Grant Details
Grant Number: |
3U19CA214253-04S1 Interpret this number |
Primary Investigator: |
Haiman, Christopher |
Organization: |
University Of Southern California |
Project Title: |
Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Stress (RESPOND) |
Fiscal Year: |
2021 |
Abstract
Abstract – Project 2 of RESPOND (from Parent Grant)
Prostate cancer (PCa) incidence and mortality rates are highest in African American (AA) men compared to any
other racial/ethnic population. These long-standing racial/ethnic differences have yet to be explained. Genome-
wide association studies of PCa conducted in AA men have provided clear support for genetic differences in the
allelic architecture of PCa across populations and strong support for a genetic basis underlying population
differences in risk. There are also multiple lines of evidence to support a genetic contribution to aggressive/fatal
PCa including recent sequencing studies that have provided support for rare (<1%) protein coding variation in
contributing to aggressive PCa susceptibility. Cancer development and progression involves both the germline
and somatic genomes however to date, discovery and characterization efforts of germline risk loci and somatic
alterations in PCa have been conducted in isolation. We propose that large-scale efforts are warranted for the
discovery of common and rare genetic variation that contributes to aggressive PCa susceptibility in AA men. In
addition, through combining germline and somatic variation we expect to reveal novel biological mechanisms
underlying PCa aggressiveness. In this Project, we seek to identify genetic factors that are associated with PCa
aggressiveness in men of African ancestry. More specifically, in Aim 1, we plan to search for common germline
variants associated with PCa risk profiles in a case-case GWAS of 5,700 cases with high-risk (stage T3/T4 or
Gleason 8+ or PSA>20 ng/ml), 5,600 cases with intermediate-risk (stage T2b/T2c or Gleason 7 or PSA 10-20
ng/ml) and 3,800 cases with low-risk PCa (stage T1/T2a and Gleason ≤ 6 and PSA<10 ng/ml) from the
RESPOND cohort and the African Ancestry PCa Consortium (AAPC). In Aim 2, we will conduct exome
sequencing of these 15,000 PCa cases as well as 5,000 controls from AAPC to investigate the contribution of
rare variation on PCa aggressiveness. In both Aims 1 and 2, single variant and gene burden association testing
will be conducted by case-case comparisons of high- vs. low-risk disease, as well as by multi-nominal
polytomous logistic regression by risk category. In Aim 3, we will test the relationship between germline genetics,
lifestyle factors and somatic tumor characteristics in AA men and assess whether germline genetics and lifestyle
factors interact with somatic profiles and transcription states to distinguish PCa risk profiles. We expect these
integrated germline-risk factor-somatic analyses to reveal tumor subgroups and shared biological mechanisms
that are clinically important in the future prediction of disease progression and survival. We expect the findings
from this Project to significantly advance knowledge of susceptibility to aggressive PCa and racial/ethnic
disparities in PCa risk, and to guide the development of future preventive, early detection and prognostic
measures for AA men.
Publications
None. See parent grant details.