Abstract
Simple SummaryWe performed genetic analysis of 53 cancer predisposing genes in Belgian and Czech pancreatic cancer patients. In known pancreatic cancer predisposing genes, a high mutation detection ratio was observed in patients with multiple primary tumors and/or a family history of pancreatic or breast, ovarian or colon cancer or melanoma. BRCA1, BRCA2, and ATM were most frequently affected. Pathogenic variants in cancer predisposition genes for which the association with pancreatic cancer has not been firmly established, were less frequent, except for CHEK2. This observation warrants further analyses in other populations. To accurately determine risk associations our study highlights the importance of using a geographically-matched control population.(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34–0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy with a 5year survival rate of only 9% [1]
We detected 61 germline pathogenic variants (PV) in 20 out of 53 genes analyzed in both population cohorts, comprising 72 high-risk Belgian and 226 unselected Czech pancreatic ductal adenocarcinoma (PDAC) patients (Table 2 and Table S4)
In 23 PDAC patients (7.7%) 25 PV were found in other cancer predisposition genes for which a clear association with PDAC has not been established; one third of them in CHEK2
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy with a 5year survival rate of only 9% [1]. Its initial non-specific symptoms makes early diagnosis challenging and less than 20% of PDAC patients have potentially resectable tumors at the time of diagnosis [2]. Most PDAC cases appear to be sporadic, a familial background has been documented in up to 10% of the patients [2,3]. Increased PDAC prevalence associates with hereditary cancer syndromes caused by germline pathogenic/likely-pathogenic variants (PV) in BRCA2, ATM, BRCA1, PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, TP53, or STK11 [3,4]. Germline PV in the four first genes have the highest prevalence in PDAC patients; their frequency shows substantial geographic variabilities [5]. Germline PV in cancer susceptibility genes have been reported in apparently sporadic PDAC cases [7,8].
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