Loss of STAG2 Gene Improves Bladder Cancer Prognosis

Results obtained during a study conducted by Spanish cancer researchers indicated that mutations of the STAG2 (stromal antigen 2) gene suppressed development of urothelial bladder cancer (UBC) by acting through mechanisms that were different from the gene's role in preventing aneuploidy.

The protein encoded by the STAG2 gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Targeted inactivation of this gene results in chromatid cohesion defects and aneuploidy, suggesting that genetic disruption of cohesin is a cause of aneuploidy in human cancer.

Bladder cancer represents a serious public health problem in many countries, especially in Spain, where 11,200 new cases are recorded every year, one of the highest rates in the world. The majority of these tumors have a good prognosis for five-year survival after diagnosis, and most have not infiltrated the bladder muscle at the time of diagnosis.

Investigators at the Spanish National Cancer Research Center (Madrid) performed an exome sequencing study to identify genes linked to noninfiltrating bladder cancer. They analyzed the exome from 17 bladder cancer patients and subsequently validated the data by the analyzing a specific group of genes in 60 additional patients.

Results published in the October 13, 2013, online edition of the journal Nature Genetics revealed a set of previously unidentified genes mutated in these tumors coding for proteins involved in chromatin modification (MLL2, ASXL2, and BPTF), cell division (STAG2, SMC1A, and SMC1B) and DNA repair (ATM, ERCC2, and FANCA). STAG2 was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or grade, and its loss was associated with improved outcome.

Loss of STAG2 expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. Insertion of STAG2 into nonexpressing cells led to reduced colony formation. Furthermore, analysis of bladder tumor tissue from more than 670 patients indicated that alterations in STAG2 were associated with a better prognosis.

"We found up to nine altered genes that had not been described before in this type of tumor, and of these we found that STAG2 was inactive in almost 40% of the least aggressive tumors," said senior author Dr. Francisco X. Real, head of the epithelial carcinogenesis group at the Spanish National Cancer Research Centre. "Some of these genes are involved in previously undescribed genetic pathways in bladder cancer, such as cell division and DNA repair; also, we confirmed and extended other genetic pathways that had previously been described in this cancer type, such as chromatin remodeling."

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Spanish National Cancer Research Center