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Pancreatic Neoplasms: HELP
Articles by Nickolas Papadopoulos
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, N. Papadopoulos wrote the following 16 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? 2014

Lennon, Anne Marie / Wolfgang, Christopher L / Canto, Marcia Irene / Klein, Alison P / Herman, Joseph M / Goggins, Michael / Fishman, Elliot K / Kamel, Ihab / Weiss, Matthew J / Diaz, Luis A / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Hruban, Ralph H. ·Authors' Affiliations: Departments of Medicine; Surgery; · Surgery; Pathology; Oncology; · Authors' Affiliations: Departments of Medicine; · Pathology; Oncology; Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland. · Oncology; Radiation Oncology; and. · Authors' Affiliations: Departments of Medicine; Pathology; Oncology; · Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine; and. · Surgery; · Oncology; · Pathology; Oncology; · Pathology; Oncology; rhruban@jhmi.edu. ·Cancer Res · Pubmed #24924775.

ABSTRACT: Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts.

2 Article Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. 2019

Lee, B / Lipton, L / Cohen, J / Tie, J / Javed, A A / Li, L / Goldstein, D / Burge, M / Cooray, P / Nagrial, A / Tebbutt, N C / Thomson, B / Nikfarjam, M / Harris, M / Haydon, A / Lawrence, B / Tai, D W M / Simons, K / Lennon, A M / Wolfgang, C L / Tomasetti, C / Papadopoulos, N / Kinzler, K W / Vogelstein, B / Gibbs, P. ·Division of Systems Biology and Personalised Medicine, Walter & Eliza Hall Institute (WEHI), Melbourne. · Department of Medical Oncology, Royal Melbourne Hospital, Melbourne. · Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne. · Department of Medical Oncology, Western Health, Melbourne. · Department of Medical Oncology, Cabrini Health, Malvern, Australia. · Ludwig Centre and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Centre, Baltimore. · Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA. · Department of Medical Oncology, Prince of Wales Hospital, Randwick. · Department of Medical Oncology, Royal Brisbane Hospital, Brisbane. · Department of Medical Oncology, Eastern Health, Melbourne. · Department of Medical Oncology, Crown Princess Mary Cancer Centre Westmead, Westmead. · Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Melbourne. · Department of Surgery, Royal Melbourne Hospital, Melbourne. · Department of Medical Oncology, Monash Medical Centre, Clayton. · Department of Medical Oncology, Alfred Hospital, Melbourne, Australia. · Department of Medical Oncology, Auckland City Hospital, Auckland, New Zealand. · Department of Medical Oncology, National Cancer Centre, Singapore. · Centre for Epidemiology & Biostatistics, University of Melbourne, Melbourne, Australia. ·Ann Oncol · Pubmed #31250894.

ABSTRACT: BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

3 Article Precancerous neoplastic cells can move through the pancreatic ductal system. 2018

Makohon-Moore, Alvin P / Matsukuma, Karen / Zhang, Ming / Reiter, Johannes G / Gerold, Jeffrey M / Jiao, Yuchen / Sikkema, Lisa / Attiyeh, Marc A / Yachida, Shinichi / Sandone, Corinne / Hruban, Ralph H / Klimstra, David S / Papadopoulos, Nickolas / Nowak, Martin A / Kinzler, Kenneth W / Vogelstein, Bert / Iacobuzio-Donahue, Christine A. ·The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, University of California, Davis, Sacramento, CA, USA. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Canary Center for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA. · Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA. · The Ludwig Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · VU University Amsterdam, Master's Oncology Program, VU University Medical Center, Amsterdam, The Netherlands. · Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan. · Department of Art as Applied to Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Mathematics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. · Howard Hughes Medical Institute, The Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA. · The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. iacobuzc@mskcc.org. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. iacobuzc@mskcc.org. ·Nature · Pubmed #30177826.

ABSTRACT: Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.

4 Article Selected reaction monitoring approach for validating peptide biomarkers. 2017

Wang, Qing / Zhang, Ming / Tomita, Tyler / Vogelstein, Joshua T / Zhou, Shibin / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert. ·Ludwig Center, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21287; qing@jhmi.edu bertvog@gmail.com. · Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21287. · Ludwig Center, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21287. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218. ·Proc Natl Acad Sci U S A · Pubmed #29203663.

ABSTRACT: We here describe a selected reaction monitoring (SRM)-based approach for the discovery and validation of peptide biomarkers for cancer. The first stage of this approach is the direct identification of candidate peptides through comparison of proteolytic peptides derived from the plasma of cancer patients or healthy individuals. Several hundred candidate peptides were identified through this method, providing challenges for choosing and validating the small number of peptides that might prove diagnostically useful. To accomplish this validation, we used 2D chromatography coupled with SRM of candidate peptides. We applied this approach, called sequential analysis of fractionated eluates by SRM (SAFE-SRM), to plasma from cancer patients and discovered two peptides encoded by the peptidyl-prolyl

5 Article Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. 2017

Cohen, Joshua D / Javed, Ammar A / Thoburn, Christopher / Wong, Fay / Tie, Jeanne / Gibbs, Peter / Schmidt, C Max / Yip-Schneider, Michele T / Allen, Peter J / Schattner, Mark / Brand, Randall E / Singhi, Aatur D / Petersen, Gloria M / Hong, Seung-Mo / Kim, Song Cheol / Falconi, Massimo / Doglioni, Claudio / Weiss, Matthew J / Ahuja, Nita / He, Jin / Makary, Martin A / Maitra, Anirban / Hanash, Samir M / Dal Molin, Marco / Wang, Yuxuan / Li, Lu / Ptak, Janine / Dobbyn, Lisa / Schaefer, Joy / Silliman, Natalie / Popoli, Maria / Goggins, Michael G / Hruban, Ralph H / Wolfgang, Christopher L / Klein, Alison P / Tomasetti, Cristian / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Lennon, Anne Marie. ·The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Howard Hughes Medical Institute, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Sidney Kimmel Cancer Center at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Division of Systems Biology and Personalized Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3021, Australia. · Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia. · Department of Medical Oncology, Western Health, Melbourne, VIC 3021, Australia. · Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202. · Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260. · Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260. · Department of Epidemiology, Mayo Clinic, Rochester, MN 55902. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. · Department of Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. · Division of Pancreatic Surgery, Department of Surgery, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy. · Department of Pathology, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy. · The Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205. · Division of Biostatistics and Bioinformatics, Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #28874546.

ABSTRACT: The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for

6 Article Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. 2017

Makohon-Moore, Alvin P / Zhang, Ming / Reiter, Johannes G / Bozic, Ivana / Allen, Benjamin / Kundu, Deepanjan / Chatterjee, Krishnendu / Wong, Fay / Jiao, Yuchen / Kohutek, Zachary A / Hong, Jungeui / Attiyeh, Marc / Javier, Breanna / Wood, Laura D / Hruban, Ralph H / Nowak, Martin A / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Iacobuzio-Donahue, Christine A. ·Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria. · Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA. · Department of Mathematics, Harvard University, Cambridge, Massachusetts, USA. · Center for Mathematical Sciences and Applications, Harvard University, Cambridge, Massachusetts, USA. · Department of Mathematics, Emmanuel College, Boston, Massachusetts, USA. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA. · Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ·Nat Genet · Pubmed #28092682.

ABSTRACT: The extent of heterogeneity among driver gene mutations present in naturally occurring metastases-that is, treatment-naive metastatic disease-is largely unknown. To address this issue, we carried out 60× whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted functional consequences, accounted for all intratumoral heterogeneity. Even with respect to these passenger mutations, our analysis suggests that the genetic similarity among the founding cells of metastases was higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of known driver gene mutations among metastases in the same patient has critical and encouraging implications for the success of future targeted therapies in advanced-stage disease.

7 Article A novel approach for selecting combination clinical markers of pathology applied to a large retrospective cohort of surgically resected pancreatic cysts. 2017

Masica, David L / Dal Molin, Marco / Wolfgang, Christopher L / Tomita, Tyler / Ostovaneh, Mohammad R / Blackford, Amanda / Moran, Robert A / Law, Joanna K / Barkley, Thomas / Goggins, Michael / Irene Canto, Marcia / Pittman, Meredith / Eshleman, James R / Ali, Syed Z / Fishman, Elliot K / Kamel, Ihab R / Raman, Siva P / Zaheer, Atif / Ahuja, Nita / Makary, Martin A / Weiss, Matthew J / Hirose, Kenzo / Cameron, John L / Rezaee, Neda / He, Jin / Joon Ahn, Young / Wu, Wenchuan / Wang, Yuxuan / Springer, Simeon / Diaz, Luis L / Papadopoulos, Nickolas / Hruban, Ralph H / Kinzler, Kenneth W / Vogelstein, Bert / Karchin, Rachel / Lennon, Anne Marie. ·*Drs Masica and Dal Molin contributed equally as first authors. · Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland. · Departments of the Sol Goldman Pancreatic Cancer Research Center. · Departments of Pathology. · Departments of Surgery. · Departments of Oncology. · Departments of Medicine. · Departments of Biostatistics and Bioinformatics. · Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland. · Departments of Radiology. · †Drs Lennon and Karchin contributed equally as senior authors amlennon@jhmi.edu karchin@jhu.edu. ·J Am Med Inform Assoc · Pubmed #27330075.

ABSTRACT: OBJECTIVE: Our objective was to develop an approach for selecting combinatorial markers of pathology from diverse clinical data types. We demonstrate this approach on the problem of pancreatic cyst classification. MATERIALS AND METHODS: We analyzed 1026 patients with surgically resected pancreatic cysts, comprising 584 intraductal papillary mucinous neoplasms, 332 serous cystadenomas, 78 mucinous cystic neoplasms, and 42 solid-pseudopapillary neoplasms. To derive optimal markers for cyst classification from the preoperative clinical and radiological data, we developed a statistical approach for combining any number of categorical, dichotomous, or continuous-valued clinical parameters into individual predictors of pathology. The approach is unbiased and statistically rigorous. Millions of feature combinations were tested using 10-fold cross-validation, and the most informative features were validated in an independent cohort of 130 patients with surgically resected pancreatic cysts. RESULTS: We identified combinatorial clinical markers that classified serous cystadenomas with 95% sensitivity and 83% specificity; solid-pseudopapillary neoplasms with 89% sensitivity and 86% specificity; mucinous cystic neoplasms with 91% sensitivity and 83% specificity; and intraductal papillary mucinous neoplasms with 94% sensitivity and 90% specificity. No individual features were as accurate as the combination markers. We further validated these combinatorial markers on an independent cohort of 130 pancreatic cysts, and achieved high and well-balanced accuracies. Overall sensitivity and specificity for identifying patients requiring surgical resection was 84% and 81%, respectively. CONCLUSIONS: Our approach identified combinatorial markers for pancreatic cyst classification that had improved performance relative to the individual features they comprise. In principle, this approach can be applied to any clinical dataset comprising dichotomous, categorical, and continuous-valued parameters.

8 Article Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. 2016

Roberts, Nicholas J / Norris, Alexis L / Petersen, Gloria M / Bondy, Melissa L / Brand, Randall / Gallinger, Steven / Kurtz, Robert C / Olson, Sara H / Rustgi, Anil K / Schwartz, Ann G / Stoffel, Elena / Syngal, Sapna / Zogopoulos, George / Ali, Syed Z / Axilbund, Jennifer / Chaffee, Kari G / Chen, Yun-Ching / Cote, Michele L / Childs, Erica J / Douville, Christopher / Goes, Fernando S / Herman, Joseph M / Iacobuzio-Donahue, Christine / Kramer, Melissa / Makohon-Moore, Alvin / McCombie, Richard W / McMahon, K Wyatt / Niknafs, Noushin / Parla, Jennifer / Pirooznia, Mehdi / Potash, James B / Rhim, Andrew D / Smith, Alyssa L / Wang, Yuxuan / Wolfgang, Christopher L / Wood, Laura D / Zandi, Peter P / Goggins, Michael / Karchin, Rachel / Eshleman, James R / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Hruban, Ralph H / Klein, Alison P. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts. · The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland. · Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Memorial Sloan Kettering Cancer Center, New York, New York. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. inGenious Targeting Laboratory, Ronkonkoma, New York. · Department of Psychiatry, University of Iowa, Iowa City, Iowa. · Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Medicine, University of Michigan, Ann Arbor, Michigan. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. ·Cancer Discov · Pubmed #26658419.

ABSTRACT: SIGNIFICANCE: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.

9 Article Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis. 2015

Dal Molin, Marco / Zhang, Ming / de Wilde, Roeland F / Ottenhof, Niki A / Rezaee, Neda / Wolfgang, Christopher L / Blackford, Amanda / Vogelstein, Bert / Kinzler, Kenneth W / Papadopoulos, Nickolas / Hruban, Ralph H / Maitra, Anirban / Wood, Laura D. ·Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. ldwood@jhmi.edu. ·Clin Cancer Res · Pubmed #25623214.

ABSTRACT: PURPOSE: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTS). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival. EXPERIMENTAL DESIGN: We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs. RESULTS: KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival. CONCLUSIONS: Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC.

10 Article Intraductal papillary mucinous neoplasm in a neonate with congenital hyperinsulinism and a de novo germline SKIL gene mutation. 2015

Jiao, Yuchen / Lumpkins, Kimberly / Terhune, Julia / Hruban, Ralph H / Klein, Alison / Kinzler, Kenneth W / Papadopoulos, Nickolas / Vogelstein, Bert / Strauch, Eric. ·Departments of Oncology and Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Division of Pediatric Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: klumpkins@smail.umaryland.edu. · Division of Pediatric Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA. ·Pancreatology · Pubmed #25464936.

ABSTRACT: A 3 day old infant with persistent severe hypoglycemia was found to have a cystic pancreatic tumor. Cessation of glucose infusion led to severe hypoglycemia. Pancreaticoduodenectomy was performed and revealed an intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia. Sequencing of the IPMN revealed a KRAS gene mutation not present in surrounding normal tissues. Deep sequencing of the patient's blood for KRAS mutations showed no evidence of mosaicism. Whole exome sequencing of the blood of the patient and both parents revealed a de novo germline SKIL mutation in the child that was not present in either parent. This suggests a possible role for SKIL in the pathogenesis of pancreatic tumors.

11 Article Familial and sporadic pancreatic cancer share the same molecular pathogenesis. 2015

Norris, Alexis L / Roberts, Nicholas J / Jones, Siân / Wheelan, Sarah J / Papadopoulos, Nickolas / Vogelstein, Bert / Kinzler, Kenneth W / Hruban, Ralph H / Klein, Alison P / Eshleman, James R. ·Department of Pathology, The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins University School of Medicine, Room 344, Cancer Research Building-II, 1550 Orleans Street, Baltimore, MD, 21231, USA. ·Fam Cancer · Pubmed #25240578.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is nearly uniformly lethal, with a median overall survival in 2014 of only 6 months. The genetic progression of sporadic PDAC (SPC) is well established, with common somatic alterations in KRAS, p16/CDKN2A, TP53, and SMAD4/DPC4. Up to 10 % of all PDAC cases occur in families with two or more affected first-degree relatives (familial pancreatic cancer, FPC), but these cases do not appear to present at an obviously earlier age of onset. This is unusual because most familial cancer syndrome patients present at a substantially younger age than that of corresponding sporadic cases. Here we collated the reported age of onset for FPC and SPC from the literature. We then used an integrated approach including whole exomic sequencing, whole genome sequencing, RNA sequencing, and high density SNP microarrays to study a cohort of FPC cell lines and corresponding germline samples. We show that the four major SPC driver genes are also consistently altered in FPC and that each of the four detection strategies was able to detect the mutations in these genes, with one exception. We conclude that FPC undergoes a similar somatic molecular pathogenesis as SPC, and that the same gene targets can be used for early detection and minimal residual disease testing in FPC patients.

12 Article Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. 2014

Jiao, Yuchen / Yonescu, Raluca / Offerhaus, G Johan A / Klimstra, David S / Maitra, Anirban / Eshleman, James R / Herman, James G / Poh, Weijie / Pelosof, Lorraine / Wolfgang, Christopher L / Vogelstein, Bert / Kinzler, Kenneth W / Hruban, Ralph H / Papadopoulos, Nickolas / Wood, Laura D. ·Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD, USA. ·J Pathol · Pubmed #24293293.

ABSTRACT: Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.

13 Article ATM mutations in patients with hereditary pancreatic cancer. 2012

Roberts, Nicholas J / Jiao, Yuchen / Yu, Jun / Kopelovich, Levy / Petersen, Gloria M / Bondy, Melissa L / Gallinger, Steven / Schwartz, Ann G / Syngal, Sapna / Cote, Michele L / Axilbund, Jennifer / Schulick, Richard / Ali, Syed Z / Eshleman, James R / Velculescu, Victor E / Goggins, Michael / Vogelstein, Bert / Papadopoulos, Nickolas / Hruban, Ralph H / Kinzler, Kenneth W / Klein, Alison P. ·Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA. ·Cancer Discov · Pubmed #22585167.

ABSTRACT: SIGNIFICANCE: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.

14 Article Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. 2011

Wu, Jian / Matthaei, Hanno / Maitra, Anirban / Dal Molin, Marco / Wood, Laura D / Eshleman, James R / Goggins, Michael / Canto, Marcia I / Schulick, Richard D / Edil, Barish H / Wolfgang, Christopher L / Klein, Alison P / Diaz, Luis A / Allen, Peter J / Schmidt, C Max / Kinzler, Kenneth W / Papadopoulos, Nickolas / Hruban, Ralph H / Vogelstein, Bert. ·Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. ·Sci Transl Med · Pubmed #21775669.

ABSTRACT: More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

15 Article Altered telomeres in tumors with ATRX and DAXX mutations. 2011

Heaphy, Christopher M / de Wilde, Roeland F / Jiao, Yuchen / Klein, Alison P / Edil, Barish H / Shi, Chanjuan / Bettegowda, Chetan / Rodriguez, Fausto J / Eberhart, Charles G / Hebbar, Sachidanand / Offerhaus, G Johan / McLendon, Roger / Rasheed, B Ahmed / He, Yiping / Yan, Hai / Bigner, Darell D / Oba-Shinjo, Sueli Mieko / Marie, Suely Kazue Nagahashi / Riggins, Gregory J / Kinzler, Kenneth W / Vogelstein, Bert / Hruban, Ralph H / Maitra, Anirban / Papadopoulos, Nickolas / Meeker, Alan K. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. ·Science · Pubmed #21719641.

ABSTRACT: The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.

16 Article DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. 2011

Jiao, Yuchen / Shi, Chanjuan / Edil, Barish H / de Wilde, Roeland F / Klimstra, David S / Maitra, Anirban / Schulick, Richard D / Tang, Laura H / Wolfgang, Christopher L / Choti, Michael A / Velculescu, Victor E / Diaz, Luis A / Vogelstein, Bert / Kinzler, Kenneth W / Hruban, Ralph H / Papadopoulos, Nickolas. ·Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. ·Science · Pubmed #21252315.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex, and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX (α thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.