Human bladder cancer: key genetic risk areas identified

jorgemata — Sun, 04 May 2008 09:42:04 -0700

Description

A genome-wide map of human bladder cancer has identified key genetic risk areas for the disease's development, according to a study published in Laboratory Investigation (http://www.nature.com/labinvest), which names six critical regions and offers new strategies for understanding the genetic changes underlying the progression of apparently normal tissue to cancer.

Bladder cancer is the sixth most common kind of cancer in the United States with 68,810 new cases and 14,100 deaths estimated in 2008. Like the majority of human cancers, bladder cancer arises from a number of spontaneous genetic changes that are challenging to pinpoint. These genetic changes are thought to be accompanied by microscopic changes in bladder tissue.

To identify factors that contribute to bladder cancer development, Bogdan Czerniak and colleagues from several Texan institutes mapped genome-wide changes across the entire surface of bladders containing cancer. They identified large regions of supposedly normal bladder tissue, containing expansions of cells with alterations in one or more of the six susceptible chromosomal regions. These 'forerunner genes' set the clock at an even earlier time point for the eventual development of cancer, which potentially includes environmental events that promote cancer.

This research provides important new insight into the earliest genetic origins of cancer, which could assist in the detection and prevention of bladder and other cancers.

The abstract says:

“The search for the genomic sequences involved in human cancers can be greatly facilitated by maps of genomic imbalances identifying the involved chromosomal regions, particularly those that participate in the development of occult preneoplastic conditions that progress to clinically aggressive invasive cancer. The integration of such regions with human genome sequence variation may provide valuable clues about their overall structure and gene content. By extension, such knowledge may help us understand the underlying genetic components involved in the initiation and progression of these cancers. We describe the development of a genome-wide map of human bladder cancer that tracks its progression from in situ precursor conditions to invasive disease. Testing for allelic losses using a genome-wide panel of 787 microsatellite markers was performed on multiple DNA samples, extracted from the entire mucosal surface of the bladder and corresponding to normal urothelium, in situ preneoplastic lesions, and invasive carcinoma. Using this approach, we matched the clonal allelic losses in distinct chromosomal regions to specific phases of bladder neoplasia and produced a detailed genetic map of bladder cancer development. These analyses revealed three major waves of genetic changes associated with growth advantages of successive clones and reflecting a stepwise conversion of normal urothelial cells into cancer cells. The genetic changes map to six regions at 3q22–q24, 5q22–q31, 9q21–q22, 10q26, 13q14, and 17p13, which may represent critical hits driving the development of bladder cancer. Finally, we performed high-resolution mapping using single nucleotide polymorphism markers within one region on chromosome 13q14, containing the model tumor suppressor gene RB1, and defined a minimal deleted region associated with clonal expansion of in situ neoplasia. These analyses provided new insights on the involvement of several non-coding sequences mapping to the region and identified novel target genes, termed forerunner (FR) genes, involved in early phases of cancer development.”

Biomedical Sciences and Biotechnology

Source

Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy. Tadeusz Majewski, Sangkyou Lee, Joon Jeong, Dong-Sup Yoon, Andrzej Kram, Mi-Sook Kim, Tomasz Tuziak, Jolanta Bondaruk, Sooyong Lee, Weon-Seo Park, Kuang S Tang, Woonbok Chung, Lanlan Shen, Saira S Ahmed, Dennis A Johnston, H Barton Grossman, Colin P Dinney, Jain-Hua Zhou, R Alan Harris, Carrie Snyder, Slawomir Filipek, Steven A Narod, Patrice Watson7, Henry T Lynch, Adi Gazdar, Menashe Bar-Eli, Xifeng F Wu, David J McConkey, Keith Baggerly, Jean-Pierre Issa, William F Benedict, Steven E Scherer and Bogdan Czerniak. Laboratory Investigation on-line May 05, 2008; doi:10.1038/labinvest.2008.27