Landscape of genomic alterations in patients with chemoradiation resistant cervical cancer using whole-genome sequencing.
Authors: Kumar Prashant , Chauhan Richa , Trivedi Vinita , Dhawale Ekta R. , Sambath Janani , George Irene A. , Manda Srikanth S. , Ariyannur Prasanth , Kommu Raja Sekhar , Singh Manisha , Venkataramanan R. 
Published: July 2024

e17531 Background: Cervical cancer is a pressing global health concern and ranks as the second most prevalent female malignancy in India. Unfortunately, 80% of cases are diagnosed at locally advanced stages, leading to significant morbidity and mortality. Standard treatment for locally advanced cervical cancer involves concurrent pelvic radiotherapy and chemotherapy (CCRT). However, a substantial 30%-40% of patients experience CCRT treatment failure. The genomic alterations owing to CCRT resistance are largely unknown. This pilot study aims to identify genomic alterations associated with differential responses to concurrent chemoradiotherapy in cervical cancer patients. Methods: We collected 36 fresh tissue biopsies along with 5 ml of blood from stage IIIB cervical cancer patients. From the total of 36 cervical cancer patients, based on RECIST (Response evaluation criteria in solid tumors) criteria 19 patients were classified as responders and 17 patients were categorized as non-responders to CCRT. Genomic DNA was extracted from both tumor tissue and paired blood samples. Subsequently, whole genome sequencing was performed using the Novaseq 6000 platform, achieving a sequencing depth of 30x-50x coverage with 2x150bp paired reads. The data was further analyzed for Single Nucleotide Variants (SNVs), Copy Number Alterations (CNAs), Structural Variants (SVs), and mutational signatures. Results: In our study, we identified several notable mutated genes, with MUC12 (35%), MUC4 (31%), MACF1 (27%), and OBSCN (27%) being the most prominent. The mutational spectrum encompassed well-known significantly mutated genes such as FBXW7, SPEN, PIK3CA, KMT2C, KMT2D, ARID1A, and STK11, as well as potential novel candidates, genes not previously associated with cervical cancer, such as PKHD1L1, PLEC, and LRP1B. Pathway analysis revealed that several signaling pathways were enriched in cervical cancer, including Notch signaling, Hippo signaling, and RTK/RAS signaling pathways. Mutational signature analysis revealed a prevalence of APOBEC mutagenesis pattern. Copy number alterations displayed amplifications in regions such as 3q, 9p, 14q, and 11p which encompass genes like PIK3CA, JAK2, CD274, and AKT1. Comparative analysis of genomic alterations between chemoradiation resistant and sensitive patients identified mutations in genes related to Notch signaling and TNF signaling, which were exclusively present in the non-responder group. Conclusions: This study represents an initial attempt to understand the genomic landscape of cervical cancer in Indian population using whole genome sequencing approach and its association with responses to CCRT. These findings not only pave the way for further research but also hold promise for the development of targeted therapies, offering potential enhancements in the management of chemoradiation-resistant cervical cancer patients.