Back to Search Start Over

Tumor-Naïve Multimodal Profiling of Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma.

Authors :
Burgener JM
Zou J
Zhao Z
Zheng Y
Shen SY
Huang SH
Keshavarzi S
Xu W
Liu FF
Liu G
Waldron JN
Weinreb I
Spreafico A
Siu LL
de Almeida JR
Goldstein DP
Hoffman MM
De Carvalho DD
Bratman SV
Source :
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Aug 01; Vol. 27 (15), pp. 4230-4244. Date of Electronic Publication: 2021 Jun 22.
Publication Year :
2021

Abstract

Purpose: Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naïve methods are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naïve detection of ctDNA by simultaneous profiling of mutations and methylation.<br />Experimental Design: We conducted CAncer Personalized Profiling by deep Sequencing (CAPP-seq) and cell-free Methylated DNA ImmunoPrecipitation and high-throughput sequencing (cfMeDIP-seq) for detection of ctDNA-derived somatic mutations and aberrant methylation, respectively. We analyzed 77 plasma samples from 30 patients with stage I-IVA human papillomavirus-negative HNSCC as well as plasma samples from 20 risk-matched healthy controls. In addition, we analyzed leukocytes from patients and controls.<br />Results: CAPP-seq identified mutations in 20 of 30 patients at frequencies similar to that of The Tumor Genome Atlas (TCGA). Differential methylation analysis of cfMeDIP-seq profiles identified 941 ctDNA-derived hypermethylated regions enriched for CpG islands and HNSCC-specific methylation patterns. Both methods demonstrated an association between ctDNA abundance and shorter fragment lengths. In addition, mutation- and methylation-based ctDNA abundance was highly correlated ( r > 0.85). Patients with detectable pretreatment ctDNA by both methods demonstrated significantly worse overall survival (HR = 7.5; P = 0.025) independent of clinical stage, with lack of ctDNA clearance post-treatment strongly correlating with recurrence. We further leveraged cfMeDIP-seq profiles to validate a prognostic signature identified from TCGA samples.<br />Conclusions: Tumor-naïve detection of ctDNA by multimodal profiling may facilitate biomarker discovery and clinical use in low ctDNA abundance applications.<br /> (©2021 The Authors; Published by the American Association for Cancer Research.)

Details

Language :
English
ISSN :
1557-3265
Volume :
27
Issue :
15
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
34158359
Full Text :
https://doi.org/10.1158/1078-0432.CCR-21-0110