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Landscape of genomic alterations in Indian Urinary Bladder cancer patients

ABSTRACT: Urinary bladder is an open system and is under constant carcinogenic insults leading to chromosomal aberrations. Chronic retention of urine in the bladder is considered one of the reasons for initiation of bladder cancer. Here, we have explored the genomic alterations in Indian BlCa patients by CGH-SNP microarray. The microarray data (n=10) revealed several alterations throughout the genome. Genomic regions like 2p25.3 [chr2: 3557810-3575411], 4p16.3 [chr4: 656211-657032], 7p22.3 [chr7: 990730-1000575], 10q26.13 [chr10: 123137874-123148372], 16q24.3 [chr16: 88835825-88837868], 17p11.2 [chr17: 17477220-17506264], 19q13.33 [chr19: 49861971-49862491], 20q13.33 [chr20: 63406442-63415195; 63415195-63495407] etc. were found to be frequently (≥40%) amplified among the 10 BlCa samples. Regions like 2q37.2 [chr2: 235384329- 235479250], 8p23.3-11.21 [chr 8: 236477- 39291988], 10q21.1-26.3 [chr 10: 55309072- 133391562], 11p12 [chr 11: 37327799- 38803561], 12q24.31-24.33 [chr 12: 128515048- 133047983], and 13q13.3-34 [chr 13: 35583974- 113996673] etc. are identified as common deletion (30%). Chromosomal regions like 2p25.3, 16q24.3 and 20q13.33 showed the highest frequency of amplification (70%), whereas 2q37.2, 10q21.1, 11p12, 11q22.3, etc. showed the highest frequency of deletion (30%). Chromosome 7, 15 and 21 showed the least alterations in these samples. Almost a complete loss in 8p chromosomal arm (8p23.1-11.22), chromosome 11q (11q14.1-25) and chromosome 13 (13q13.3-34) were found in 30% of samples, signifying their plausible role in development of BlCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122514 | GEO | 2020/11/01

REPOSITORIES: GEO

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Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment

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Landscape of genomic alterations in Indian Urinary Bladder cancer patients

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