title: Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.
abstract: Pancreatic cancer is one of the most challenging cancers. Whole genome sequencing studies have been conducted to elucidate the underlying fundamentals underscoring disease behavior. Studies have identified a subgroup of pancreatic cancer patients with distinct molecular and clinical features. Genetic fingerprinting of these tumors is consistent with an unstable genome and defective DNA repair pathways, which creates unique susceptibility to agents inducing DNA damage. BRCA1/2 mutations, both germline and somatic, which lead to impaired DNA repair, are found to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Recent studies have elucidated that PARP inhibitors and platinum agents may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. In this review we discuss the characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as a novel treatment approach.
authors.affiliation: a Department of Medicine , Icahn School of Medicine at Mount Sinai St Luke's Roosevelt Hospital Center , New York , NY , USA.
authors.forename: Ibrahim H
authors.initials: IH
authors.lastname: Sahin
authors.affiliation: b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.|c Department of Medicine , Weill Cornell Medical College , New York , NY , USA.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Lowery
authors.affiliation: b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.|c Department of Medicine , Weill Cornell Medical College , New York , NY , USA.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.affiliation: b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Salo-Mullen
authors.affiliation: b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.|c Department of Medicine , Weill Cornell Medical College , New York , NY , USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsen
authors.affiliation: b Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.|c Department of Medicine , Weill Cornell Medical College , New York , NY , USA.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: O'Reilly
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D025202:Molecular Diagnostic Techniques; D058990:Molecular Targeted Therapy; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods*; D011237:Predictive Value of Tests
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases
keywords: ARID1; ATM; BRCA1; BRCA2; DNA repair; MSH; PALB2; PARP inhibitors; PARP1; Pancreatic cancer; cisplatin; genomic instability; synthetic lethality