Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer

Abstract

Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conduct whole-genome and targeted sequencing in urothelial bladder carcinomas (UBCs, the most common type of bladder cancer). Recurrent mutations in noncoding regions affecting gene regulatory elements and structural variations (SVs) leading to gene disruptions are prevalent. Notably, we find recurrent ADGRG6 enhancer mutations and FRS2 duplications which are associated with higher protein expression in the tumor and poor prognosis. Functional assays demonstrate that depletion of ADGRG6 or FRS2 expression in UBC cells compromise their abilities to recruit endothelial cells and induce tube formation. Moreover, pathway assessment reveals recurrent alterations in multiple angiogenesis-related genes. These results illustrate a multidimensional genomic landscape that highlights noncoding mutations and SVs in UBC tumorigenesis, and suggest ADGRG6 and FRS2 as novel pathological angiogenesis regulators that would facilitate vascular-targeted therapies for UBC.

Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers

“…The most frequently mutated gene, GPR126, is a G-protein coupled receptor that can bind to basement membrane protein type IV collagen [29]. The effects of the non-coding mutations in GPR126 have recently been investigated in 2 studies with apparently discordant results [21,22]. In a series of 196 patients, Wu et al reported that GPR126 mutations are more common in older patients and in NMIBC rel- ative to MIBC, and immunohistochemistry showed that UBCs with mutations expressed more GPR126 protein [21].…”

“…The effects of the non-coding mutations in GPR126 have recently been investigated in 2 studies with apparently discordant results [21,22]. In a series of 196 patients, Wu et al reported that GPR126 mutations are more common in older patients and in NMIBC rel- ative to MIBC, and immunohistochemistry showed that UBCs with mutations expressed more GPR126 protein [21]. They also demonstrated significantly worse overall survival for both NMIBC and MIBC patients with mutations.…”

“…WGS analyses have also identified non-coding variants in TBC1D12, LEPROTL1 and GPR126 [19,20]. In a WGS study of 65 UBCs, Wu et al confirmed the presence of recurrent non-coding mutations in GPR126, PLEKHS1, TBC1D12, WDR74 and LEPROTL1, and went on to validate GPR126 mutations in a further 196 UBCs [21]. Non-coding mutations in GPR126 have also been investigated in a cohort of 103 UBCs [22], and non-coding mutations in PLEKHS1 in a separate cohort of 81 UBCs [7].…”

“…In this study we use targeted deep-sequencing to analyse non-coding regions in GPR126, PLEKHS1, TBC1D12, LEPROTL1 and WDR74 in tumours from 302 UBC patients. These regions were selected on the basis of published reports, albeit in a limited number of UBCs in some cases, that they are frequently mutated [18][19][20][21][22]. However, these hotspots/putative hotspots have not been studied in combination in a large cohort of UBC patients.…”

Expression profiles of miRNAs in giant cell tumor of bone showed miR‐187‐5p and miR‐1323 can regulate biological functions through inhibiting FRS2

“…Dey's team launched a research that inhibition of FRS2 could block the PI3K/AKT signaling to induce apoptosis and suppress the proliferation and translocation in breast cancer . Song Wu et al figured out that FRS2 had an obviously upregulation in bladder cancer through whole‐genome sequencing, which could recruit endothelial cells and induce tube formation . Based on these studies, we conducted immunohistochemistry in GCTB tissues and adjacent normal tissues, and found that FRS2 was highly expressed in tumor tissues.…”