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. 2020 Apr;19(4):2713-2720.
doi: 10.3892/ol.2020.11356. Epub 2020 Jan 28.

Changes in the gene mutation profiles of circulating tumor DNA detected using CAPP-Seq in neoadjuvant chemotherapy-treated advanced ovarian cancer

Tomoko Noguchi  1 , Kazuko Sakai  2 , Naoyuki Iwahashi  1 , Kaho Matsuda  1 , Hitomi Matsukawa  1 , Tamaki Yahata  1 , Saori Toujima  1 , Kazuto Nishio  2 , Kazuhiko Ino  1
Affiliations

Changes in the gene mutation profiles of circulating tumor DNA detected using CAPP-Seq in neoadjuvant chemotherapy-treated advanced ovarian cancer

Tomoko Noguchi et al. Oncol Lett. 2020 Apr.

Abstract

Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) is a novel ultrasensitive next-generation sequencing-based approach that is used to detect circulating tumor DNA (ctDNA). The aim of the present study was to compare the gene mutation profiles and blood tumor mutation burden (bTMB) measured between pre- and post-neoadjuvant chemotherapy (NAC), utilizing CAPP-seq for plasma ctDNA in patients with advanced ovarian cancer. The current study included 10 patients (6 NAC-sensitive and 4 NAC-resistant) clinically diagnosed as having stage III or IV ovarian cancer and were administered NAC between May 2017 and February 2019. The plasma ctDNA samples were collected at pre- and post-NAC, and comprehensive gene mutation analysis was performed using CAPP-seq. In 5 out of 6 NAC-sensitive cases, the variant allele frequency (VAF) of non-synonymous somatic mutations decreased following NAC. In 2 out of the 4 NAC-resistant cases, the VAF of non-synonymous somatic mutations increased, and new somatic mutations emerged following NAC. In regard to TP53 mutation, the rate of TP53 mutation in the NAC-resistant cases was significantly higher compared with NAC-sensitive cases. Finally, the bTMB decreased significantly after NAC treatment in the NAC-sensitive cases, even though there were no significant differences in the pretreatment bTMB levels between the NAC-sensitive and NAC-resistant cases. These results indicated that gene mutation can be profiled and monitored using liquid biopsy-based CAPP-Seq in patients with advanced ovarian cancer with NAC treatment, and TP53 mutation in the ctDNA and bTMB may be novel biomarkers that can be used for patient monitoring during NAC treatment.

Keywords: CAncer Personalized Profiling by deep sequencing; circulating tumor DNA; liquid biopsy; neoadjuvant chemotherapy; ovarian cancer.

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Figures

Figure 1.
Figure 1.
Profiling of non-synonymous somatic mutations and amplification detected in circulating tumor DNA obtained (A) pre-NAC and (B) post-NAC. The number in the box indicated VAF of gene mutations. Blue, non-synonymous somatic mutations in NAC-sensitive patient groups; Red, non-synonymous somatic mutations in NAC-sensitive patient groups; Green, copy number gain. NAC, neoadjuvant chemotherapy; VAF, variant allele frequency.
Figure 2.
Figure 2.
Changes of the allele fractions for somatic mutations detected using CAPP-Seq in NAC-sensitive cases. In Case 1, 2, 3, 4 and 6, the allele frequency of somatic mutations detected by CAPP-seq decreased during treatment. CAPP-Seq, Cancer Personalized Profiling by deep Sequencing; NAC, neoadjuvant chemotherapy.
Figure 3.
Figure 3.
Changes of allele fractions for somatic mutations detected using CAPP-Seq in NAC-resistant cases. In Case 7 and 10, allele frequency of somatic mutations detected using CAPP-seq (except SLC39A12 p.G436W in Case 10) increased during treatment. CAPP-Seq, Cancer Personalized Profiling by deep Sequencing; NAC, neoadjuvant chemotherapy.
Figure 4.
Figure 4.
Changes in the VAF of TP53 in the NAC-sensitive and -resistant patient groups. (A) Change of TP53 VAF decreased during treatment in NAC-sensitive groups (blue), whereas the change of TP53 VAF increased during treatment in NAC-resistant groups (red). (B) Significant difference in the change of TP53 VAF was observed between NAC-sensitive (blue) and NAC-resistant (red) patient group (P=0.01). The statistical analyses were performed using the Mann-Whitney U test. P<0.05 was considered to indicate a statistically significant difference. VAF, variant allele frequency; NAC, neoadjuvant chemotherapy.
Figure 5.
Figure 5.
(A) Changes of bTMB in NAC-sensitive and -resistant cases. bTMB at the baseline was calculated using CAPP-seq. No significant difference was observed between NAC-sensitive and -resistant patient groups. (B) Changes in the bTMB post-NAC compared with measured pre-NAC in NAC-sensitive patient groups. (C) Changes in the bTMB post-NAC compared with measured post-NAC in NAC-resistant patient groups. A significant decrease of bTMB during NAC was observed in NAC-sensitive patient groups (P<0.05). Statistical analyses were performed using the Mann-Whitney U test. P<0.05 was considered to indicate a statistically significant difference. bTMB, blood tumor mutation burden; NAC, neoadjuvant chemotherapy; CAPP-Seq, Cancer Personalized Profiling by deep Sequencing.
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