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New Knowledge Of Bladder Cancer Causing Genes Helps In Targeted Treatment

By Cathy Whims on September 15, 2014

It seems that cancer care is very simple; we just need to find the cancer causing mutated gene and turn it off or fix it.

But, unfortunately in rare cases cancer is caused by single mutated gene.

In most of the cases cancer is caused by many genes altering together.

Thus the challenge here is to find out which altering genes are to be blamed for which type of cancer.

An important step is taken to answer this question by a collaborative study between researchers at the University of Colorado Cancer Center and the National Cancer Institute (NCI).

The finding of study were published in today’s issue of the journal named “Clinical Cancer Research”

Dan Theodorescu, MD, PhD is the senior author of this paper, and he is also a professor of Urology and Pharmacology, director of the University of Colorado Cancer Center.

Michael Nickerson PhD is the lead author, and is a staff scientist and lead author from the National Cancer Institute.

Researchers of this study specifically examined a mutation-rich genome layer, which is called by the name exome of 54 bladder tumors. It was primarily taken from Caucasian patients.

This is first study which showed BAP1 gene alterations in 15% of tumors. BAP1 gene is probably a suppressor of tumor. Thus, BAP1 gene alteration in bladder cancers may be without an important check on the growth and survival of bladder cancer tissue. [Bladder Cancer Pathophysiology]

Somatic alterations of the BAP1 gene will result in development of high frequency tumors (10/14, 71 percent) with defects in genes encoding BRCA1 and BRCA2 pathway proteins, pathways which are implicated previously in breast and other types of cancers.

Secondly, highly independent genetic pathway was found in 69% of 54 tumors. In this genetic pathway, TERT promoter alterations were created, which is actually an effective second subset of bladder cancer.

These mutations in TERT promoter did not significantly correlate with somatic alterations of genes related to other cancers. This shows that this mutation in gene confers a presumed oncogenic benefit, which is independent of alterations in genes causing other cancers.

In 24% of tumors, frequent alteration on the gene named KDM6A is observed. According to the this study, enhancement of in vitro proliferation, in vivo tumor growth, and cell migration can be obtained with experimental depletion of KDM6A in human bladder cancer cells. This confirms the role of gene KDM6A as a cancer driver and tumor suppressor in bladder tissue.

Many other surprising relationships between the types of alterations in genes in bladder cancers were revealed by this study. Somatic alterations in BAP1 may correlate with papillary features in some types of bladder cancers.

This mutation is significantly more in Caucasian patients when compared to Chinese patients. This indicates that somatic alterations of BAP1 are influenced by ethnicity, lifestyle, or exposure.

Mutations in genes BAP1 and KDM6A were more significantly co-occurred in tumors. This indicates that these mutations most probably supply mutually reinforcing survival advantages to cancer cells.

Finally, just 4 genes encoding chromatin remodeling enzymes, BAP1, KDM6A, ARID1A, and STAG2 were altered in 46% of 54 tumors and demonstrate a major contribution from somatic mutations targeting chromatin remodeling functions in bladder cancer.

Dan Theodorescu said that with this study they were able to identify new bladder cancer subtypes, which are related to somatic and germline alterations of genes observed in patients tumor. These subtypes may be vulnerable to subtype-specific therapeutic targeting.

He added that many tumors had cells, which targeted mutation of BRCA DNA repair pathway. This indicates that these cells are more likely to reduce the efficiency of repairing DNA.

Michael Nickerson said that chemotherapeutic drugs should significantly sensitive on the tumor cells that cause DNA damage. This gives a real possible benefit to patients by getting targeted treatment.