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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.
Nevler, Avinoam; Muller, Alexander J; Cozzitorto, Joseph A; Goetz, Austin; Winter, Jordan M; Yeo, Theresa P; Lavu, Harish; Yeo, Charles J; Prendergast, George C; Brody, Jonathan R.
Afiliação
  • Nevler A; Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, Thomas Jefferson University, Philadelphia, PA.
  • Muller AJ; 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.
  • Cozzitorto JA; Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, Thomas Jefferson University, Philadelphia, PA.
  • Goetz A; Jefferson Pancreas, Biliary and Related Cancer Center and Department of Surgery, Thomas Jefferson University, Philadelphia, PA.
  • Winter JM; 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.
  • Yeo TP; 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.
  • Lavu H; 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.
  • Yeo CJ; 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.
  • Prendergast GC; 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.
  • Brody JR; 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.
J Am Coll Surg ; 226(4): 596-603, 2018 04.
Article em En | MEDLINE | ID: mdl-29426021
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Polimorfismo de Nucleotídeo Único / Carcinoma Ductal Pancreático / Indolamina-Pirrol 2,3,-Dioxigenase / Mutação com Perda de Função Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies / Screening_studies Limite: Female / Humans / Male Idioma: En Revista: J Am Coll Surg Assunto da revista: GINECOLOGIA / OBSTETRICIA Ano de publicação: 2018 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Polimorfismo de Nucleotídeo Único / Carcinoma Ductal Pancreático / Indolamina-Pirrol 2,3,-Dioxigenase / Mutação com Perda de Função Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies / Screening_studies Limite: Female / Humans / Male Idioma: En Revista: J Am Coll Surg Assunto da revista: GINECOLOGIA / OBSTETRICIA Ano de publicação: 2018 Tipo de documento: Article País de publicação: Estados Unidos