Abstract
PURPOSEHepatocellular carcinoma (HCC) is a highly heterogeneous disease, with more than 40% of patients initially diagnosed with multinodular HCCs. Although circulating cell-free DNA (cfDNA) has been shown to effectively detect somatic mutations, little is known about its utility to capture intratumor heterogeneity in patients with multinodular HCC undergoing systemic treatment.MATERIALS AND METHODSTumor biopsies and plasma were synchronously collected from seven prospectively recruited patients with HCC before and during systemic therapy. Plasma-derived cfDNA and matched germline were subjected to high-depth targeted sequencing with molecular barcoding. The mutational profile of the cfDNA was compared with whole-exome sequencing from matched tumor biopsies.RESULTSGenomic data revealed that out of the seven patients, five were considered intrahepatic metastasis and two multicentric HCCs. cfDNA captured the majority of mutations in the tumors and detected significantly more mutations than tumor biopsies. Driver mutations such as CTNNB1 S33C, NRAS Q61R, ARID1A R727fs, and NF1 E2368fs as well as standard-of-care biomarkers of response to targeted therapy were detected only in cfDNA. In the two patients with multicentric HCC, cfDNA detected mutations derived from the genetically independent and spatially distinct nodules. Moreover, cfDNA was not only able to capture clonal mutations but also the subclonal mutations detected in only one of the multiple biopsied nodules. Furthermore, serial cfDNA detected variants of tumor origin emerging during treatment.CONCLUSIONThis study revealed that the genetic analysis of cfDNA captures the intratumor heterogeneity in multinodular HCC highlighting the potential for cfDNA as a sensitive and noninvasive tool for precision medicine.
Highlights
Hepatocellular carcinoma (HCC), the most common primary liver cancer, is the third leading cause of cancerrelated deaths.[1]
Genomic data revealed that out of the seven patients, five were considered intrahepatic metastasis and two multicentric HCCs. cell-free DNA (cfDNA) captured the majority of mutations in the tumors and detected significantly more mutations than tumor biopsies
This study revealed that the genetic analysis of cfDNA captures the intratumor heterogeneity in multinodular HCC highlighting the potential for cfDNA as a sensitive and noninvasive tool for precision medicine
Summary
Hepatocellular carcinoma (HCC), the most common primary liver cancer, is the third leading cause of cancerrelated deaths.[1]. In patients with advanced HCC, where chemoembolization is not appropriate or has failed, systemic therapy is the only available option.[2]. One major challenge in the treatment of HCC is high tumor heterogeneity because of the existence of multinodular HCCs, and the high intratumor molecular diversity.[3]. 41% to 75% of patients are initially diagnosed with multinodular HCCs, which limits the access to curative treatment options and leads to poor prognosis.[4-6]. Multinodular HCCs represent intrahepatic metastasis (IM) of a single cancer or multicentric occurrence (MC).[7,8]. The high tumor heterogeneity, especially in multicentric HCC, assessed from the view of a single tumor biopsy can lead to underestimation of the genetic heterogeneity of the tumor and could present a major challenge to precision medicine and biomarker development Multinodular HCCs represent intrahepatic metastasis (IM) of a single cancer or multicentric occurrence (MC).[7,8] Whole-exome sequencing (WES) analysis of paired and recurrent HCC showed that IM pairs shared 15%-93% of mutations, whereas MC pairs only 0%-0.28%.7 The high tumor heterogeneity, especially in multicentric HCC, assessed from the view of a single tumor biopsy can lead to underestimation of the genetic heterogeneity of the tumor and could present a major challenge to precision medicine and biomarker development
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