Genetic profiling using plasma-derived cell-free DNA in therapy-naïve hepatocellular carcinoma patients: a pilot study.

Ng CKY1,2, Di Costanzo GG3, Tosti N1, Paradiso V1, Coto-Llerena M2, Roscigno G4, Perrina V1, Quintavalle C1, Boldanova T1,5, Wieland S2, Marino-Marsilia G6, Lanzafame M1, Quagliata L1, Condorelli G4, Matter MS1, Tortora R3, Heim MH2,5, Terracciano LM1, Piscuoglio S1.

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Abstract

BACKGROUND:

Hepatocellular carcinomas (HCCs) are not routinely biopsied, resulting in a lack of tumor materials for molecular profiling. Here we sought to determine if plasma-derived cell-free DNA (cfDNA) captures the genetic alterations of HCC in patients who have not undergone systemic therapy.

PATIENTS AND METHODS:

Frozen biopsies from the primary tumor and plasma were synchronously collected from 30 prospectively recruited, systemic treatment-naïve HCC patients. Deep sequencing of the DNA from the biopsies, plasma-derived cfDNA and matched germline was performed using a panel targeting 46 coding and non-coding genes frequently altered in HCCs.

RESULTS:

In 26/30 patients, at least one somatic mutation was detected in biopsy and/or cfDNA. Somatic mutations in HCC-associated genes were present in the cfDNA of 63% (19/30) patients and could be detected 'de novo' without prior knowledge of the mutations present in the biopsy in 27% (8/30) patients. Mutational load and the variant allele fraction of the mutations detected in the cfDNA positively correlated with tumor size and Edmondson grade. Crucially, among the seven patients in whom the largest tumor was ≥5cm or was associated with metastasis, at least one mutation was detected 'de novo' in the cfDNA of 86% (6/7) cases. In these patients, cfDNA and tumor DNA captured 87% (80/92) and 95% (87/92) of the mutations, suggesting that cfDNA and tumor DNA captured similar proportions of somatic mutations.

CONCLUSION:

In patients with high disease burden, the use of cfDNA for genetic profiling when biopsy is unavailable may be feasible. Our results support further investigations into the clinical utility of cfDNA in a larger cohort of patients.