Clonal diversity in KRAS mutant colorectal adenocarcinoma under treatment: Monitoring of cfDNA using reverse hybridization and DNA sequencing platforms

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Emese Sarolta Bádon , Attila Mokánszki , Anikó Mónus , Csilla András , Gábor Méhes
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引用次数: 1

Abstract

Biological heterogeneity is a key feature of malignancies that significantly contributes to disease progression and therapy resistance. Residual/relapsed tumor foci may represent genetically divergent subclones, which remain uncovered as repeated and multiple tumor sampling is usually limited. The analysis of circulating free DNA (cfDNA) from the peripheral blood plasma (also called a liquid biopsy, LB) is a new achievement that provides an effective tool for follow-up monitoring of cancer-related genetic status. The present study highlights the phenomenon of mutational variability observed in patients with metastatic KRAS mutant colorectal cancer (mCRC) during treatment with bevacizumab in combination in a longitudinal fashion.

The prospective study included 490 mCRC patients evaluated between 2020 and 2022 in our institution. Out of the 211 KRAS mutant cases (43.06%) 12 tumors were identified with multiple KRAS gene variants (5.68%). Detailed follow-up investigations were possible in 3 of these patients including the genotyping of the primary and available metastatic tumors, and the peripheral blood cfDNA. cfDNA was collected from three different time points before and between cycles of combined treatment with bevacizumab chemotherapy. KRAS gene variants were identified using reverse-hybridization strips, and next-generation sequencing (NGS), and confirmed by conventional Sanger sequencing.

Interestingly, surgery and multiple treatment cycles reorganized the mutational profiles in the selected cases. The effect of the treatments resulted either in the overrepresentation of one of the pre-existing gene variants or in the appearance of new KRAS variants absent in the primary sample, according to the plasma cfDNA findings. Besides the KRAS variants demonstrated by targeted analysis, NGS mutational profiling identified some additional pathogenic variants from the cfDNA samples (including NRAS and MET alterations).

In conclusion, plasma cfDNA sampling enables the monitoring of mutational heterogeneity and subclonal dynamics of the actual metastatic tumor mass in mCRC. The pattern of molecular profile potentially reflects a differential drug response determining further progression.

KRAS突变结直肠癌治疗中的克隆多样性:使用反向杂交和DNA测序平台监测cfDNA
生物异质性是恶性肿瘤的一个关键特征,它显著导致疾病进展和治疗耐药性。残留/复发的肿瘤灶可能代表遗传上不同的亚克隆,由于重复和多次肿瘤采样通常是有限的,这些亚克隆仍然没有被发现。外周血浆循环游离DNA(cfDNA)的分析(也称为液体活检,LB)是一项新的成果,为癌症相关遗传状态的后续监测提供了有效的工具。本研究强调了转移性KRAS突变型癌症(mCRC)患者在贝伐单抗联合纵向治疗期间观察到的突变变异现象。该前瞻性研究包括我们机构在2020年至2022年间评估的490名mCRC患者。在211例KRAS突变病例(43.06%)中,有12例肿瘤被鉴定为具有多种KRAS基因变异(5.68%)。其中3例患者可能进行了详细的随访研究,包括原发性和可用转移性肿瘤的基因分型,以及外周血cfDNA。从贝伐单抗化疗联合治疗周期之前和周期之间的三个不同时间点收集cfDNA。使用反向杂交条和下一代测序(NGS)鉴定KRAS基因变体,并通过传统的Sanger测序进行确认。有趣的是,手术和多个治疗周期重组了选定病例的突变谱。根据血浆cfDNA的发现,治疗的效果要么导致一种预先存在的基因变体的过度表达,要么导致新的KRAS变体在原始样本中缺失。除了通过靶向分析证明的KRAS变体外,NGS突变图谱还从cfDNA样本中鉴定了一些额外的致病性变体(包括NRAS和MET改变)。总之,血浆cfDNA采样能够监测mCRC中实际转移肿瘤块的突变异质性和亚克隆动力学。分子图谱的模式可能反映了决定进一步进展的不同药物反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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