High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer

Abstract

Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis. Methods: Patients from two cohorts were studied, the High Risk Cohort (HRC) which included 584 PDAC patients who received genetic counseling at MD Anderson Cancer Center and a General Cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations was determined and clinical characteristics including survival were analyzed. Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared to the GC: 17.3% vs 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC (OR: 1.93 +/−1.03–3.70, P: 0.039) and GC (4.78 +/−1.10–32.95, P: 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR= 0.44, 95% CI of HR: 0.25–0.76, p: 0.030). Discussion Germline mutations are highly prevalent in patients with PDAC of early-onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset.

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

“…Deleterious variants in the known pancreatic cancer susceptibility genes account for ~10–20% of the familial clustering of pancreatic cancer 26 32 33. Deleterious variants have also been reported in ~5–10% of patients with apparently sporadic pancreatic cancer 34–39. These variants also confer risk for other cancers 40.…”

Pancreatic Cancer Exposome Profile to Aid Early Detection and Inform Prevention Strategies

“…BRCA2 gene mutations account for the highest proportion of known causes of familial PCa; they have been consistently associated with a moderate-high PCa risk, except for one study reporting 22-fold increased risk [ 136 , 137 ]. Additionally, a recent cohort found a positive association between germline BRCA1/2 carriers and early-onset PCa [ 138 ]. A total of three epidemiological studies found no association between BRCA1 and incidence of PCa [ 136 , 137 , 139 ].…”

The Management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline

“…In a recent pancreas surveillance study in high-risk individuals (HRIs) by Abe et al [ 56 ], the cumulative incidence of PDAC in the group with germline PV in known PDAC predisposing genes (including 12 PJS patients) was higher than in the familial risk (FPC) group. Bannon et al also demonstrated that germline PVs in PDAC predisposing genes are highly prevalent in patients with early onset PDAC [ 57 ]. Nevertheless, in the previous version of this guideline, Beggs et al did not recommend routine surveillance for pancreatic cancer in PJS because of a lack of sufficient evidence regarding its benefit and cost effectiveness; surveillance should be undertaken only in the framework of a clinical research study [ 5 ].…”