Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer death in the USA and one of the deadliest cancers. Since most patients with pancreatic cancer present with advanced disease, in order to detect curable early-stage lesions, one needs to screen individuals. In our Cancer of the Pancreas Screening (CAPS) clinical trials we have screened ~500 individuals at increased risk of developing pancreatic cancer based on family history or gene mutation status. We find ~5-10% have lesions requiring resection (cancers, cysts-intraductal papillary mucinous neoplasms (IPMNs)), ~10-30% have cysts that require surveillance. The prevalence of lesions increases with age, especially over age 60. In our early CAPS trials, we initiated screening at age 40, later at age 50 and we now suspect screening may be more effective when initiated later (age 55). Although we can identify cysts, we cannot reliably identify very early invasive cancer or microscopic pancreatic intraepithelial neoplasias (PanINs) which are the commonest precursor to pancreatic cancer. Accurate markers are needed to identify these lesions, markers that can be reliably detected in pancreatic fluids and can be used for pancreatic screening. Recently, we found ~99% of low-grade PanINs harbor mutations, mutations that can be detected in pancreatic duct lavages (""""""""pancreatic juice""""""""). We found TP53 mutations in pancreatic juice collected non-invasively during endoscopic ultrasound are detected in patients with pancreatic cancer and patients undergoing pancreatic screening with carcinoma in situ or invasive cancer, not in disease controls or those with low-grade dysplasia. Thus, juice analysis has the potential to provide accurate evidence of cancer or high-grade PanIN. To further evaluate the utility of pancreatic juice analysis we propose:
Aim #1 : To determine the diagnostic accuracy of mutations detected in pancreatic fluid as indicators of pancreatic neoplasia. We will use nextgen sequencing to search for mutations in patients with pancreatic cancer, chronic pancreatitis, or normal pancreata.
Aim #2 : To determine the contribution of PanIN mutations to pancreatic fluid mutations among patients undergoing pancreatic resection. We will identify signature mutations of patient's PanIN and search for these mutations in their pre-op pancreatic fluid.
Aim #3 : To compare the prevalence of mutations in cyst fluid vs. pancreatic fluid among a prospective cohort of patients undergoing pancreatic cyst evaluation.
Aim #4 : To determine the prevalence of pancreatic lesions and pancreatic fluid mutations among high-risk individuals undergoing pancreatic screening. We will enroll a new older-age high-risk cohort (age >55) and continue surveillance of patients enrolled in prior CAPS trials.

Public Health Relevance

Pancreatic cancer is the deadliest of the common cancers and the 4th commonest cause of cancer death. Pancreatic screening of asymptomatic individuals at increased risk of developing pancreatic cancer to detect precancerous lesions is the probably best way to reduce the mortality from this disease. We propose to screen the pancreas of high risk individuals using pancreatic imaging and measurement of pancreatic fluid mutations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA176828-01A1
Application #
8589991
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Wagner, Paul D
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$416,716
Indirect Cost
$159,484
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Tamura, Koji; Yu, Jun; Hata, Tatsuo et al. (2018) Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc Natl Acad Sci U S A 115:4767-4772
Raman, Aadhithya; Lennon, Anne Marie (2018) Cyst Fluid Biomarkers - Diagnosis and Prediction of Malignancy for Cystic Lesions of the Pancreas. Visc Med 34:178-181
Poruk, Katherine E; Griffin, James; Makary, Martin A et al. (2018) Blood Type as a Predictor of High-Grade Dysplasia and Associated Malignancy in Patients with Intraductal Papillary Mucinous Neoplasms. J Gastrointest Surg :
Canto, Marcia Irene; Almario, Jose Alejandro; Schulick, Richard D et al. (2018) Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance. Gastroenterology 155:740-751.e2
Robinson, Cemre; Estrada, Andrea; Zaheer, Atif et al. (2018) Clinical and Radiographic Gastrointestinal Abnormalities in McCune-Albright Syndrome. J Clin Endocrinol Metab 103:4293-4303
Hata, Tatsuo; Suenaga, Masaya; Marchionni, Luigi et al. (2018) Genome-Wide Somatic Copy Number Alterations and Mutations in High-Grade Pancreatic Intraepithelial Neoplasia. Am J Pathol 188:1723-1733
Ayars, Michael; O'Sullivan, Eileen; Macgregor-Das, Anne et al. (2017) IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth. Oncotarget 8:83370-83383
Suenaga, Masaya; Sadakari, Yoshihiko; Almario, Jose Alejandro et al. (2017) Using an endoscopic distal cap to collect pancreatic fluid from the ampulla (with video). Gastrointest Endosc 86:1152-1156.e2
Pea, Antonio; Yu, Jun; Rezaee, Neda et al. (2017) Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas. Ann Surg 266:133-141
Shindo, Koji; Yu, Jun; Suenaga, Masaya et al. (2017) Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol 35:3382-3390

Showing the most recent 10 out of 25 publications