A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants

Abstract

Background:The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%À10%. The genetic basis is unknown in the majority of families although around 10%À13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes. Methods: Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. Findings: Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC. Interpretation: The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. Funding: This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013À2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Tem atica de investigaci on cooperativa en c ancer: RTICC (RD12/0036/0073) and La Asociaci on Española contra el C ancer: AECC (Grupos Coordinados Estables 2016).

Cystic Fibrosis, CFTR, and Colorectal Cancer

“…But for the great majority of cancer studies, loss of CFTR expression and/or activity is linked with cancer incidence, and in the majority of these reports, CFTR mutations or downregulation of CFTR expression in epithelial cancers is associated with rapid cancer growth, epithelial to mesenchymal transition (EMT), a reduction in cellular apoptosis, enhanced metabolic potential, and elevated patient morbidity and mortality. Down regulation of CFTR expression and/or mutations that disrupt CFTR function have been reported in non-small-cell lung cancer (NSCLC) [33,86,[126][127], glioblastoma [128], bladder cancer [34][35][36], esophageal cancer [129,130], pancreatic cancer [131][132][133], nasopharyngeal cancer [134], prostate cancer [94], and breast cancer [37,95]. In many of these malignancies, loss of CFTR correlated with increased tumor stage and reduced disease-free or overall survival.…”

The Latest Advancement in Pancreatic Ductal Adenocarcinoma Therapy: A Review Article for the Latest Guidelines and Novel Therapies

“…Moreover, the deep location of the pancreas, aggressive nature of PDAC, and lack of reliable screening tests make it very hard for a primary physicians to catch and diagnose the disease at earlier and more manageable stages. PDAC commonly occurs as a sequence of accumulating genetic mutations in somatic cells, and less commonly, due to mutations in germline cells, particularly the case in familial PDAC [5,6]. With the advantage of next-generation gene sequencing, the PDAC pathophysiology is now better understood, and there is an emerging need for adding pathological classification to the current clinical and anatomical staging to formulate more personalized treatment plans [7,8].…”

Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival

“…Family history is also an important risk factor and approximately 10% of PDAC cases have a hereditary or familial basis [ 5 ]. Hereditary pancreatic cancer are associated with a known cancer syndrome such as hereditary breast–ovarian cancer (HBOC), Peutz–Jeghers (PJ), Hereditary Pancreatitis (HP), Familial Atypical Multiple Mole Melanoma (FAMMM), and Lynch syndrome and harbor germline pathogenic mutations in genes such as BRCA2, MLH1, and CDKN2A [ 6 ]. Whereas, Familial Pancreatic Cancer (FPC) is defined as a family with at least one pair of affected first degree relatives with no identified genetic basis and account for 4–10% of PDAC patients [ 7 , 8 ].…”