Integrative comparison of the genomic and transcriptomic landscape between prostate cancer patients of predominantly African or European genetic ancestry

Autor: Yi Fan, Janos L. Tanyi, Junjie Jiang, Timothy R. Rebbeck, Jiao Yuan, Zhongyi Hu, Yutian Pan, Rugang Zhang, Mu Xu, Tianli Zhang, Youyou Zhang, Meixiao Long, Xiaowen Hu, Kevin H. Kensler, Lin Zhang, Kathleen T. Montone
Rok vydání: 2020
Předmět:
Male
Cancer Research
Oncogene Proteins
Fusion
Gene Expression
QH426-470
Biochemistry
Cohort Studies
Transcriptome
Prostate cancer
0302 clinical medicine
Basic Cancer Research
Medicine and Health Sciences
RNA-Seq
Genetics (clinical)
Genetics
0303 health sciences
biology
Prostate Cancer
Incidence
Prostate Diseases
Nuclear Proteins
Genomics
Middle Aged
3. Good health
Nucleic acids
Gene Expression Regulation
Neoplastic
Oncology
Receptors
Androgen
Chromatin Immunoprecipitation Sequencing
RNA
Long Noncoding
Anatomy
Transcriptome Analysis
Research Article
Urology
Genetic genealogy
White People
03 medical and health sciences
Cancer Genomics
Exocrine Glands
Genomic Medicine
Biomarkers
Tumor
medicine
Humans
PTEN
Non-coding RNA
Molecular Biology
Gene
Genotyping
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Genome
Human
PTEN Phosphohydrolase
Biology and Life Sciences
Cancers and Neoplasms
Computational Biology
Prostatic Neoplasms
Human Genetics
Health Status Disparities
Comparative Genomics
Genome Analysis
medicine.disease
Human genetics
Black or African American
Repressor Proteins
Genitourinary Tract Tumors
Mutation
Expression quantitative trait loci
Long non-coding RNAs
biology.protein
RNA
Prostate Gland
030217 neurology & neurosurgery
Zdroj: PLoS Genetics
PLoS Genetics, Vol 16, Iss 2, p e1008641 (2020)
ISSN: 1553-7404
Popis: Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10−03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10−02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10−03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10−48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10−125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes.
Author summary Disparities in cancer defined by self-identified race or ethnicity have been a long-standing and persistent challenge. It is well documented that certain racial and ethnic populations in the US experience higher incidence of specific cancer types, higher incidence of aggressive cancers, and higher mortality. The Cancer Genome Atlas (TCGA) data resource contains multi-omic profiles and clinical annotations of large-scale samples, and therefore serves as an excellent resource for the evaluation of the relationship between genetic ancestry and genomic alterations in cancers. In this study, we performed a cancer type specific analysis of the influence of genetic ancestry on genomic alterations in prostate cancers–a malignancy for which there are some of the largest cancer disparities by race and ethnicity in the US. We found that there is substantial heterogeneity in the genomic alterations and transcriptomic dysregulation occurring in men of African (AA) and European (EA) ancestry in the TCGA prostate cancer cohort. SPOP mutations, TMPRSS2-ERG fusions, PTEN deletions/losses, immune signaling, and expression of non-coding RNAs were identified as potential contributors to prostate cancer racial disparities. Our comprehensive characterization of genetic ancestry and genomic/transcriptomic alterations would provide new insight into the biology of prostate cancer racial disparities in the AA population.
Databáze: OpenAIRE
Externí odkaz: