Abstract 1538P
Background
Since the National Comprehensive Cancer Network have already endorsed genetic counseling for all pancreatic cancer patients, there is an urgent need to well define more pancreatic cancer susceptibility genes.
Methods
To uncover the prevalence of deleterious germline mutations in PDAC patients, unselected patients with PDAC were recruited between 2017 and 2019. DNA sample was analyzed by hybridization capture-based targeted next-generation sequencing with a 139-gene panel.
Results
Of all the 369 sequenced pancreatic ductal adenocarcinoma patients, 52 identifiable deleterious germline mutations were found in 51 (13.8%) patients, of which 47 were truncating. Twenty-five (6.8%) of these patients carried a deleterious mutation in a pancreatic cancer susceptibility gene: 13 (3.5%) with a deleterious BRCA1 (n =2) or BRCA2 (n =11) mutation, four with ATM, five with PALB2, and one each with a APC, MSH6 and TP53 mutation. Moreover, 17 (4.6%) patients had deleterious mutations in additional DNA damage repair (DDR) genes including NBN (n =1), RECQL4 (n =1), WRN (n =1) of the homologous recombination repair pathway, ERCC2 (n =1), ERCC4 (n =1), ERCC5 (n =1) of the nucleotide excision repair pathway, BRIP1 (n =2), FANCD2 (n =2), FANCM (n =2) of the Fanconi anemia pathway, MRE11A (n =1), RAD50 (n =1) of the nonhomologous end-joining pathway, MUTYH (n =2) and MSH3 (n =1). Besides, five PDACs were found to carry a deleterious mutation in another cancer predisposition gene (one each involving CDH1, EPCAM, PTCH2, RET and BARD1). One patient with a deleterious PALB2 frameshift deletion had a PTCH2 mutation as well. The prevalence of deleterious germline mutations decreased with the increase of diagnosis age, with frequencies of 20.5% (8/39), 17.1% (26/152), and 9.6% (17/178) in the aged groups under 45, 45-60 and above 60, respectively. In a univariate analysis, statistical significance was reached in the aged under 60 group (P = 0.02).
Conclusions
We found that nearly 14% PDAC patients carry deleterious germline mutations, mainly in established pancreatic cancer susceptibility genes and DDR genes. Cancer-specific defects in DDR genes open up opportunities to utilize synthetic lethality approach, so a boarder range of genes including our identification should be recommended.
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
X. Li, T. Ma, H. Yuan: Full/Part-time employment: Genetron Health (Beijing) Technology, Co. Ltd. All authors have declared no conflicts of interest.