土耳其队列中膀胱癌的基因组图谱:揭示独特的突变谱及临床见解

Introduction: Bladder cancer is predominantly urothelial carcinoma, and the majority of patients present with non-muscle-invasive bladder cancer (NMIBC), which has a high recurrence rate, or muscle-invasive bladder cancer (MIBC), which is less common but has a high risk of metastasis. Tumor heterogeneity is a characteristic feature of bladder cancer and is associated with a high mutational burden. While chemotherapy is an important treatment modality, tumor heterogeneity ultimately leads to drug resistance and post-treatment recurrence. Identifying the molecular mechanisms underlying both NMIBC and MIBC tumors and identifying biomarkers and therapeutic targets is crucial for disease treatment. Advances in next-generation sequencing technology have enabled advances in understanding the molecular mechanisms of bladder cancer, defining tumor heterogeneity at the genomic levels, and enabling more clinically relevant targeted therapies and effective immunotherapies. This first project, initiated within the National Cancer Genome Project in Turkiye, aimed to discover novel cancer-specific variants through whole genome and transcriptome analyses of bladder cancer tumors. Methods: Sixty patients diagnosed with bladder cancer were included in the study. DNA was isolated from tumor tissue and blood samples taken from patients with a mass measuring 2 cm or larger on imaging and/or diagnostic cystoscopy who gave informed consent. Two patients were excluded from the study due to different diagnosis. Library preparation from the patients' genetic and somatic DNA samples was performed as recommended by the Illumina PCR-free tagmentation kit. Whole genome sequencing was performed on an Illumina Novaseq 6000 instrument. Somatic and germline variant calling analyses were performed using Illumina Dragen software. Results: Tumor and blood samples from 48 male (82.75%) and 10 female (17.25%) patients were analyzed. Of the patients, 24.13% (14 patients) reported non-smoking, while 31.03% reported a history of cancer in a first-degree relative. Clinic evaluation revealed 19 (32.75%) of the patients had MIBC, and 39 (67.24%) had NMIBC. The mean age was 67.4±10.54. Of the pathogenic variants obtained through filtering, 45.40% were determined missense mutations, and 22.95% were stop-gained. Most frequently mutated genes detected in our study population were TERT (52.54%), PTPRG (40.67%), and FGFR2/FGFR3 (38.98%), respectively. In previous studies, frequently mutated TP53 and KRAS mutations were observed at a rate of 37.28%, while MYC mutations were observed at a rate of 33.89% in our analysis. Conclusion: Despite the limited number of patients enrolled in the study, our results unveiled a unique mutational spectrum of bladder cancer in Turkiye. The resulting data will be a valuable resource for understanding drug resistance in bladder cancer and developing therapeutic approaches.