Spanish Researchers Sequence Non-infiltrating Bladder Cancer Exome

Identification of new genetic pathways and new genes involved in bladder cancer

Researchers at the Spanish National Cancer Research Centre (CNIO) performed the first exome sequencing for non-infiltrating bladder cancer. The results, published online on 13 October 2013 in the Nature Genetics, reveal new genetic pathways involved in the disease, such as cellular division and DNA repair, as well as new genes that might be crucial for understanding the biology of this illness and its evolution. The genetic signature of these patients may be a first step towards improving patient management.

A bladder tumour sample containing mutations in the STAG2 gene

A bladder tumour sample containing mutations in the STAG2 gene. Image credit: Spanish National Cancer Research Centre (CNIO)

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 tumours have a good prognosis, 70-80% five-year survival after diagnosis, and they do not infiltrate the bladder muscle at the time of diagnosis in around 80% of cases.

Despite this, many of the tumours recur, requiring periodic cytoscopic tumour surveillance. This type of follow-up affects patients' quality of life, at the same time as incurring significant healthcare costs.

The CNIO researchers coordinated by Francisco Real, head of the Epithelial Carcinogenesis Group and Nuria Malats, head of the Genetic and Molecular Epidemiology Group, have performed the first exome sequencing for non-infiltrating bladder cancer, the most frequent type of bladder cancer and the one with the highest risk of recurrence.

There is very little known about the biology of bladder cancer, which would be useful for classifying patients, predicting relapses and even preventing the disease, according to Cristina Balbás, a predoctoral researcher in Real's laboratory who is the lead author of the study.

The work consisted of analysing the exome from 17 patients diagnosed with bladder cancer and subsequently validating the data via the study of a specific group of genes in 60 additional patients. The researchers found up to nine altered genes that hadn't been described before in this type of tumour, and of these they found that STAG2 was inactive in almost 40% of the least aggressive tumours.

Some of these genes are involved in previously undescribed genetic pathways in bladder cancer, such as cell division and DNA repair. The researchers also confirmed and extended other genetic pathways that had previously been described in this cancer type, such as chromatin remodelling.

An unknown gene in bladder cancer

The STAG2 gene was been associated with cancer just over 2 years ago. There was little known about it, and nothing about its relationship to bladder cancer. Previous studies suggest it participates in chromosome separation during cell division, which is where it might be related to cancer, although it has also been associated with maintenance of DNA´s 3D structure or in gene regulation.

Contrary to what might be expected, the article reveals that tumours with an alteration in this gene frequently lack changes in the number of chromosomes, which indicates, according to Real, that "this gene participates in bladder cancer via different mechanisms than chromosome separation".

The authors have also found, by analysing tumour tissue from more than 670 patients, that alterations in STAG2 are associated, above all, with tumours from patients with a better prognosis.

How and why these phenomena work still needs to be discovered but the researchers predict that mutations in STAG2 and other additional genes that they showed to be altered could provide new therapeutic opportunities in some patient subgroups.

The research project was carried-out in close collaboration with other CNIO groups and units, including the Chromosome Dynamics Group, the Computational and Structural Biology Group, the Molecular Cytogenetics Group, as well as the Genomics Unit, and the Bioinformatics Unit. The National Genome Analysis Centre and the Hospital del Mar's Urology Service in Barcelona have also played an important role in the project, as have other Spanish hospitals and universities.

This work has been made possible thanks to the support of the Spanish Ministry of Economy and Competitiveness, the National Institute of Health Carlos III, the Spanish Association Against Cancer, the "la Caixa" Foundation, the Banco Santander Foundation, the European Union's 7th Framework Programme and the National Institute of Health in the USA.


C. Balbás-Martínez, A. Sagrera, E. Carrillo-de-Santa-Pau, et al. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.
Nature Genetics 2013 Oct 13. doi: 10.1038/ng.2799. [Epub ahead of print]