii]
AID - 10.1016/j.jamcollsurg.2017.12.052 [doi]
PST - ppublish
SO  - J Am Coll Surg. 2018 Apr;226(4):596-603. doi: 10.1016/j.jamcollsurg.2017.12.052. 
      Epub 2018 Feb 7.