Genomic Instability Changes of Circulating Tumor DNA Reflect the Responses to Chemotherapy or Targeted Therapy in Advanced Gastric Cancer

Abstract

Background: Gastric cancer is characterized by frequent somatic copy number alterations (SCNV) and a high level of genomic instability. In this study, we investigated the genomic instability changes of circulating tumor DNA (ctDNA). Methods: A total of 101 plasmas and paired blood cells from 26 patients with AGC before (n = 26) and after (n = 75) drug treatment were collected. Plasma ctDNA was separated and assessed for SCNV by whole-genome sequencing (WGS), and the whole genome abnormality score (WGAS) was calculated. We next assessed the correlations between WGAS and therapeutic response. Findings: Genomic instability was observed in 20 of 26 patients (77%) prior to drug treatment. For patients with genomic instability prior to treatment, the response rate (55%, 11/20) was higher than that (17%, 1/6) of patients with stable genomes. Notably, genomic instability fluctuated during therapy, with 93% (14/15) of post-therapeutic ctDNAs showing low-genomic instability when sensitive to drug therapy and 52% (13/25) of ctDNAs with developed resistance to therapy showing high genomic instability. For ctDNAs with developed resistance, the genomic instability patterns were identical to those before treatment, but the instability level was lower than the pretherapeutic level. Interpretation: We found that genomic instability based on ctDNA could be used to predict and monitor therapeutic response in gastric cancer, although validation in a larger cohort will be necessary. Funding Statement: This work was supported by the National Key Research and Development Program of China (No. 2017YFC1308900, 2017YFC0908400) and the Beijing Municipal Science & Technology Commission Program (No. Z161100002616036). Declaration of Interests: The authors declare no conflict of competing interest. Ethics Approval Statement: This study was approved by the Medical Ethics Committee of Peking University Cancer Hospital, and written informed consent was obtained from all of the patients for their samples to be used in the future.