TY - JOUR
T1 - Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts
AU - Paniccia, Alessandro
AU - Polanco, Patricio M.
AU - Boone, Brian A.
AU - Wald, Abigail I.
AU - McGrath, Kevin
AU - Brand, Randall E.
AU - Khalid, Asif
AU - Kubiliun, Nisa
AU - O'Broin-Lennon, Anne Marie
AU - Park, Walter G.
AU - Klapman, Jason
AU - Tharian, Benjamin
AU - Inamdar, Sumant
AU - Fasanella, Kenneth
AU - Nasr, John
AU - Chennat, Jennifer
AU - Das, Rohit
AU - DeWitt, John
AU - Easler, Jeffrey J.
AU - Bick, Benjamin
AU - Singh, Harkirat
AU - Fairley, Kimberly J.
AU - Sarkaria, Savreet
AU - Sawas, Tarek
AU - Skef, Wasseem
AU - Slivka, Adam
AU - Tavakkoli, Anna
AU - Thakkar, Shyam
AU - Kim, Victoria
AU - Vanderveldt, Hendrikus Dutch
AU - Richardson, Allyson
AU - Wallace, Michael B.
AU - Brahmbhatt, Bhaumik
AU - Engels, Megan
AU - Gabbert, Charles
AU - Dugum, Mohannad
AU - El-Dika, Samer
AU - Bhat, Yasser
AU - Ramrakhiani, Sanjay
AU - Bakis, Gennadiy
AU - Rolshud, Daniil
AU - Millspaugh, Gordon
AU - Tielleman, Thomas
AU - Schmidt, Carl
AU - Mansour, John
AU - Marsh, Wallis
AU - Ongchin, Melanie
AU - Centeno, Barbara
AU - Monaco, Sara E.
AU - Ohori, N. Paul
AU - Lajara, Sigfred
AU - Thompson, Elizabeth D.
AU - Hruban, Ralph H.
AU - Bell, Phoenix D.
AU - Smith, Katelyn
AU - Permuth, Jennifer B.
AU - Vandenbussche, Christopher
AU - Ernst, Wayne
AU - Grupillo, Maria
AU - Kaya, Cihan
AU - Hogg, Melissa
AU - He, Jin
AU - Wolfgang, Christopher L.
AU - Lee, Kenneth K.
AU - Zeh, Herbert
AU - Zureikat, Amer
AU - Nikiforova, Marina N.
AU - Singhi, Aatur D.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - Background & Aims: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. Methods: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound–guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. Results: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. Conclusions: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.
AB - Background & Aims: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. Methods: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound–guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. Results: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. Conclusions: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.
KW - Diagnosis
KW - Early Detection
KW - Pancreas
KW - Pancreatic Cancer
KW - Pancreatic Neoplasm
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U2 - 10.1053/j.gastro.2022.09.028
DO - 10.1053/j.gastro.2022.09.028
M3 - Article
C2 - 36209796
AN - SCOPUS:85144588925
SN - 0016-5085
VL - 164
SP - 117-133.e7
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -