Comprehensive Molecular Profiling of Prostate Cancer in African American Population: Unraveling Molecular Heterogeneity
Abstract
Prostate cancer is a complex disease with multiple tumors originating independently at different stages of growth. Although morphological differences have been well recognized, the underlying molecular complexity in each tumor foci has not been well studied. Tumor growth in each foci can be determined by independent driver molecular aberration(s). Understanding the molecular level of differences in each tumor foci would help to differentiate the patients who may undergo indolent or aggressive disease course. Further, morphological differences mostly help to understand the stage of the disease, but it is not possible to select appropriate targeted therapy. If different tumor foci carry different driver molecular aberrations, targeted therapy for single molecular aberrations may not yield the curative benefit to the patients. Conventionally, systematic sampling of large tumor foci or high Gleason grade tumor foci have been considered for various genetic and molecular studies. In this approach, smaller tumor foci with important driver molecular aberration and high metastatic potential can be easily missed. Therefore, using our novel approach, we propose to screen the entire prostate tissue to assess molecular differences in each tumor foci using well-characterized prostate cancer-specific molecular markers. Given the distinct ancestral background of the African American genome, there may be fundamental molecular differences that may drive the prostate cancer differently compared with other ethnic groups. Such differences are not studied in detail to understand the racial differences to offer better and more effective treatment options. Recent studies on in-depth molecular characterization of prostate cancer using next-generation sequencing approach revealed extensive genetic aberrations in different regions of prostate cancer. From these studies, driver or targetable aberrations within the spectrum of complex molecular aberrations are not identified other than revealing the genomic complexity of the disease. Therefore, in this study, we will for the first time attempt to characterize the entire prostate cancer landscape for molecular differences in each tumor foci in African American and compare with Caucasian prostate cancer to understand the racial disparity. We selected a panel of well-characterized prostate cancer driver molecular aberrations, including ERG, SPINK1, ETV1, ETV4, ETV5, and PTEN, to study the expression pattern on whole mount prostatectomy tissues (entire prostate tissue -- not sampling of specific tumor foci). In this approach, we will be able to study individual tumor foci, irrespective of the size, to assess the differences in the molecular aberrations and assess tumor molecular heterogeneity and correlate with clinical and biochemical parameters to understand the association with disease progression and clinical outcome. Our preliminary analysis of whole mount prostate tissues from 368 patients revealed hitherto unidentified molecular subsets of prostate cancer with more than one driver molecular aberration in different foci in a vast majority of patients. We observed cases with expression of ERG, SPINK1, and ETV1 in three distinct tumor foci in the same patient and associated PTEN deletion. We also observed many cases with two driver aberrations in two independent tumor foci and additional tumor foci negative for the selected markers. Such observations revealed the extent of genomic complexity of prostate cancer and confirm the independent origin of each tumor foci. Until now, analyses based on systematic sampling of dominant/index tumor nodule alone eluded the observation of these distinct subsets of patients. We are in the process of analyzing the clinical implications of such observations in each patient by considering the ethnic origin, and other clinical and biochemical parameters. Based on our encouraging preliminary studies, we would like to extend the analysis to at least
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610544
Entities
People
- Nallasivam Palanisamy
Organizations
- Henry Ford Health
- United States Army