Shafqat F. Ehsan, Rui Wang, Xiaogang Wu, Tatiana V. Karpinets, Julianna K. Bronk, Chiraag Kapadia, Xingzhi Song, Andrew M. Futreal, Ann H. Klopp, Tim Harris, Jianhua Zhang, Lauren E. Colbert

Abstract A029: DDR pathway genes in CRT resistance: Insights from longitudinal whole exome sequencing in cervical cancer

  • Cancer Research
  • Oncology
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Abstract Background: Cervical cancer patients undergoing CRT face a 40% mortality rate, and the genetic underpinnings of radiation response variability remain under-explored. Our laboratory has developed a noninvasive cervical swab biopsy method, complemented by a custom computational pipeline that facilitates longitudinal whole-exome sequencing (WES) from samples with minimal tumor purity. This investigation used the pipeline for the identification of persistent or clonally expanded genes during CRT. The aim is to identify genes and pathways associated with radiation resistance. Methods: Tumor swabs from 30 cervical cancer patients were collected at baseline (week 1) and CRT completion (week 5) paired with corresponding buccal samples. We performed whole exome sequencing, adjusting for calculated tumor purity with strict mutation calling using several tools. Results: Our analysis revealed genes in known DNA damage and repair (DDR) pathways, in addition to unique genes not previously associated with DDR and radiation response, including BAGE3, CGREF1, XRCC5, ATM, LINP1, etc. Future work will include validation of these identified genes in vitro radiation sensitivity screening and validation in large-scale datasets, such as The Cancer Genome Atlas, and network and pathway analysis. Discussion: This exploratory analysis suggests that serial sequencing during chemoradiation to identify novel radiation sensitization targets is feasible and further study is needed. Their recurring involvement in DDR pathways underscores their pivotal role in CRT resistance mechanisms. Conclusions: Through longitudinal WES, we've deepened the understanding of CRT resistance and flagged potential targets for improved radiosensitization strategies in cervical cancer. Future Directions: We are moving towards experimental validation of these genes in patient-derived organoids using CRISPR/Cas9 and CyTOF. Additionally, we'll be screening FDA-approved drugs to pinpoint effective radiosensitizers. A major upcoming effort is the development of a CRT resistance map, enhanced by machine learning, promising a transformative impact on cervical cancer treatment. Citation Format: Shafqat F. Ehsan, Rui Wang, Xiaogang Wu, Tatiana V. Karpinets, Julianna K. Bronk, Chiraag Kapadia, Xingzhi Song, Andrew M. Futreal, Ann H. Klopp, Tim Harris, Jianhua Zhang, Lauren E. Colbert. DDR pathway genes in CRT resistance: Insights from longitudinal whole exome sequencing in cervical cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A029.

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