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

Jian Wu, Yuchen Jiao, Marco Dal Molin, Anirban Maitra, Roeland F. De Wilde, Laura D. Wood, James R. Eshleman, Michael G. Goggins, Christopher L. Wolfgang, Marcia I. Canto, Richard D. Schulick, Barish H. Edil, Michael A. Choti, Volkan Adsay, David S. Klimstra, G. Johan A Offerhaus, Alison P. Klein, Levy Kopelovich, Hannah Carter, Rachel KarchinPeter J. Allen, C. Schmidt, Yoshiki Naito, Luis A. Diaz, Kenneth W. Kinzler, Nickolas Papadopoulos, Ralph H. Hruban, Bert Vogelstein

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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.

Original languageEnglish
Pages (from-to)21188-21193
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number52
DOIs
StatePublished - Dec 27 2011

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Exome
Ubiquitin
Cysts
Pancreas
Mutation
Neoplasms
Serous Cystadenoma
Ubiquitin-Protein Ligases
Ligases
Pancreatic Cyst

ASJC Scopus subject areas

  • General

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Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. / Wu, Jian; Jiao, Yuchen; Dal Molin, Marco; Maitra, Anirban; De Wilde, Roeland F.; Wood, Laura D.; Eshleman, James R.; Goggins, Michael G.; Wolfgang, Christopher L.; Canto, Marcia I.; Schulick, Richard D.; Edil, Barish H.; Choti, Michael A.; Adsay, Volkan; Klimstra, David S.; Offerhaus, G. Johan A; Klein, Alison P.; Kopelovich, Levy; Carter, Hannah; Karchin, Rachel; Allen, Peter J.; Schmidt, C.; Naito, Yoshiki; Diaz, Luis A.; Kinzler, Kenneth W.; Papadopoulos, Nickolas; Hruban, Ralph H.; Vogelstein, Bert.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 52, 27.12.2011, p. 21188-21193.

Research output: Contribution to journalArticle

Wu, J, Jiao, Y, Dal Molin, M, Maitra, A, De Wilde, RF, Wood, LD, Eshleman, JR, Goggins, MG, Wolfgang, CL, Canto, MI, Schulick, RD, Edil, BH, Choti, MA, Adsay, V, Klimstra, DS, Offerhaus, GJA, Klein, AP, Kopelovich, L, Carter, H, Karchin, R, Allen, PJ, Schmidt, C, Naito, Y, Diaz, LA, Kinzler, KW, Papadopoulos, N, Hruban, RH & Vogelstein, B 2011, 'Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 52, pp. 21188-21193. https://doi.org/10.1073/pnas.1118046108
Wu, Jian ; Jiao, Yuchen ; Dal Molin, Marco ; Maitra, Anirban ; De Wilde, Roeland F. ; Wood, Laura D. ; Eshleman, James R. ; Goggins, Michael G. ; Wolfgang, Christopher L. ; Canto, Marcia I. ; Schulick, Richard D. ; Edil, Barish H. ; Choti, Michael A. ; Adsay, Volkan ; Klimstra, David S. ; Offerhaus, G. Johan A ; Klein, Alison P. ; Kopelovich, Levy ; Carter, Hannah ; Karchin, Rachel ; Allen, Peter J. ; Schmidt, C. ; Naito, Yoshiki ; Diaz, Luis A. ; Kinzler, Kenneth W. ; Papadopoulos, Nickolas ; Hruban, Ralph H. ; Vogelstein, Bert. / Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 52. pp. 21188-21193.
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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.",
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T1 - Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

AU - Wu, Jian

AU - Jiao, Yuchen

AU - Dal Molin, Marco

AU - Maitra, Anirban

AU - De Wilde, Roeland F.

AU - Wood, Laura D.

AU - Eshleman, James R.

AU - Goggins, Michael G.

AU - Wolfgang, Christopher L.

AU - Canto, Marcia I.

AU - Schulick, Richard D.

AU - Edil, Barish H.

AU - Choti, Michael A.

AU - Adsay, Volkan

AU - Klimstra, David S.

AU - Offerhaus, G. Johan A

AU - Klein, Alison P.

AU - Kopelovich, Levy

AU - Carter, Hannah

AU - Karchin, Rachel

AU - Allen, Peter J.

AU - Schmidt, C.

AU - Naito, Yoshiki

AU - Diaz, Luis A.

AU - Kinzler, Kenneth W.

AU - Papadopoulos, Nickolas

AU - Hruban, Ralph H.

AU - Vogelstein, Bert

PY - 2011/12/27

Y1 - 2011/12/27

N2 - 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.

AB - 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.

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