Circulating Cell-Free DNA-Based Comprehensive Molecular Analysis of Biliary Tract Cancers Using Next-Generation Sequencing

Szilvia Lilla Csoma,Gábor Méhes,Attila Mokánszki,Csilla András,Judit Bedekovics,Anita Árokszállási,Gergő Veres

doi:10.3390/cancers14010233

Abstract

Simple SummaryIn the era of personalized oncology, next-generation sequencing plays an important role in identifying mutations that may predict the molecular pathomechanism and manage biliary tract cancers (BTC) therapy. The peripheral blood of cancer patients represents variable amounts of cell-free DNA (cfDNA) released from the tumor. Tumor-derived cfDNA in BTCs also allows the effective monitoring of the molecular genetic profile and the response to chemotherapy. Our study aimed to identify genetic aberrations in cell-free and matched tumor DNA in BTCs. We assume that the efficacy of the LB-based sequencing provides a novel perspective for BTCs therapy.Biliary tract cancer (BTC) is a rare malignancy with a long disease course and an overall poor prognosis. Despite multiple chemotherapy agents, there is no defined second-line treatment opportunity for advanced BTCs. In the era of precision oncology, NGS plays an important role in identifying mutations that may predict the molecular pathomechanism and manage the BTC therapy. The peripheral blood liquid biopsy (LB) of cancer patients represents variable amounts of cell-free DNA (cfDNA) released from tumor foci of any anatomical location. Our study aimed to identify somatic mutations and tumor variant burden (TVB) in cell-free and matched tumor DNA. We found a positive correlation between the estimated tumor volume and cfDNA yield (r = 0.9326, p < 0.0001). Comparing tissue and LB results, similar TVB was observed. SNVs were proven in 84% of the cases, while in two cases, only the LB sample was informative for molecular analysis. The most important aberrations in BTCs, such as FGFR2, IDH1, IDH2, KRAS, and TP53, could be detected in matched LB samples. Our prospective study demonstrates a minimally invasive testing approach to identify molecular genetic alterations in cholangiocarcinoma and gallbladder cancers. Clinical applications of cfDNA reflect by capturing the outstanding spatial tumor heterogeneity and guarantee novel aspects for the precision oncology treatment.

Highlights

Biliary tract cancers (BTCs) are rare malignancies with an extended disease course with an inadequate prognosis and restricted oncotherapeutic options [1,2]
Tissue biopsy was performed in intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC) cases, while resection was carried out only in potential operable gallbladder carcinoma (GBC) cases, as well
Little information was found about the utility of liquid biopsy (LB) to identify diagnostic and prognostic biomarkers in BTCs [26], so for this reason we aimed to quantify and analyze cell-free DNA (cfDNA) management of patients affected by BTC

Summary

Introduction

Biliary tract cancers (BTCs) are rare malignancies with an extended disease course with an inadequate prognosis and restricted oncotherapeutic options [1,2]. BTC subtypes, which are as follows: intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder carcinoma (GBC). According to a recent study, the five-year survival rates for IHCC and EHCC are 12 and 30%, respectively [3]. In clinical and histopathological views, the BTC subtypes have variable features, and they are often treated [4,5]. Surgery is the curative approach; BTCs are often unresectable, gemcitabine chemotherapy and adjuvant with capecitabine remain the basic curative decision in BTCs treatment [6,7,8]. Gemcitabine was not effective in the PRODIGE

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