Targeted Molecular Profiling of Circulating Cell-Free DNA in Patients With Advanced Hepatocellular Carcinoma.
Targeted Molecular Profiling of Circulating Cell-Free DNA in Patients With Advanced Hepatocellular Carcinoma.
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DOI：
10.1200/po.23.00272
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发表时间：
2023-09
影响因子：
4.6
通讯作者：
Darren Cowzer;Jessica B White;J. Chou;Pin-Jung Chen;Tae-Hyung Kim;D. Khalil;I. El Dika;Katrina Columna;A. Yaqubie;Joseph S Light;J. Shia;H. Yarmohammadi;J. Erinjeri;Alice C. Wei;W. Jarnagin;Richard K G Do;D. Solit;M. Capanu;Ronak H. Shah;M. Berger;G. Abou-Alfa;J. Harding
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作者：
Darren Cowzer;Jessica B White;J. Chou;Pin-Jung Chen;Tae-Hyung Kim;D. Khalil;I. El Dika;Katrina Columna;A. Yaqubie;Joseph S Light;J. Shia;H. Yarmohammadi;J. Erinjeri;Alice C. Wei;W. Jarnagin;Richard K G Do;D. Solit;M. Capanu;Ronak H. Shah;M. Berger;G. Abou-Alfa;J. Harding
肿瘤来源的循环无细胞DNA（cfDNA）的下一代测序（NGS）可能有助于肝细胞癌（HCC）患者的诊断、鉴别和治疗。cfDNA突变谱的操作特征必须在常规临床实施之前确定。这是一项单中心、回顾性研究，主要目的是确定晚期HCC患者匹配肿瘤样本的NGS之间的循环cfDNA基因组改变沿着血浆-组织基因型一致性。使用临床验证的129基因NGS测定分析cfDNA;使用美国食品和药物管理局授权的NGS肿瘤测定分析匹配的基于组织的NGS。结果来自51例组织学确诊的HCC患者的53份血浆样本进行了基于NGS的cfDNA分析。在92.2%的患者中检测到基因组改变，最常见的突变基因包括TERT启动子（57%），TP 53（47%），CTNNB 1（37%），ARID 1A（18%）和TSC 2（14%）。总共有37例（73%）患者接受了配对肿瘤NGS，在患者匹配的血浆样本中观察到的突变一致性很高：TERT（83%），TP 53（94%），CTNNB 1（92%），ARID 1A（100%）和TSC 2（71%）。在37个肿瘤血浆样品中的10个（27%）中，通过cfDNA分析检测到在患者匹配的肿瘤中未检测到的改变。在37%的病例中发现了潜在的可操作突变，包括TSC 1/2（18%）、BRCA 1/2（8%）和PIK 3CA（8%）中的致癌/可能致癌改变。较高的平均变异等位基因分数与甲胎蛋白升高、肿瘤体积增大和既往未接受过系统治疗相关，但与初治患者的总生存率无关。结论：考虑到肿瘤-血浆NGS的高度一致性，HCC中cfDNA的肿瘤突变谱代表了基于组织的基因组谱的替代方案;然而，可能需要血液和肿瘤的基因分型来检测所有临床上可操作的基因组改变。
PURPOSE Next-generation sequencing (NGS) of tumor-derived, circulating cell-free DNA (cfDNA) may aid in diagnosis, prognostication, and treatment of patients with hepatocellular carcinoma (HCC). The operating characteristics of cfDNA mutational profiling must be determined before routine clinical implementation. METHODS This was a single-center, retrospective study with the primary objective of defining genomic alterations in circulating cfDNA along with plasma-tissue genotype agreement between NGS of matched tumor samples in patients with advanced HCC. cfDNA was analyzed using a clinically validated 129-gene NGS assay; matched tissue-based NGS was analyzed with a US Food and Drug Administration-authorized NGS tumor assay. RESULTS Fifty-three plasma samples from 51 patients with histologically confirmed HCC underwent NGS-based cfDNA analysis. Genomic alterations were detected in 92.2% of patients, with the most commonly mutated genes including TERT promoter (57%), TP53 (47%), CTNNB1 (37%), ARID1A (18%), and TSC2 (14%). In total, 37 (73%) patients underwent paired tumor NGS, and concordance was high for mutations observed in patient-matched plasma samples: TERT (83%), TP53 (94%), CTNNB1 (92%), ARID1A (100%), and TSC2 (71%). In 10 (27%) of 37 tumor-plasma samples, alterations were detected by cfDNA analysis that were not detected in the patient-matched tumors. Potentially actionable mutations were identified in 37% of all cases including oncogenic/likely oncogenic alterations in TSC1/2 (18%), BRCA1/2 (8%), and PIK3CA (8%). Higher average variant allele fraction was associated with elevated alpha-fetoprotein, increased tumor volume, and no previous systemic therapy, but did not correlate with overall survival in treatment-naïve patients. CONCLUSION Tumor mutation profiling of cfDNA in HCC represents an alternative to tissue-based genomic profiling, given the high degree of tumor-plasma NGS concordance; however, genotyping of both blood and tumor may be required to detect all clinically actionable genomic alterations.