A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

Simeon Springer; Yuxuan Wang; Marco Dal Molin; David L. Masica; Yuchen Jiao; Isaac Kinde; Amanda Blackford; Siva P Raman; Christopher L. Wolfgang; Tyler Tomita; Noushin Niknafs; Christopher Douville; Janine Ptak; Lisa Dobbyn; Peter J. Allen; David S. Klimstra; Mark A. Schattner; C. Max Schmidt; Michele Yip-Schneider; Oscar W. Cummings; Randall E. Brand; Herbert J. Zeh; Aatur D. Singhi; Aldo Scarpa; Roberto Salvia; Giuseppe Malleo; Giuseppe Zamboni; Massimo Falconi; Jin Young Jang; Sun Whe Kim; Wooil Kwon; Seung Mo Hong; Ki Byung Song; Song Cheol Kim; Niall Swan; Jean Murphy; Justin Geoghegan; William Brugge; Carlos Fernandez-Del Castillo; Mari Mino-Kenudson; Richard David Schulick; Barish H. Edil; Volkan Adsay; Jorge Paulino; Jeanin Van Hooft; Shinichi Yachida; Satoshi Nara; Nobuyoshi Hiraoka; Kenji Yamao; Susuma Hijioka; Schalk Van Der Merwe; Michael Goggins; Marcia Irene Canto; Nita Ahuja; Kenzo Hirose; Martin Makary; Matthew J Weiss; John Cameron; Meredith Pittman; James R. Eshleman; Luis A. Diaz; Nickolas Papadopoulos; Kenneth W. Kinzler; Rachel Karchin; Ralph H. Hruban; Bert Vogelstein; Anne Marie Lennon

doi:10.1053/j.gastro.2015.07.041

A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

Simeon Springer, Yuxuan Wang, Marco Dal Molin, David L. Masica, Yuchen Jiao, Isaac Kinde, Amanda Blackford, Siva P Raman, Christopher L. Wolfgang, Tyler Tomita, Noushin Niknafs, Christopher Douville, Janine Ptak, Lisa Dobbyn, Peter J. Allen, David S. Klimstra, Mark A. Schattner, C. Max Schmidt, Michele Yip-Schneider, Oscar W. CummingsRandall E. Brand, Herbert J. Zeh, Aatur D. Singhi, Aldo Scarpa, Roberto Salvia, Giuseppe Malleo, Giuseppe Zamboni, Massimo Falconi, Jin Young Jang, Sun Whe Kim, Wooil Kwon, Seung Mo Hong, Ki Byung Song, Song Cheol Kim, Niall Swan, Jean Murphy, Justin Geoghegan, William Brugge, Carlos Fernandez-Del Castillo, Mari Mino-Kenudson, Richard David Schulick, Barish H. Edil, Volkan Adsay, Jorge Paulino, Jeanin Van Hooft, Shinichi Yachida, Satoshi Nara, Nobuyoshi Hiraoka, Kenji Yamao, Susuma Hijioka, Schalk Van Der Merwe, Michael Goggins, Marcia Irene Canto, Nita Ahuja, Kenzo Hirose, Martin Makary, Matthew J Weiss, John Cameron, Meredith Pittman, James R. Eshleman, Luis A. Diaz, Nickolas Papadopoulos, Kenneth W. Kinzler, Rachel Karchin, Ralph H. Hruban, Bert Vogelstein, Anne Marie Lennon

Research output: Contribution to journal › Article › peer-review

227 Scopus citations

Abstract

Background and Aims The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. Methods We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. Results We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. Conclusions We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Original language	English (US)
Pages (from-to)	1501-1510
Number of pages	10
Journal	Gastroenterology
Volume	149
Issue number	6
DOIs	https://doi.org/10.1053/j.gastro.2015.07.041
State	Published - Nov 2015

Keywords

Diagnosis
IPMN
Molecular
Pancreatic Cyst

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2015.07.041

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Springer, S., Wang, Y., Dal Molin, M., Masica, D. L., Jiao, Y., Kinde, I., Blackford, A., Raman, S. P., Wolfgang, C. L., Tomita, T., Niknafs, N., Douville, C., Ptak, J., Dobbyn, L., Allen, P. J., Klimstra, D. S., Schattner, M. A., Schmidt, C. M., Yip-Schneider, M., ... Lennon, A. M. (2015). A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts. Gastroenterology, 149(6), 1501-1510. https://doi.org/10.1053/j.gastro.2015.07.041

Springer, S, Wang, Y, Dal Molin, M, Masica, DL, Jiao, Y, Kinde, I, Blackford, A, Raman, SP, Wolfgang, CL, Tomita, T, Niknafs, N, Douville, C, Ptak, J, Dobbyn, L, Allen, PJ, Klimstra, DS, Schattner, MA, Schmidt, CM, Yip-Schneider, M, Cummings, OW, Brand, RE, Zeh, HJ, Singhi, AD, Scarpa, A, Salvia, R, Malleo, G, Zamboni, G, Falconi, M, Jang, JY, Kim, SW, Kwon, W, Hong, SM, Song, KB, Kim, SC, Swan, N, Murphy, J, Geoghegan, J, Brugge, W, Fernandez-Del Castillo, C, Mino-Kenudson, M, Schulick, RD, Edil, BH, Adsay, V, Paulino, J, Van Hooft, J, Yachida, S, Nara, S, Hiraoka, N, Yamao, K, Hijioka, S, Van Der Merwe, S, Goggins, M , Canto, MI , Ahuja, N, Hirose, K, Makary, M, Weiss, MJ, Cameron, J, Pittman, M, Eshleman, JR, Diaz, LA, Papadopoulos, N , Kinzler, KW, Karchin, R, Hruban, RH , Vogelstein, B & Lennon, AM 2015, 'A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts', Gastroenterology, vol. 149, no. 6, pp. 1501-1510. https://doi.org/10.1053/j.gastro.2015.07.041

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title = "A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts",

abstract = "Background and Aims The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. Methods We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. Results We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. Conclusions We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.",

keywords = "Diagnosis, IPMN, Molecular, Pancreatic Cyst",

author = "Simeon Springer and Yuxuan Wang and {Dal Molin}, Marco and Masica, {David L.} and Yuchen Jiao and Isaac Kinde and Amanda Blackford and Raman, {Siva P} and Wolfgang, {Christopher L.} and Tyler Tomita and Noushin Niknafs and Christopher Douville and Janine Ptak and Lisa Dobbyn and Allen, {Peter J.} and Klimstra, {David S.} and Schattner, {Mark A.} and Schmidt, {C. Max} and Michele Yip-Schneider and Cummings, {Oscar W.} and Brand, {Randall E.} and Zeh, {Herbert J.} and Singhi, {Aatur D.} and Aldo Scarpa and Roberto Salvia and Giuseppe Malleo and Giuseppe Zamboni and Massimo Falconi and Jang, {Jin Young} and Kim, {Sun Whe} and Wooil Kwon and Hong, {Seung Mo} and Song, {Ki Byung} and Kim, {Song Cheol} and Niall Swan and Jean Murphy and Justin Geoghegan and William Brugge and {Fernandez-Del Castillo}, Carlos and Mari Mino-Kenudson and Schulick, {Richard David} and Edil, {Barish H.} and Volkan Adsay and Jorge Paulino and {Van Hooft}, Jeanin and Shinichi Yachida and Satoshi Nara and Nobuyoshi Hiraoka and Kenji Yamao and Susuma Hijioka and {Van Der Merwe}, Schalk and Michael Goggins and Canto, {Marcia Irene} and Nita Ahuja and Kenzo Hirose and Martin Makary and Weiss, {Matthew J} and John Cameron and Meredith Pittman and Eshleman, {James R.} and Diaz, {Luis A.} and Nickolas Papadopoulos and Kinzler, {Kenneth W.} and Rachel Karchin and Hruban, {Ralph H.} and Bert Vogelstein and Lennon, {Anne Marie}",

note = "Funding Information: Funding This work supported by The Lustgarten Foundation for Pancreatic Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, The Virginia and D. K. Ludwig Fund for Cancer Research, Susan Wojcicki and Dennis Troper, The Michael Rolfe Foundation, National Institutes of Health grant P50 CA62924, Associazione Italiana Ricerca Cancro (12182) Italian Ministry of Research (FIRB RBAP10AHJB) and Health (FIMP J33G13000210001). Publisher Copyright: {\textcopyright} 2015 AGA Institute.",

year = "2015",

month = nov,

doi = "10.1053/j.gastro.2015.07.041",

language = "English (US)",

volume = "149",

pages = "1501--1510",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "6",

}

TY - JOUR

T1 - A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

AU - Springer, Simeon

AU - Wang, Yuxuan

AU - Dal Molin, Marco

AU - Masica, David L.

AU - Jiao, Yuchen

AU - Kinde, Isaac

AU - Blackford, Amanda

AU - Raman, Siva P

AU - Wolfgang, Christopher L.

AU - Tomita, Tyler

AU - Niknafs, Noushin

AU - Douville, Christopher

AU - Ptak, Janine

AU - Dobbyn, Lisa

AU - Allen, Peter J.

AU - Klimstra, David S.

AU - Schattner, Mark A.

AU - Schmidt, C. Max

AU - Yip-Schneider, Michele

AU - Cummings, Oscar W.

AU - Brand, Randall E.

AU - Zeh, Herbert J.

AU - Singhi, Aatur D.

AU - Scarpa, Aldo

AU - Salvia, Roberto

AU - Malleo, Giuseppe

AU - Zamboni, Giuseppe

AU - Falconi, Massimo

AU - Jang, Jin Young

AU - Kim, Sun Whe

AU - Kwon, Wooil

AU - Hong, Seung Mo

AU - Song, Ki Byung

AU - Kim, Song Cheol

AU - Swan, Niall

AU - Murphy, Jean

AU - Geoghegan, Justin

AU - Brugge, William

AU - Fernandez-Del Castillo, Carlos

AU - Mino-Kenudson, Mari

AU - Schulick, Richard David

AU - Edil, Barish H.

AU - Adsay, Volkan

AU - Paulino, Jorge

AU - Van Hooft, Jeanin

AU - Yachida, Shinichi

AU - Nara, Satoshi

AU - Hiraoka, Nobuyoshi

AU - Yamao, Kenji

AU - Hijioka, Susuma

AU - Van Der Merwe, Schalk

AU - Goggins, Michael

AU - Canto, Marcia Irene

AU - Ahuja, Nita

AU - Hirose, Kenzo

AU - Makary, Martin

AU - Weiss, Matthew J

AU - Cameron, John

AU - Pittman, Meredith

AU - Eshleman, James R.

AU - Diaz, Luis A.

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W.

AU - Karchin, Rachel

AU - Hruban, Ralph H.

AU - Vogelstein, Bert

AU - Lennon, Anne Marie

N1 - Funding Information: Funding This work supported by The Lustgarten Foundation for Pancreatic Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, The Virginia and D. K. Ludwig Fund for Cancer Research, Susan Wojcicki and Dennis Troper, The Michael Rolfe Foundation, National Institutes of Health grant P50 CA62924, Associazione Italiana Ricerca Cancro (12182) Italian Ministry of Research (FIRB RBAP10AHJB) and Health (FIMP J33G13000210001). Publisher Copyright: © 2015 AGA Institute.

PY - 2015/11

Y1 - 2015/11

N2 - Background and Aims The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. Methods We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. Results We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. Conclusions We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

AB - Background and Aims The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. Methods We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. Results We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. Conclusions We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

KW - Diagnosis

KW - IPMN

KW - Molecular

KW - Pancreatic Cyst

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JO - Gastroenterology

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A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

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