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Open AccessArticle

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

1
Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain
2
Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5. Pabellón 11, 28029 Madrid, Spain
3
Translational Genomics Core Facility, Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
4
Department of Biochemistry, Universidad Autónoma de Madrid (UAM), Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
5
Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain
6
Cancer Stem Cell and Fibroinflammatory Group, Chronic Diseases and Cancer, Area 3- IRYCIS, 28029 Madrid, Spain
7
Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
8
Department of Medicine and Medical Specialties, Medicine Faculty, Alcala University, Plaza de San Diego, s/n, 28801 Alcalá de Henares, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to the manuscript.
Academic Editor: Fabrizio Bianchi
Cancers 2021, 13(7), 1612; https://doi.org/10.3390/cancers13071612
Received: 12 March 2021 / Accepted: 27 March 2021 / Published: 31 March 2021
(This article belongs to the Special Issue Cancer Biomarkers in Body Fluids)
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. KRAS mutations occur in up to 95% of cases and render the tumor resistant to many types of therapy. Therefore, these patients are treated with traditional cytotoxic agents, according to guidelines. The familial or hereditary form of the disease accounts for up to 10–15% of cases. We hypothesized that hereditary and Familial Pancreatic Cancer cases (H/FPC) have a distinct tumor specific mutation profile due to the presence of pathogenic germline mutations and we used circulating free DNA (cfDNA) in plasma to assess this hypothesis. H/FPC cases were mainly KRAS mutation negative and harbored tumor specific mutations that are potential treatment targets in the clinic. Thus, we conclude that cases with a hereditary or familial background can be treated with newer and more effective agents that may ultimately improve their overall survival.
Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10–15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment. View Full-Text
Keywords: liquid biopsy; cfDNA; hereditary and familial pancreatic cancer; somatic mutation profiling; potentially druggable genes liquid biopsy; cfDNA; hereditary and familial pancreatic cancer; somatic mutation profiling; potentially druggable genes
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MDPI and ACS Style

Earl, J.; Barreto, E.; Castillo, M.E.; Fuentes, R.; Rodríguez-Garrote, M.; Ferreiro, R.; Reguera, P.; Muñoz, G.; Garcia-Seisdedos, D.; López, J.V.; Sainz, B., Jr.; Malats, N.; Carrato, A. 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. Cancers 2021, 13, 1612. https://doi.org/10.3390/cancers13071612

AMA Style

Earl J, Barreto E, Castillo ME, Fuentes R, Rodríguez-Garrote M, Ferreiro R, Reguera P, Muñoz G, Garcia-Seisdedos D, López JV, Sainz B Jr., Malats N, Carrato A. 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. Cancers. 2021; 13(7):1612. https://doi.org/10.3390/cancers13071612

Chicago/Turabian Style

Earl, Julie; Barreto, Emma; Castillo, María E.; Fuentes, Raquel; Rodríguez-Garrote, Mercedes; Ferreiro, Reyes; Reguera, Pablo; Muñoz, Gloria; Garcia-Seisdedos, David; López, Jorge V.; Sainz, Bruno, Jr.; Malats, Nuria; Carrato, Alfredo. 2021. "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" Cancers 13, no. 7: 1612. https://doi.org/10.3390/cancers13071612

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