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Principal Investigator: Christopher Alan Haiman
Organization: UNIVERSITY OF SOUTHERN CALIFORNIA
Fiscal Year: 2024
Award: $634,844
Funding agency: National Cancer Institute
Abstract
There is strong evidence that prostate cancer (PCa) is a heritable phenotype. In addition to greater risk observed
in men with a family history of PCa, genome-wide association studies (GWAS) have identified over 400 common
independent risk variants, which explain ~40% of the familial risk. It is increasingly recognized that much of the
unknown heritability for PCa may also be due to variants of low minor allele frequency (<1%). While large, multi-
ancestry genome-wide reference panels (e.g., TOPMed) have been developed to facilitate studies of less
common alleles (down to 0.1%), they cannot be used to enumerate and accurately study very rare alleles that
can only be characterized via sequencing. Pathogenic variants in DNA repair pathway genes (e.g., BRCA2,
ATM, NBN, CHEK2, PALB2), identified through candidate gene studies, provide strong support for exceedingly
rare (<0.1%) protein coding variation contributing to overall PCa and aggressive disease susceptibility.
Unfortunately, we remain limited in our ability to comprehensively survey and study very rare variation genome-
or exome-wide due to high sequencing costs, limiting current sample sizes. Here, we propose to combine existing
whole-exome (WES) and whole-genome (WGS) sequence data from multi-ancestry biobanks and cohorts to
conduct the first, large-scale study of rare coding variation in PCa and to integrate tumor somatic and germline
mutation data to elucidate the biology of gene-risk associations. In Aim 1, we will leverage existing WES data for
>90,000 PCa cases (58,000 European ancestry, 20,000 African ancestry, 4,000 Asian ancestry and 6,700
Latino/Hispanic) and >500,000 controls within biobanks and cohorts in the US and UK and conduct exome-wide
analyses of overall PCa and aggressive disease phenotypes. In Aim 2, we will examine the combined effect of
rare coding variants and a polygenic risk score (PRS) on risk of overall PCa and aggressive disease and estimate
absolute risks for the combined effects of rare coding variants and PRS in prospective biobanks and cohorts
across populations. In Aim 3, we will integrate somatic tumor and germline variation data to inform genes and
biological pathways involved in PCa and aggressive disease. For this Aim, we have assembled a somatic
resource of >7,000 PCa patients with germline exome/PRS data and somatic mutation profiling from WES and
WGS studies, including >2,000 with transcriptomic data. We expect this study to provide the most comprehensive
and well-powered examination of rare coding variation in PCa across populations to date. Findings from this
study will have immediate clinical translation by informing personalized risk prediction and the development of
novel risk-based screening strategies for overall and aggressive PCa. Integrating germline and somatic data will
also define biological mechanisms that may be clinically important for understanding how to treat and prevent
PCa and lethal disease across populations.
Terms: <African><African ancestry><African descent><Allele Frequency><Alleles><Allelic Imbalance><Allelomorphs><Asian><Asian ancestry><Asian descent><BRCA2><BRCA2 gene><Biological><Biology><Breast Cancer 2 Gene><Breast Cancer Type 2 Susceptibility Gene><CDS1><CHEK2><CHEK2 gene><CHK2><Cancer Patient><Candidate Disease Gene><Candidate Gene><Cds1 kinase><Chk2 protein kinase><Clinical><Code><Coding System><DNA Repair Pathway><Data><Development><Diagnosis><Diathesis><Disease><Disease susceptibility><Disorder><Early Onset Gene Breast Cancer 2><European><European ancestry><Expression Signature><FANCD1><Family Medical History><Family Medical History Epidemiology><Family history of><Frequencies><GWA study><GWAS><Gene Expression Profile><Gene Frequency><Genes><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Risk><Genetic Susceptibility><Genetic Variation><Genetic defect><Genetic propensity><Genome><Germ Lines><Germ-Line Mutation><Germline Mutation><Gleason Grade><Gleason Grade for Prostate Cancer><Gleason Score><Gleason Score for Prostate Cancer><Gleason Sum><Gleason-SC><Hereditary Breast Cancer 2><Hereditary Mutation><Heritability><Heterogeneity><Hispanic><Individualized risk prediction><Inherited Predisposition><Inherited Susceptibility><Latino><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Metastatic Prostate Cancer><Minor><Modeling><Modification><Mutate><Mutation><PALB2><PALB2 gene><PP1425><Pathogenicity><Pathway interactions><Phenotype><Population><Predisposition gene><Prostate CA><Prostate CA Prevention><Prostate Cancer><Prostate Carcinoma Metastatic><Prostate malignancy><Prostatic Cancer><Protein Truncation><Proteins><RAD53><Reporting><Research Resources><Resources><Risk><Risk-associated variant><Sample Size><Somatic Mutation><Survey Instrument><Surveys><Susceptibility Gene><TOPMed><Testing><Time><Trans-Omics for Precision Medicine><Variant><Variation><allelic frequency><biobank><biologic><biorepository><brca 2 gene><check point kinase 2><checkpoint kinase 2><clinical translation><clinically translatable><cohort><cost><data diversity><density><developmental><disease phenotype><disease risk><disorder risk><diverse data><driver lesion><driver mutation><entire genome><exome><exomes><full genome><gene expression pattern><gene expression signature><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><genome mutation><genome scale><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome-wide><genomewide><genomewide association scan><genomewide association studies><genomewide association study><germ-line defect><germline variant><high risk><liability to disease><man><men><novel><partner and localizer of BRCA2><pathway><personalized risk prediction><polygenic risk score><predisposing gene><prevent><prevent prostate cancer><preventing><prospective><prostate cancer prevention><prostate cancer risk><rare allele><rare mutation><rare variant><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><screening><screenings><serine-threonine-protein kinase Chk2><somatic variant><susceptibility allele><susceptibility locus><susceptibility variant><transcriptional profile><transcriptional signature><transcriptomics><tumor><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>