Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

Abstract

PURPOSE To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium

“…These variants also confer risk for other cancers 40. Therefore, germline testing should be considered for individuals eligible for pancreatic cancer surveillance 41 42. Recent National Comprehensive Cancer Network (NCCN) guidelines recommend offering gene testing for patients with newly diagnosed pancreatic ductal adenocarcinoma; this recommendation did not reach consensus among CAPS experts (online supplementary table S2).…”

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020

“…[56][57][58][59][60] Harboring a pathogenic or likely pathogenic variant has been found to be associated with a greater incidence of pancreatic cancer than family history alone (without the presence of an associated germline variant). 61 Germline mutations commonly found in pancreatic adenocarcinoma include BRCA1, BRCA2, CDKN2A, mismatch repair genes associated with Lynch syndrome (MSH2, MLH1, MSH6, PMS2, EPCAM), ATM, PALB2, STK11, and TP53. 57,58,[61][62][63][64][65][66][67][68][69][70][71] BRCA2 and CDKN2A are generally the most prevalent, with rates in moderate-to high-risk families ranging from 2% to 6% for BRCA2 and 1.5% to 2.5% for CDKN2A.…”

“…61 Germline mutations commonly found in pancreatic adenocarcinoma include BRCA1, BRCA2, CDKN2A, mismatch repair genes associated with Lynch syndrome (MSH2, MLH1, MSH6, PMS2, EPCAM), ATM, PALB2, STK11, and TP53. 57,58,[61][62][63][64][65][66][67][68][69][70][71] BRCA2 and CDKN2A are generally the most prevalent, with rates in moderate-to high-risk families ranging from 2% to 6% for BRCA2 and 1.5% to 2.5% for CDKN2A. 58,59,72,73 In addition, hereditary pancreatitis, which is associated with a significantly increased risk for pancreatic cancer, is associated with the genes PRSS1 and SPINK1.…”

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

“…In addition to tumour biopsies, NGS has been performed using multiple types of specimens, such as pancreatic cyst fluid [ 5 ], secretin-stimulated juice [ 6 ], and cell-free DNA collected from the blood [ 7 ]. The use of more easily acquired specimens not only facilitates PDAC screening [ 8 ] but also obviates complications and costs.…”