Somatic Mutations in Circulating Cell-Free DNA and Risk for Hepatocellular Carcinoma in Hispanics.

Jingjing Jiao,Susan P Fisher-Hoch,Jessica I Sanchez,Laura Beretta,Erika J Thompson,P Andrew Futreal,Jianhua Zhang,Joseph B Mccormick,Xizeng Mao

doi:10.3390/ijms22147411

Abstract

Hispanics are disproportionally affected by liver fibrosis and hepatocellular carcinoma (HCC). Advanced liver fibrosis is a major risk factor for HCC development. We aimed at identifying somatic mutations in plasma cell-free DNA (cfDNA) of Hispanics with HCC and Hispanics with advanced liver fibrosis but no HCC. Targeted sequencing of over 262 cancer-associated genes identified nonsynonymous mutations in 22 of the 27 HCC patients. Mutations were detected in known HCC-associated genes (e.g., CTNNB1, TP53, NFE2L2, and ARID1A). No difference in cfDNA concentrations was observed between patients with mutations and those without detectable mutations. HCC patients with higher cfDNA concentrations or higher number of mutations had a shorter overall survival (p < 0.001 and p = 0.045). Nonsynonymous mutations were also identified in 17 of the 51 subjects with advanced liver fibrosis. KMT2C was the most commonly mutated gene. Nine genes were mutated in both subjects with advanced fibrosis and HCC patients. Again, no significant difference in cfDNA concentrations was observed between subjects with mutations and those without detectable mutations. Furthermore, higher cfDNA concentrations and higher number of mutations correlated with a death outcome in subjects with advanced fibrosis. In conclusion, cfDNA features are promising non-invasive markers for HCC risk prediction and overall survival.

Highlights

The incidence of hepatocellular carcinoma (HCC) has nearly tripled in the United States in the past 30 years and continues to rise, faster than for any other cancer in both men and women [1,2,3]
Mutations were more commonly identified in cell-free DNA (cfDNA) from HCC patients than in cfDNA from subjects with advanced liver fibrosis/cirrhosis (81.5% vs. 33.3%, p < 0.001), 0.001), and detected, when detected, a higher number of mutations
We applied targeted next-generation sequencing to the analysis of circulating cfDNA in Hispanics from South Texas with either HCC or advanced fibrosis/cirrhosis

Summary

Introduction

The incidence of HCC has nearly tripled in the United States in the past 30 years and continues to rise, faster than for any other cancer in both men and women [1,2,3]. It has the second lowest 5-year survival (18%), after pancreatic cancer [1]. This is largely due to the fact that the majority of HCC cases are diagnosed at an advanced stage when curative treatment options are limited [3,4]. 5-year survival can reach ~70% for early-stage HCC patients who undergo curative therapy [5,6]. Detection of early-stage HCC is a major necessary step in improving overall survival

Methods

Results

Conclusion