Abstract
BACKGROUNDPancreatic cancer is one of the deadliest cancers, with low long-term survival rates. Despite recent advances in treatment, it is important to identify and screen high-risk individuals for cancer prevention. Familial pancreatic cancer (FPC) accounts for 4%–10% of pancreatic cancers. Several germline mutations are related to an increased risk and might offer screening and therapy options. In this study, we aimed to identity of a susceptibility gene in a family with FPC.METHODSWhole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry were also queried.RESULTSThe identical germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer and the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the 2 sisters. Apart from the PALLD mutation, commonly mutated genes that characterize pancreatic ductal adenocarcinoma were found in both tumor samples. However, the 2 patients harbored different somatic KRAS mutations (G12D and G12V). Healthy siblings did not have the PALLD mutation, indicating a disease-specific impact. Compartment-specific gene expression data and IHC showed expression in cancer-associated fibroblasts (CAFs).CONCLUSIONWe identified a germline mutation of the palladin (PALLD) gene in 2 siblings in Europe, affected by familial pancreatic cancer, with a significant overexpression in CAFs, suggesting that stromal palladin could play a role in the development, maintenance, and/or progression of pancreatic cancer.FUNDINGDFG SFB 1321
Highlights
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer [1], still has a 5-year survival below 10% [2, 3] and represents the fourth leading cause of cancer-related deaths [4] in the European and US populations [5]
We identified a germline mutation of the palladin (PALLD) gene in 2 siblings in Europe, affected by familial pancreatic cancer, with a significant overexpression in CAFs, suggesting that stromal palladin could play a role in the development, maintenance, and/or progression of pancreatic cancer
A CT scan of the abdomen and thorax revealed a mass in the uncinate process of the pancreas, radiographically consistent with pancreatic adenocarcinoma (Figure 1A)
Summary
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer [1], still has a 5-year survival below 10% [2, 3] and represents the fourth leading cause of cancer-related deaths [4] in the European and US populations [5]. Even though most cases of pancreatic cancers are sporadic with known risk factors While the genetic background responsible for most cases of FPC is still unknown, some of the genes responsible for its development have been identified. A large European study analyzed 106 FPC families through 3 generations and found that from one generation to the the age of death from PC was younger with each generation [26]. We aimed to identity of a susceptibility gene in a family with FPC
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