Integration of Germline and Somatic Immunogenomic Analyses in African-American Prostate Cancer
Abstract
Background: African-American (AA) men are more likely to be diagnosed with advanced prostate cancer (PCa) and are nearly 2.5 times more likely to die from the disease than Non-Latino White (WH) men. Some of this disparity may be accounted for by differences in access to care or social determinants of health; however, there is emerging evidence of significant biological differences between PCa arising in AA and WH men. Though enormous resources have been deployed for molecular phenotyping of WH PCa cohorts, progress on molecular characterization of AA tumors will be critical for realizing the promise of precision medicine equally across all populations. In recent years, our research groups at Johns Hopkins University (JHU) and Northshore have studied the molecular and immune landscape of PCa arising in AA men. We have assembled a large cohort of surgically treated AA primary PCa cases with long-term follow-up for metastasis. Enriched for high-risk disease, this cohort has been profiled for genomic alterations specific to the tumor, as well as for the immune environment in the tumor, and we have been among the first to integrate these data. In parallel, we have worked on discovering the patient-level (germline) genetic alterations in over 1,300 surgically treated cases of AA primary PCa to characterize novel genetic drivers of aggressive AA PCa. Though we have made substantial progress to date, the next challenge is to integrate these two datasets: the patient-level genetic data and the tumor-level data (including tumor-specific genetic alterations and the tumor immune microenvironment). For the known genetic variants associated with risk of PCa in AA patients, little is understood about how they may associate with somatic molecular alterations, immune microenvironment, or tumor pathology. Hypothesis/Objective: Here, we hypothesize that the study of primary tumors from AA PCa patients with defined patient-level (germline) alterations is critical to elucidate the mechanism by which AA genetic variants confer increased risk of lethal PCa and/or modify the immune milieu. Specific Aims: In Aim 1, we will study the tumor characteristics in AA men carrying a specific genetic alteration known to be associated with risk of PCa. Located on chromosome 8q24, this alteration occurs in ~6% of men of African ancestry and is among the most important common risk variants yet discovered in AA. This SNP lies in an intergenic region containing multiple genes, including some non-coding genes whose expression is elevated in PCa and linked to expression of the nearby oncogene c-MYC. Here, we will test the association of this 8q24 variant with (1) pathologic features and clinical outcomes in 1,300 surgically treated AA patients and (2) somatic molecular alterations (including MYC gene copy number gain) or expression of MYC or the adjacent non-coding genes in 200 AA tumors, with validation of significant findings in tumor tissue from a subset of 1,300 cases described above. In Aim 2, we will assess whether the number of germline copies of a gene in an AA patient is associated with the immune tumor microenvironment. Patients of different ancestries often have different numbers of copies of immune-related genes, which can increase or decrease expression of these genes in every cell in the patient’s body. The pro-inflammatory chemokine gene CCL3L1, a chemoattractant for T-cells and macrophages, has increased germline copy number in patients of African vs. European ancestry, with reproducibly associated increased gene expression in AA prostate tumors. We will assess germline copy number of CCL3L1, CCL3, and CCL4 in the 1,300 AA patient cohort and the 200/200 AA/WH patient cohorts. Then we will test whether copy number is associated with (1) clinical-pathologic characteristics after prostatectomy (1,300 patient cohort); (2) tumor mRNA expression of CCL3L1, CCL3, and CCL4 (200/200 patient cohort); or (3) quantitative immune profil
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210167
Entities
People
- Tamara L Lotan
Organizations
- Johns Hopkins University
- United States Army