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.

Julie Earl,Reyes Ferreiro,Nuria Malats,María Castillo,David Garcia-Seisdedos,Emma Barreto,Alfredo Carrato,Gloria Muñoz,Raquel Fuentes,Bruno Sainz,Jorge López,Mercedes Rodríguez-Garrote,Pablo Reguera

doi:10.3390/cancers13071612

Abstract

Simple SummaryPancreatic 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.

Highlights

The incidence and mortality rates of adenocarcinoma of the pancreas (PDAC) are almost equal [1]
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]
High-risk family members of H/Familial Pancreatic Cancer (FPC) cases in the secondary screening program that were diagnosed with pancreatic cysts or intraductal papillary mucinous neoplasm (IPMN) were included and one case that was initially included in the study as a possible Pancreatic ductal adenocarcinoma (PDAC), but was later confirmed as an IPMN

Summary

Introduction

The incidence and mortality rates of adenocarcinoma of the pancreas (PDAC) are almost equal [1]. KRAS somatic mutations are present in around 90% of sporadic tumors and TP53, CDKN2A, and SMAD4 mutations are commonly found. None of these somatic changes are druggable at present time. PDAC tumors have an average of 63 somatic alterations that affect different signaling pathways [3]. The best described common risk factors for sporadic PDAC include tobacco, alcohol, diabetes, chronic pancreatitis, and obesity [4]. 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]. The Spanish familial pancreatic cancer registry (PANGENFAM) was established in 2009 with the principal objective to characterize the phenotypic and genetic background of FPC [9]

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