Novel Complex Structural Variants and Epigenetic Alterations Link the Genomes of Prostate Cancer in African Americans with Outcome Disparity
Abstract
Prostate cancer is the most common non-skin cancer among men in the United States, with approximately >180,000 new cases diagnosed each year and >30,000 annual deaths attributable to the disease. Among the remarkable advances of the last two decades in diagnostic and treatment modalities for prostate cancer, one emerging aspect of the disease is study of the underlying genetic alterations and mechanisms of prostate cancer development and progression. Understanding of the genomics – the study of genes, their changes, structure, and function – of prostate cancer increases our understanding of the disease and informs new and promising treatment strategies. Notably, however, almost all the established knowledge of prostate cancer genomics is derived from the study of men of predominantly European heritage, notwithstanding the fact that American men of African descent (African Americans) experience prostate cancer twice as commonly as European Americans, with more aggressive disease and higher rates of death from advanced prostate cancers. It is known there are a variety of contributors to differential prostate cancer outcomes between African Americans and non-African Americans – including care delivery mechanisms, care access, and socioeconomic considerations – but also suggestions of differences in the underlying biology of African American tumors. Among these are possible differences in the alterations and behavior of cancer genes, which are the code cells used to make proteins and allow cells to function. In the proposed work, we will establish “Afro-NY,” the largest African American cohort of advanced prostate cancer specimens for genomic analysis. In doing so, we will contribute to the understanding of the biological reasons related to genes, both those in the tumor and inherited genes relevant to ancestry. Men of African heritage with lethal prostate cancer will have both tissue and blood collected for our analysis. The broad African diaspora is considered, with special focus on the groups represented in the New York City area and Western New York, including men from Puerto Rico, Jamaica, Dominican Republic, Haiti, West Indies, and directly from Africa. The risks to the participating individuals are minimal, as tissue collection is via standard of care biopsies or surgical resection that would otherwise be performed, as well as routine blood collection. Enhancing biological understanding via genomic analysis will help to define the genomic biology contributing to lethal prostate cancer in African American men and will improve the ability to rationally apply current and emerging therapies to these men as well as provide direction for the development of future treatments and diagnostic tools. Additionally, such knowledge may help to identify the highest risk types of prostate cancer, allowing treatment prior to the development of lethal cancer progression. Among the foci of the study will be analysis of genetic changes, either those that were inherited from parents or developed within the cancer cells alone, that affect the cell’s ability to repair damage to or defects in DNA, specifically in a process called homologous repair. It is known in prostate cancer that some men’s cells are unable to efficiently repair damage to DNA, making the cells susceptible to a class of drugs known as PARP inhibitors. Preliminary evidence suggests that defects in these pathways may be more common in men of African descent. Another strength of the proposed work that distinguishes it further from all prior efforts is the use by our group of unique computational tools to identify and categorize complex structural variants, which are a subtype of genomic alterations. These changes in the DNA disrupt the predicted, orderly nature of our genetic material, reflecting dysfunction of the cell’s growth and resulting in further alterations in normal function, including cancer development and spread. It is the intention of the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110762
Entities
People
- Juan Miguel Mosquera
Organizations
- United States Army
- Weill Cornell Medicine