Circulating Cell-Free DNA Captures the Intratumor Heterogeneity in Multinodular Hepatocellular Carcinoma.

Coto-Llerena, Mairene; Benjak, Andrej; Gallon, John; Meier, Marie-Anne; Boldanova, Tuyana; Terracciano, Luigi M; Ng, Charlotte K Y; Piscuoglio, Salvatore (2022). Circulating Cell-Free DNA Captures the Intratumor Heterogeneity in Multinodular Hepatocellular Carcinoma. JCO precision oncology, 6, e2100335. American Society of Clinical Oncology 10.1200/PO.21.00335

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PURPOSE

Hepatocellular 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 METHODS

Tumor 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.

RESULTS

Genomic 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.

CONCLUSION

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Benjak, Andrej and Ng, Kiu Yan Charlotte

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2473-4284

Publisher:

American Society of Clinical Oncology

Language:

English

Submitter:

Pubmed Import

Date Deposited:

11 Mar 2022 11:45

Last Modified:

20 Mar 2022 01:59

Publisher DOI:

10.1200/PO.21.00335

PubMed ID:

35263170

BORIS DOI:

10.48350/167232

URI:

https://boris.unibe.ch/id/eprint/167232

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