title: Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways.
abstract: More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 ± 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel-Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.
authors.affiliation: Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.forename: Marco
authors.initials: M
authors.lastname: Dal Molin
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Roeland F
authors.initials: RF
authors.lastname: de Wilde
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: Michael G
authors.initials: MG
authors.lastname: Goggins
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Canto
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Barish H
authors.initials: BH
authors.lastname: Edil
authors.forename: Michael A
authors.initials: MA
authors.lastname: Choti
authors.forename: Volkan
authors.initials: V
authors.lastname: Adsay
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Allen
authors.forename: C Max
authors.initials: CM
authors.lastname: Schmidt
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Naito
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
mesh_terms: D000328:Adult; D001483:Base Sequence; D018291:Cystadenoma, Mucinous / Q000235:genetics*; D018293:Cystadenoma, Serous / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics; D010181:Pancreatic Cyst / Q000235:genetics* / Q000473:pathology; D018300:Papilloma, Intraductal / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein