Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

• Type of Material: Article
• Authors: Jian Wu, Johns Hopkins Kimmel Cancer Center; Yuchen Jiao, Johns Hopkins Kimmel Cancer Center; Marco Dal Molin, Johns Hopkins Medical Institutions; Anirban Maitra, Johns Hopkins Medical Institutions; Roeland F. de Wilde, Johns Hopkins Medical Institutions; Laura D. Wood, Johns Hopkins Medical Institutions; James R. Eshleman, Johns Hopkins Medical Institutions; Michael G. Goggins, Johns Hopkins Medical Institutions; Christopher L. Wolfgang, Johns Hopkins Medical Institutions; Marcia I. Canto, Johns Hopkins Medical Institutions; Richard D. Schulick, Johns Hopkins Medical Institutions; Barish H. Edil, Johns Hopkins Medical Institutions; Michael A. Choti, Johns Hopkins Medical Institutions; Volkan Adsay, Emory University; David S. Klimstra, Emory University; G. Johan A. Offerhaus, University Medical Center of Utrecht; Alison P. Klein, Johns Hopkins Kimmel Cancer Center; Levy Kopelovich, National Institutes of Health; Hannah Carter, The Johns Hopkins University; Rachel Karchin, The Johns Hopkins University; Peter J. Allen, The Johns Hopkins University; C. Max Schmidt, Indiana University; Yoshiki Naito, Kurume University School of Medicine; Luis A. Diaz, Jr., Johns Hopkins Kimmel Cancer Center; Kenneth W. Kinzler, Johns Hopkins Kimmel Cancer Center; Nickolas Papadopoulos, Johns Hopkins Kimmel Cancer Center; Ralph H. Hruban, Johns Hopkins Kimmel Cancer Center; Bert Vogelstein, Johns Hopkins Kimmel Cancer Center
• Language: English
• Date: 2011-12-27
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © Wu et al.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1118046108
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 108
• Issue: 52
• Start Page: 21188
• End Page: 21193
• Grant/Funding Information: This work was supported by the Lustgarten Foundation for Pancreatic Cancer Research; the Virginia and D. K. Ludwig Fund for Cancer Research; The Sol Goldman Pancreatic Cancer Research Center; the Joseph L. Rabinowitz Fund; the Michael Rolfe Foundation; the Stringer Foundation; the family of Ted and Julie Smith; the Indiana Genomics Initiative of Indiana University, which is supported, in part, by Lilly Endowment, Inc.; the J. C. Monastra Foundation; Swim Across America; National Science Foundation Grant DBI-1845275; National Institutes of Health Grants CA 62924, CA 57345, CA 152432, and CA 43460; and National Cancer Institute Contracts N01-CN-43302, N01-CN-43309, and NCI grant P01CA134292.
• Keywords: LINDAU TUMOR-SUPPRESSOR; FLUID ANALYSIS; DISEASE; MULTIDISCIPLINARY SCIENCES; Science & Technology - Other Topics; MANAGEMENT; BETA-CATENIN; Multidisciplinary Sciences; COLORECTAL-CANCER; PREVALENCE; Science & Technology; DIFFERENTIAL-DIAGNOSIS; LESIONS; PROTEIN
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology; Health Sciences, Medicine and Surgery

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 proteinwith 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 fewgenetic 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.