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PBRM1 presents a potential ctDNA marker to monitor response to neoadjuvant chemotherapy in cervical cancer.

ABSTRACT: Neoadjuvant chemotherapy (NACT) is a therapeutic option for locally advanced cervical cancer (LACC) patients. This study was aimed to identify potential liquid biopsy biomarkers to monitor the NACT response. Through targeted next-generation sequencing (NGS) analysis of circulating tumor DNA (ctDNA) and tumor tissue DNA (ttDNA) taken from LACC patients undergoing platinum-based NACT, 64 genes with mutations emerge during NACT in the non-responders but none in the responders. Among them, the PBRM1, SETD2, and ROS1 mutations were frequently detected in the ctDNA and ttDNA of the non-responders, and mutant PBRM1 was associated with poorer survival of patients. In vitro, PBRM1 knockdown promoted resistance to cisplatin through boosting STAT3 signaling in cervical cancer cells, while it sensitized tumor cells to poly-ADP-ribose-polymerase inhibitor olaparib. These findings suggest that mutant PBRM1 is a potential ctDNA marker of emerging resistance to NACT and of increased sensitivity to olaparib, which warrants further clinical validation.

SUBMITTER: Li W

PROVIDER: S-EPMC10897912 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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PBRM1 presents a potential ctDNA marker to monitor response to neoadjuvant chemotherapy in cervical cancer.

Li Wenhan W Huang Yuhui Y Xiao Man M Zhao Jing J Du Shi S Wang Zehua Z Hu Sha S Yang Lu L Cai Jing J

iScience 20240209 3

Neoadjuvant chemotherapy (NACT) is a therapeutic option for locally advanced cervical cancer (LACC) patients. This study was aimed to identify potential liquid biopsy biomarkers to monitor the NACT response. Through targeted next-generation sequencing (NGS) analysis of circulating tumor DNA (ctDNA) and tumor tissue DNA (ttDNA) taken from LACC patients undergoing platinum-based NACT, 64 genes with mutations emerge during NACT in the non-responders but none in the responders. Among them, the <i>PB ...[more]

PMID: 38414861

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Project description:Concurrent chemoradiotherapy is the standard treatment for locally advanced uterine cervical cancer. However, effective neoadjuvant chemotherapy (NAC) can reduce tumor size and facilitate hysterectomy for locally advanced uterine cervical cancer. NAC treatment could improve the prognosis of patients with locally advanced cervical cancer. However, if NAC is ineffective, radiotherapy must be pursued. This causes a delay in initiating the core treatment and results in a worse prognosis. Therefore, the identification of predictive markers of whether NAC is likely to be effective for the treatment of locally advanced uterine cervical cancer could improve patient prognosis. Uncoupling protein 2 (UCP2) is broadly expressed in cancer cells, and suppresses mitochondrial reactive oxygen species (ROS) production. UCP2 contributes to both carcinogenesis and chemoresistance by reducing ROS. Downregulation of UCP2 results in significantly increased cell death following chemotherapy. The present study investigated the association between UCP2 expression and NAC effectiveness. A total of 58 patients with locally advanced uterine cervical cancer (stage IIIA or IIIB) treated at Osaka City University Hospital between April 1995 and March 2010 were examined. Tumor tissue samples were obtained by punch biopsy prior to NAC. UCP2 expression was examined immunohistochemically and scored using a weighted scoring system. Patients were divided into NAC effective (n=34) and ineffective (n=24) groups. Furthermore, UCP2 expression in human uterine cervical cancer cells was inhibited by genipin, and changes in cisplatin sensitivity were examined. UCP2 weighted score was higher in the NAC ineffective group than in the NAC effective group (P=0.038). Additionally, the low UCP2 expression group was more sensitive to NAC than the high UCP2 expression group (P=0.041). Sensitivity to cisplatin was significantly increased when UCP2 was inhibited in human uterine cervical cancer cells in vitro. UCP2 expression may become a predictive marker of whether NAC is effective for patients with locally advanced uterine cervical cancer, which could improve patient prognosis.

Dataset Information

PBRM1 presents a potential ctDNA marker to monitor response to neoadjuvant chemotherapy in cervical cancer.

Publications

PBRM1 presents a potential ctDNA marker to monitor response to neoadjuvant chemotherapy in cervical cancer.

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