Sharbatoghli Mina, Fattahi Fahimeh, Aboulkheyr Es Hamidreza, Akbari Arvand, Akhavan Setareh, Ebrahimi Marzieh, Asadi-Lari Mohsen, Totonchi Mehdi, Madjd Zahra
Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
Front Genet. 2022 Jul 22;13:938985. doi: 10.3389/fgene.2022.938985. eCollection 2022.
Analysis of circulating tumor DNA (ctDNA) can be used to characterize and monitor cancers. Recently, non-invasive prenatal testing (NIPT) as a new next-generation sequencing (NGS)-based approach has been applied for detecting ctDNA. This study aimed to investigate the copy number variations (CNVs) utilizing the non-invasive prenatal testing in plasma ctDNA from ovarian cancer (OC) patients who were treated with neoadjuvant chemotherapy (NAC). The plasma samples of six patients, including stages II-IV, were collected during the pre- and post-NAC treatment that were divided into NAC-sensitive and NAC-resistant groups during the follow-up time. CNV analysis was performed using the NIPT via two methods "an open-source algorithm WISECONDORX and NextGENe software." Results of these methods were compared in pre- and post-NAC of OC patients. Finally, bioinformatics tools were used for data mining from The Cancer Genome Atlas (TCGA) to investigate CNVs in OC patients. WISECONDORX analysis indicated fewer CNV changes on chromosomes before treatment in the NAC-sensitive rather than NAC-resistant patients. NextGENe data indicated that CNVs are not only observed in the coding genes but also in non-coding genes. CNVs in six genes were identified, including HSF1, TMEM249, MROH1, GSTT2B, ABR, and NOMO2, only in NAC-resistant patients. The comparison of these six genes in NAC-resistant patients with The Cancer Genome Atlas data illustrated that the total alteration frequency is amplification, and the highest incidence of the CNVs (≥35% based on TCGA data) is found in MROH1, TMEM249, and HSF1 genes on the chromosome (Chr) 8. Based on TCGA data, survival analysis showed a significant reduction in the overall survival among chemotherapy-resistant patients as well as a high expression level of these three genes compared to that of sensitive samples (all, < 0.0001). The continued Chr8 study using WISECONDORX revealed CNV modifications in NAC-resistant patients prior to NAC therapy, but no CNV changes were observed in NAC-sensitive individuals. Our findings showed that low coverage whole-genome sequencing analysis used for NIPT could identify CNVs in ctDNA of OC patients before and after chemotherapy. These CNVs are different in NAC-sensitive and -resistant patients highlighting the potential application of this approach in cancer patient management.
循环肿瘤DNA（ctDNA）分析可用于癌症的特征描述和监测。最近，作为一种基于新一代测序（NGS）的新方法，无创产前检测（NIPT）已被应用于检测ctDNA。本研究旨在利用无创产前检测研究接受新辅助化疗（NAC）的卵巢癌（OC）患者血浆ctDNA中的拷贝数变异（CNV）。收集了6例II-IV期患者在NAC治疗前和治疗后的血浆样本，在随访期间将其分为NAC敏感组和NAC耐药组。使用NIPT通过“开源算法WISECONDORX和NextGENe软件”两种方法进行CNV分析。在OC患者的NAC治疗前和治疗后比较了这些方法的结果。最后，使用生物信息学工具从癌症基因组图谱（TCGA）中挖掘数据，以研究OC患者的CNV。WISECONDORX分析表明，在NAC敏感患者而非NAC耐药患者中，治疗前染色体上的CNV变化较少。NextGENe数据表明，CNV不仅在编码基因中观察到，而且在非编码基因中也观察到。仅在NAC耐药患者中鉴定出6个基因的CNV，包括HSF1、TMEM249、MROH1、GSTT2B、ABR和NOMO2。将NAC耐药患者中的这6个基因与癌症基因组图谱数据进行比较表明，总体改变频率为扩增，并且在染色体（Chr）8上的MROH1、TMEM249和HSF1基因中发现CNV的发生率最高（基于TCGA数据≥35%）。基于TCGA数据，生存分析显示化疗耐药患者的总生存率显著降低，并且与敏感样本相比，这三个基因的表达水平较高（所有P值均<0.0001）。使用WISECONDORX对Chr8进行的持续研究显示，NAC耐药患者在NAC治疗前存在CNV改变，但在NAC敏感个体中未观察到CNV变化。我们的研究结果表明，用于NIPT的低覆盖全基因组测序分析可以识别OC患者化疗前后ctDNA中的CNV。这些CNV在NAC敏感和耐药患者中有所不同，突出了这种方法在癌症患者管理中的潜在应用。
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