title: Familial and sporadic pancreatic cancer share the same molecular pathogenesis.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is nearly uniformly lethal, with a median overall survival in 2014 of only 6 months. The genetic progression of sporadic PDAC (SPC) is well established, with common somatic alterations in KRAS, p16/CDKN2A, TP53, and SMAD4/DPC4. Up to 10 % of all PDAC cases occur in families with two or more affected first-degree relatives (familial pancreatic cancer, FPC), but these cases do not appear to present at an obviously earlier age of onset. This is unusual because most familial cancer syndrome patients present at a substantially younger age than that of corresponding sporadic cases. Here we collated the reported age of onset for FPC and SPC from the literature. We then used an integrated approach including whole exomic sequencing, whole genome sequencing, RNA sequencing, and high density SNP microarrays to study a cohort of FPC cell lines and corresponding germline samples. We show that the four major SPC driver genes are also consistently altered in FPC and that each of the four detection strategies was able to detect the mutations in these genes, with one exception. We conclude that FPC undergoes a similar somatic molecular pathogenesis as SPC, and that the same gene targets can be used for early detection and minimal residual disease testing in FPC patients.
authors.affiliation: Department of Pathology, The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins University School of Medicine, Room 344, Cancer Research Building-II, 1550 Orleans Street, Baltimore, MD, 21231, USA.
authors.forename: Alexis L
authors.initials: AL
authors.lastname: Norris
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Roberts
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Wheelan
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics*