Dr. Seth P. Lerner
Dr. Lerner is the director of Urologic Oncology and the Multidisciplinary Bladder Cancer Program at Baylor, and he currently directs its research initiative focused on discovering new approaches to diagnosing and treating bladder cancer based on molecular drivers of disease. For the past 7 years, he has also co-chaired the TCGA Analysis Working Group project for muscle-invasive bladder cancer.
The Cancer Genome Atlas Project
Launched in 2006 as a collaborative project between the National Cancer Institute and the National Human Genome Research Institute, TCGA has generated comprehensive maps of key genomic changes in 33 different types of cancer, including 10 rare tumors.
TCGA “is a quintessential example of team science,” Dr. Lerner said. The goal is “to create an atlas [of genomic changes] using an integrated multiplatform analysis and have all the data available in the public domain for researchers worldwide to use.”
TCGA has resulted in discoveries of novel cancer mutations and a better understanding of the pathways and mechanisms involved in cancer development. For example, Dr. Lerner and colleagues recently reported mutational changes in 58 genes in a group of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms.1 A high-mutation subset with a 5-year survival rate of 75% was identified by mutation signature clustering, whereas mRNA expression clustering yielded five expression-based subtypes that are associated with overall survival and may provide insights about stratified response to treatments.
This research “provided a more precise definition of expression-based molecular subtypes and mutation signature-
based subtypes. This has implications from the biological standpoint and potentially from the therapeutic standpoint by affecting the response to chemotherapy and immuno-oncology agents,” Dr. Lerner said. “Another fascinating finding is how noncoding RNA, including microRNA and long noncoding RNA, further modify the expression-based subtypes.”
Dr. Lerner recognized his lead collaborators on this research as A. Gordon Robertson, PhD, of Canada’s Michael Smith Genome Sciences Centre; Jaegil Kim, PhD, of the Broad Institute; David J. Kwiatkowski, MD, PhD, of Harvard Medical School; and John N. Weinstein, MD, PhD, of The University of Texas MD Anderson Cancer Center.
As far as the long-term implications of TCGA are concerned, Dr. Lerner said the project “identifies a number of different opportunities that are really important to pursue because there is a large group of patients who do not respond to available oncology agents. They represent an unmet need for the development of other therapeutic approaches, like targeted therapies.”
Validating and Applying the Data
Dr. Lerner sees the validation of data obtained from TCGA as a priority and challenge to the field.
“We have an obligation to use data from TCGA and research from other groups to conduct the necessary clinical trials so that we can get the right treatment for the right patient,” Dr. Lerner said. “This is the essence of precision medicine.”
According to Dr. Lerner, there are important questions that still need to be answered: “How do we take TCGA findings into the clinic and apply them to other patient populations—are these findings truly generalizable? How do we take next-generation sequencing into the clinic so that we can use that data in a user-friendly way?”
During his lecture on February 9, he will highlight some of the key findings of exome sequencing and how expression-based subtypes may be used in the context of clinical trials in the future.
“I’ll try to paint a picture of the future and how we can use these data to arrive at a precision medicine–based approach to treating invasive bladder cancer.”
−Jasenka Piljac Žegarac, PhD