Liotta, L., Lange, S., Maurer, H. C., Olive, K. P., Braren, R., Pfarr, N., Muckenhuber, A., Jesinghaus, M., Weichert, W., Steiger, K., Burger, S., Friess, H., Schmid, R. M., Alguel, H., Jost, P., Ramser, J., Fischer, C., Quante, A. S., Reichert, M., and Quante, M. (2021). JCI Insight 6
Background and aims: Pancreatic cancer is one of the deadliest cancers, still with low long term survival rates. Despite recent advances in treatment, it is extremely important to screen high-risk individuals in order to establish preventive and early detection measures and, in some cases, molecular driven therapeutic options. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are known to be related with an increased risk and might offer novel screening and therapy options. In this study, our goal was to discover the identity of a familial pancreatic cancer gene in two members of a family with FPC.
Methods: Whole 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 was used to characterize PALLD expression.
Results: A germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer. The identical PALLD mutation was identified in the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the two sisters. Apart from the PALLD mutation, commonly mutated genes that characterize PDAC (KRAS and CDKN2A) were found in both tumor samples. However, the two patients harbored different somatic KRAS mutations (respectively G12D in the index patient and G12V in the index patient's sister). Analysis for PALLD mutation in the healthy siblings of the two sisters was negative, indicating that the identified PALLD mutation might have a disease specific impact. Of note, compartment-specific gene expression data and IHC suggested a predominant role in cancer associated fibroblasts (CAFs).
Conclusion: We identified a germline mutation of the palladin (PALLD) gene in two siblings in Europe, affected by familial pancreatic cancer, with a predominant function in the tumor stroma.