Patients with deleterious germline mutations: a heterogeneous population for pancreatic cancer screening?

Abstract

Background: Many germline mutations are associated with an increased risk of pancreatic adenocarcinoma (PDAC). Screening at our institution is currently offered for mutation carriers or patients with at least one first-degree relative or two family members with PDAC. High-risk screening protocol includes complete history and physical examination, tumor markers (CA19-9 and CEA), and crosssectional imaging (CT or MRI/MRCP with Gadolinium and Secretin enhancement), followed by semi-annual to annual clinic visits. Little data exists on the benefits of screening and surveillance for high-risk individuals with inherited genetic syndromes. Intraductal papillary mucinous neoplasm (IPMN) are well-established cystic precursors of PDAC. We hypothesized that patients with deleterious germline mutations in a pancreatic cancer susceptibility gene have a higher prevalence of IPMN. Methods: All consecutive patients undergoing going surveillance at our Pancreatic Cyst and Cancer Early Detection Center from 2013 to 2019 were included in the present study. We analyzed the prevalence and risk factors for IPMN in this high-risk population. Prevalence was compared to historical data from extensive literature review. Results: Of the 1166 patients in the surveillance program, 358 (31%) had a germline mutation and/or a strong family history of PDAC without a known mutation. Gender ratio was 3.5 in favor of women with a median age of 58 years, and a median follow-up of 2.7 years [range 1month-6years]. 201 patients (56%) were known to harbor a deleterious germline mutation, the most common being BRCA2 in 89 patients (25%). A total of 250 patients (70%) had a family history of pancreatic cancer. 132 patients had an IPMN (37%) and 8 had a PDAC (2%). The prevalence of IPMN was higher in the mutation carriers than in the general population (18% vs. 1%, p<0.0001). In multivariate analysis, germline mutation (RR=3.2; 95% CI 1.6-6.4, p=0.001), age, and symptoms were independent predictors of presence of IPMN, with no influence of family history of pancreatic cancer (p=0.22). Interestingly, the prevalence of IPMN was not distributed equally between all mutation types, ranging from 67% in patients with Peutz-Jeghers to 43% in HNPCC patients, 24% in BRCA2 patients, 14% in patients with ATM mutation, and 0% in CDKN2A, PALB2 or FAMM/p16 mutation patients. Conclusion: In this series, 18% of mutation carriers harbored IPMN. A strong family history of PDAC was not an independent risk factor for developing IPMN. The prevalence of IPMN was highly variable depending on the mutation subtype. This series suggests that not all mutation carriers may develop precancerous lesions, and relying on cross-sectional imaging alone for screening and follow-up may be suboptimal. Genetic testing for patients with positive family history may help better tailor surveillance modalities for this high-risk population.

Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer

“…Germline variants in PC susceptibility genes in individuals with IPMN include STK11 , MSH2 , MSH6 , PMS2 , BRCA2 , BRCA1 , ATM , CDKN2A , PALB2 , and APC. 20,24–30 Next-generation sequencing analysis of the proband revealed a germline MSH6 missense variant (p.Tyr1066Cys), suggesting its potential role as a susceptibility variant for both IPMN and PC. Because of the highly conserved nature of this tyrosine residue and the large physicochemical differences between tyrosine and cysteine, MSH6 missense variant (p.Tyr1066Cys) is often identified as pathogenic by various in silico pathogenicity prediction tools.…”

Intraductal Papillary Mucinous Neoplasms in Hereditary Cancer Syndromes

“…Other studies have analyzed mutations in IPMNs and extrapancreatic malignancy among patients with hereditary syndromes and have reported similar genetic alterations ( Table 5 ). A multivariate analysis revealed that germline mutations among patients with hereditary cancer syndromes was a predictor of the presence of IPMNs (relative risk, 3.2; 95% confidence interval (CI): 1.6–6.4) independent of family history of pancreatic cancer ( p = 0.22) [ 80 ]. These data suggest that hereditary syndromes may predispose patients to IPMNs, which, in turn, increases the risk of PDAC formation.…”