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Pancreatic Neoplasms: HELP
Articles by Nicholas J. Roberts
Based on 18 articles published since 2009
(Why 18 articles?)
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Between 2009 and 2019, Nicholas Roberts wrote the following 18 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Inherited pancreatic cancer. 2017

Chen, Fei / Roberts, Nicholas J / Klein, Alison P. ·Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. · Department of Pathology, Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institution, Baltimore, MD, USA. · Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Pathology, Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institution, Baltimore, MD, USA. aklein1@jhmi.edu. ·Chin Clin Oncol · Pubmed #29307198.

ABSTRACT: Pancreatic cancers arise through a series of genetic events both inherited and acquired. Inherited genetic changes, both high penetrance and low penetrance, are an important component of pancreatic cancer risk, and may be used to characterize populations who will benefit from early detection. Furthermore, pancreatic cancer patients with inherited mutations may be particularly sensitive to certain targeted agents, providing an opportunity to personalized treatment. Family history of pancreatic cancer is one of the strongest risk factors for the disease, and is associated with an increased risk of caners at other sites, including but not limited to breast, ovarian and colorectal cancer. The goal of this chapter is to discuss the importance of family history of pancreatic cancer, and the known genes that account for a portion of the familial clustering of pancreatic cancer.

2 Review Genome-wide sequencing to identify the cause of hereditary cancer syndromes: with examples from familial pancreatic cancer. 2013

Roberts, Nicholas J / Klein, Alison P. ·Ludwig Center for Cancer Genetics and Therapeutics, The Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. ·Cancer Lett · Pubmed #23196058.

ABSTRACT: Advances in our understanding of the human genome and next-generation technologies have facilitated the use of genome-wide sequencing to decipher the genetic basis of Mendelian disease and hereditary cancer syndromes. However, the application of genome-wide sequencing in hereditary cancer syndromes has had mixed success, in part, due to complex nature of the underlying genetic architecture. In this review we discuss the use of genome-wide sequencing in both Mendelian diseases and hereditary cancer syndromes, highlighting the potential and challenges of this approach using familial pancreatic cancer as an example.

3 Clinical Trial Mutations in the pancreatic secretory enzymes 2018

Tamura, Koji / Yu, Jun / Hata, Tatsuo / Suenaga, Masaya / Shindo, Koji / Abe, Toshiya / MacGregor-Das, Anne / Borges, Michael / Wolfgang, Christopher L / Weiss, Matthew J / He, Jin / Canto, Marcia Irene / Petersen, Gloria M / Gallinger, Steven / Syngal, Sapna / Brand, Randall E / Rustgi, Anil / Olson, Sara H / Stoffel, Elena / Cote, Michele L / Zogopoulos, George / Potash, James B / Goes, Fernando S / McCombie, Richard W / Zandi, Peter P / Pirooznia, Mehdi / Kramer, Melissa / Parla, Jennifer / Eshleman, James R / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison Patricia / Goggins, Michael. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Health Sciences Research, Mayo Clinic, Rochester, MN 55905. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. · Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201. · The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9. · The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. · InGenious Targeting Laboratory, Ronkonkoma, NY 11779. · Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #29669919.

ABSTRACT: To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of

4 Article Histomorphology of pancreatic cancer in patients with inherited ATM serine/threonine kinase pathogenic variants. 2019

Hutchings, Danielle / Jiang, Zhengdong / Skaro, Michael / Weiss, Matthew J / Wolfgang, Christopher L / Makary, Martin A / He, Jin / Cameron, John L / Zheng, Lei / Klimstra, David S / Brand, Randall E / Singhi, Aatur D / Goggins, Michael / Klein, Alison P / Roberts, Nicholas J / Hruban, Ralph H. ·Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. · Department of Surgery, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Medicine, University of Pittsburgh Medical Center Health System, Pittsburgh, PA, USA. · Department of Pathology, University of Pittsburgh Medical Center Health System, Pittsburgh, PA, USA. · Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. nrobert8@jhmi.edu. · Department of Oncology, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. nrobert8@jhmi.edu. · Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. rhruban@jhmi.edu. · Department of Oncology, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA. rhruban@jhmi.edu. ·Mod Pathol · Pubmed #31285527.

ABSTRACT: Germline pathogenic variants in the ATM serine/threonine kinase (ATM) gene are associated with an increased risk of pancreatic ductal adenocarcinoma. It is important to identify germline ATM pathogenic variants in pancreatic cancer patients because these alterations are potentially targetable with chemotherapeutic drugs and/or radiation and have implications for other family members. As germline pathogenic variants in other genes have been associated with distinct histologic subtypes of pancreatic cancer, we studied the histomorphology of pancreatic cancer in 23 patients with germline ATM pathogenic variants. The histologic subtype was ductal adenocarcinoma in 19/23 (83%) of the patients, adenosquamous carcinoma in 1/23 (4%), and colloid (mucinous non-cystic) carcinoma in 3/23 (13%). The percentage of colloid (mucinous non-cystic) carcinomas is higher than we have previously observed in patients with familial and sporadic pancreatic cancer (1 and 2% in prior reports, p < 0.01 and p < 0.01, respectively). Three carcinomas (2 colloid carcinomas, 1 ductal adenocarcinoma) arose in association with intraductal papillary mucinous neoplasms. Among the resected pancreata, non-invasive precursor lesions, including pancreatic intraepithelial neoplasia and incipient intraductal papillary mucinous neoplasms, were identified in 83%. We conclude that pancreatic cancers in patients with germline ATM pathogenic variants are more frequently of colloid (mucinous non-cystic) morphology but are overall morphologically diverse supporting the utility of universal germline genetic testing for patients with pancreatic cancer.

5 Article Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. 2019

Fischer, Catherine G / Beleva Guthrie, Violeta / Braxton, Alicia M / Zheng, Lily / Wang, Pei / Song, Qianqian / Griffin, James F / Chianchiano, Peter E / Hosoda, Waki / Niknafs, Noushin / Springer, Simeon / Dal Molin, Marco / Masica, David / Scharpf, Robert B / Thompson, Elizabeth D / He, Jin / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Lennon, Anne Marie / Jiao, Yuchen / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: karchin@jhu.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. ·Gastroenterology · Pubmed #31175866.

ABSTRACT: BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

6 Article Prevalence of Germline Mutations Associated With Cancer Risk in Patients With Intraductal Papillary Mucinous Neoplasms. 2019

Skaro, Michael / Nanda, Neha / Gauthier, Christian / Felsenstein, Matthäus / Jiang, Zhengdong / Qiu, Miaozhen / Shindo, Koji / Yu, Jun / Hutchings, Danielle / Javed, Ammar A / Beckman, Ross / He, Jin / Wolfgang, Christopher L / Thompson, Elizabeth / Hruban, Ralph H / Klein, Alison P / Goggins, Michael / Wood, Laura D / Roberts, Nicholas J. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: nrobert8@jhmi.edu. ·Gastroenterology · Pubmed #30716324.

ABSTRACT: BACKGROUND & AIMS: Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS: We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS: We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS: In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer.

7 Article Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions. 2019

Kuboki, Yuko / Fischer, Catherine G / Beleva Guthrie, Violeta / Huang, Wenjie / Yu, Jun / Chianchiano, Peter / Hosoda, Waki / Zhang, Hao / Zheng, Lily / Shao, Xiaoshan / Thompson, Elizabeth D / Waters, Kevin / Poling, Justin / He, Jin / Weiss, Matthew J / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #30430578.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next-generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

8 Article Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. 2018

Noë, Michaël / Pea, Antonio / Luchini, Claudio / Felsenstein, Matthäus / Barbi, Stefano / Bhaijee, Feriyl / Yonescu, Raluca / Ning, Yi / Adsay, N Volkan / Zamboni, Giuseppe / Lawlor, Rita T / Scarpa, Aldo / Offerhaus, G Johan A / Brosens, Lodewijk A A / Hruban, Ralph H / Roberts, Nicholas J / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · Medical College of Wisconsin, Milwaukee, WI, USA. · Sacro Cuore Don Calabria Hospital, 37024, Negrar, Verona, Italy. · ARC-Net Research Center, University of Verona, Verona, Italy. · Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ldwood@jhmi.edu. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ldwood@jhmi.edu. ·Mod Pathol · Pubmed #29849115.

ABSTRACT: Neurofibromatosis type 1 (NF1) is a hereditary cancer predisposition syndrome characterized by frequent cutaneous and nervous system abnormalities. Patients with NF1 also have an increased prevalence of multiple gastrointestinal and peripancreatic neoplasms-neuroendocrine tumors of the ampulla that express somatostatin are particularly characteristic of NF1. In this study, we characterize the genetic alterations of a clinically well-characterized cohort of six NF1-associated duodenal neuroendocrine tumors using whole-exome sequencing. We identified inactivating somatic mutations in the NF1 gene in three of six tumors; the only other gene altered in more than one tumor was IFNB1. Copy number analysis revealed deletion/loss of heterozygosity of chromosome 22 in three of six patients. Analysis of germline variants revealed germline deleterious NF1 variants in four of six patients, as well as deleterious variants in other tumor suppressor genes in two of four patients with deleterious NF1 variants. Taken together, these data confirm the importance of somatic inactivation of the wild-type NF1 allele in the formation of NF1-associated duodenal neuroendocrine tumors and suggest that loss of chromosome 22 is important in at least a subset of cases. However, we did not identify any genes altered in the majority of NF1-associated duodenal neuroendocrine tumors that uniquely characterize the genomic landscape of this tumor. Still, the genetic alterations in these tumors are distinct from sporadic neuroendocrine tumors occurring at these sites, highlighting that unique genetic alterations drive syndromic tumors.

9 Article Immunolabeling of Cleared Human Pancreata Provides Insights into Three-Dimensional Pancreatic Anatomy and Pathology. 2018

Noë, Michaël / Rezaee, Neda / Asrani, Kaushal / Skaro, Michael / Groot, Vincent P / Wu, Pei-Hsun / Olson, Matthew T / Hong, Seung-Mo / Kim, Sung Joo / Weiss, Matthew J / Wolfgang, Christopher L / Makary, Martin A / He, Jin / Cameron, John L / Wirtz, Denis / Roberts, Nicholas J / Offerhaus, G Johan A / Brosens, Lodewijk A A / Wood, Laura D / Hruban, Ralph H. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: rhruban@jhmi.edu. ·Am J Pathol · Pubmed #29684363.

ABSTRACT: Visualizing pathologies in three dimensions can provide unique insights into the biology of human diseases. A rapid and easy-to-implement dibenzyl ether-based technique was used to clear thick sections of surgically resected human pancreatic parenchyma. Protocols were applicable to both fresh and formalin-fixed, paraffin-embedded tissue. The penetration of antibodies into dense pancreatic parenchyma was optimized using both gradually increasing antibody concentrations and centrifugal flow. Immunolabeling with antibodies against cytokeratin 19 was visualized using both light sheet and confocal laser scanning microscopy. The technique was applied successfully to 26 sections of pancreas, providing three-dimensional (3D) images of normal pancreatic tissue, pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, and infiltrating pancreatic ductal adenocarcinomas. 3D visualization highlighted processes that are hard to conceptualize in two dimensions, such as invasive carcinoma growing into what appeared to be pre-existing pancreatic ducts and within venules, and the tracking of long cords of neoplastic cells parallel to blood vessels. Expanding this technique to formalin-fixed, paraffin-embedded tissue opens pathology archives to 3D visualization of unique biosamples and rare diseases. The application of immunolabeling and clearing to human pancreatic parenchyma provides detailed visualization of normal pancreatic anatomy, and can be used to characterize the 3D architecture of diseases including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and pancreatic ductal adenocarcinomas.

10 Article IPMNs with co-occurring invasive cancers: neighbours but not always relatives. 2018

Felsenstein, Matthäus / Noë, Michaël / Masica, David L / Hosoda, Waki / Chianchiano, Peter / Fischer, Catherine G / Lionheart, Gemma / Brosens, Lodewijk A A / Pea, Antonio / Yu, Jun / Gemenetzis, Georgios / Groot, Vincent P / Makary, Martin A / He, Jin / Weiss, Matthew J / Cameron, John L / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Goggins, Michael G / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gut · Pubmed #29500184.

ABSTRACT: OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN: We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

11 Article Exome-Wide Association Study of Pancreatic Cancer Risk. 2018

Grant, Robert C / Denroche, Robert E / Borgida, Ayelet / Virtanen, Carl / Cook, Natalie / Smith, Alyssa L / Connor, Ashton A / Wilson, Julie M / Peterson, Gloria / Roberts, Nicholas J / Klein, Alison P / Grimmond, Sean M / Biankin, Andrew / Cleary, Sean / Moore, Malcolm / Lemire, Mathieu / Zogopoulos, George / Stein, Lincoln / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Canada. · Ontario Pancreas Cancer Study, Toronto, Canada. · Princess Margaret Genomics Centre, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia. · Wohl Cancer Research Centre, Institute of, Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. Electronic address: steven.gallinger@uhn.ca. ·Gastroenterology · Pubmed #29074453.

ABSTRACT: We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10

12 Article Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. 2017

Shindo, Koji / Yu, Jun / Suenaga, Masaya / Fesharakizadeh, Shahriar / Cho, Christy / Macgregor-Das, Anne / Siddiqui, Abdulrehman / Witmer, P Dane / Tamura, Koji / Song, Tae Jun / Navarro Almario, Jose Alejandro / Brant, Aaron / Borges, Michael / Ford, Madeline / Barkley, Thomas / He, Jin / Weiss, Matthew J / Wolfgang, Christopher L / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison P / Goggins, Michael. ·All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD. ·J Clin Oncol · Pubmed #28767289.

ABSTRACT: Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

13 Article Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. 2016

Robles, Ana I / Traverso, Giovanni / Zhang, Ming / Roberts, Nicholas J / Khan, Mohammed A / Joseph, Christine / Lauwers, Gregory Y / Selaru, Florin M / Popoli, Maria / Pittman, Meredith E / Ke, Xiquan / Hruban, Ralph H / Meltzer, Stephen J / Kinzler, Kenneth W / Vogelstein, Bert / Harris, Curtis C / Papadopoulos, Nickolas. ·Laboratory of Human Carcinogenesis, National Cancer Institute's Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. · Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Chemical Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. · Ludwig Center at Johns Hopkins, Baltimore, Maryland. · Ludwig Center at Johns Hopkins, Baltimore, Maryland; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Ludwig Center at Johns Hopkins, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Ludwig Center at Johns Hopkins, Baltimore, Maryland; Howard Hughes Medical Institute, Chevy Chase, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: bertvog@gmail.com. · Laboratory of Human Carcinogenesis, National Cancer Institute's Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. Electronic address: harrisc@mail.nih.gov. · Ludwig Center at Johns Hopkins, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: npapado1@jhmi.edu. ·Gastroenterology · Pubmed #26764183.

ABSTRACT: BACKGROUND & AIMS: A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS: We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS: Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS: Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer.

14 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.

15 Article A histomorphologic comparison of familial and sporadic pancreatic cancers. 2015

Singhi, Aatur D / Ishida, Hiroyuki / Ali, Syed Z / Goggins, Michael / Canto, Marcia / Wolfgang, Christopher / Meriden, Zina / Roberts, Nicholas / Klein, Alison P / Hruban, Ralph H. ·The Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University School of Medicine. · Department of Medicine, Johns Hopkins University School of Medicine. · Department of Oncology, Johns Hopkins University School of Medicine. · Department of Surgery, Johns Hopkins University School of Medicine. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. ·Pancreatology · Pubmed #25959245.

ABSTRACT: BACKGROUND: It is estimated that approximately 10% of pancreatic cancers have a familial component. Many inheritable genetic syndromes are associated with increased risk of pancreatic cancer, such as Peutz-Jeghers syndrome, hereditary breast-ovarian cancer and familial atypical multiple mole melanoma, but these conditions account for only a minority of familial pancreatic cancers. Previous studies have identified an increased prevalence of noninvasive precursor lesions, including pancreatic intraepithelial neoplasia, in the pancreata of patients with a strong family history of pancreatic cancer. A detailed investigation of the histopathology of invasive familial pancreatic cancer could provide insights into the mechanisms responsible for familial pancreatic cancer, as well as aid early detection and treatment strategies. METHODS: We have conducted a blinded review of the pathology of 519 familial and 651 sporadic pancreatic cancers within the National Familial Pancreas Tumor Registry. Patients with familial pancreatic cancer were defined as individuals from families in which at least a pair of first-degree relatives have been diagnosed with pancreatic cancer. RESULTS: Overall, there were no statistically significant differences in histologic subtypes between familial and sporadic pancreatic cancers (p > 0.05). In addition, among surgical resection specimens within the study cohort, no statistically significant differences in mean tumor size, location, perineural invasion, angiolymphatic invasion, lymph node metastasis and pathologic stage were identified (p > 0.05). CONCLUSIONS: Similar to sporadic pancreatic cancer, familial pancreatic cancer is morphologically and prognostically a heterogeneous disease.

16 Article BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. 2015

Zhen, David B / Rabe, Kari G / Gallinger, Steven / Syngal, Sapna / Schwartz, Ann G / Goggins, Michael G / Hruban, Ralph H / Cote, Michele L / McWilliams, Robert R / Roberts, Nicholas J / Cannon-Albright, Lisa A / Li, Donghui / Moyes, Kelsey / Wenstrup, Richard J / Hartman, Anne-Renee / Seminara, Daniela / Klein, Alison P / Petersen, Gloria M. ·Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Divison of General Surgery, University of Toronto, Toronto, Ontario, Canada. · Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Oncology, Karmanos Cancer Institute and Wayne State University, Detroit, Michigan, USA. · The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA. · 1] The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA [2] Ludwig Center for Cancer Genetics, Johns Hopkins University, Baltimore, Maryland, USA. · Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Myriad Genetic Laboratories, Inc., Salt Lake City, Utah, USA. · Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA. ·Genet Med · Pubmed #25356972.

ABSTRACT: PURPOSE: Familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing. METHODS: Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. We compared prevalence of deleterious mutations between familial pancreatic cancer probands and nonfamilial pancreatic cancer probands (kindreds containing at least two affected biological relatives, but not first-degree relatives). We also examined the impact of family history on breast and ovarian cancers and melanoma. RESULTS: Prevalence of deleterious mutations (excluding variants of unknown significance) among familial pancreatic cancer probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. Familial pancreatic cancer probands carry more mutations in the four genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%) (odds ratio: 2.40; 95% confidence interval: 1.06-5.44; P = 0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending on family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in familial pancreatic cancer. CONCLUSION: Genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for familial pancreatic cancer.

17 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.

18 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.