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A Genomic and Epigenomic Atlas of Prostate Cancer in Asian Populations

Year : 2020 | Category : Human, Application: RNA Sequencing, Whole Genome Bisulfite Sequencing (WGBS)

Background
Prostate cancer remains the second most common cancer in men worldwide. Our understanding of the genomic definition and molecular complexity of prostate cancer has markedly improved over the past decade, owing to the advent of next-generation sequencing-based technologies and integrative genomics. However, until now most prostate cancer genomic data has been derived from western populations. In a recent pilot study, it was found that Chinese patients with prostate cancer featured genomic abnormalities that were distinct from those of western patients. Therefore, researchers sought to define the genomic underpinnings of prostate cancer in western and Chinese men and delivered the first Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA).

Research Pipeline

  • Samples selection: 210 prostate tumor samples and non-cancerous matched healthy prostate tissue from Chinese patients
  • Library preparation: human WGS (208 tumor/normal sample pairs), WGBS (187 pairs), RNA-seq (134 pairs), and miRNA-seq (105 pairs) libraries
  • Sequencing strategy: Illumina platform, PE 150 bp for hWGS & WGBS & RNA-seq, SE 50 bp for miRNA-seq
  • Bioinformatics Analysis:

Germline mutation and somatic mutation calling
Fusion gene detection
Detection of significantly mutated genes
Noncoding mutation detection
Allele-specific expression
Clonal analysis
DNA methylation level analysis
DMR detection and analysis
miRNA clustering
Pathway comparison and visualization

Results
1. Somatic mutation landscape
Based on data from human WGS, WGBS and RNA-seq, the genomic and epigenetic mutation landscape of the CPGEA cohort (Figure 1) was comprehensively presented. Systematic comparison with published data from 2,554 prostate tumors revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of western cohorts.

Figure 1. Molecular landscape of the CPGEA cohort.

2. FOXA1 mutation in Chinese prostate cancer
Notably, FOXA1 was the most highly mutated gene in the Chinese cohort (41%) (Figure 2a). The mutational spectrum of FOXA1 in tissue samples from Chinese and western patients exhibited notable differences (Figure 2b) and suggested that FOXA1 mutations in Chinese patients may drive oncogenesis by modulating AR signaling.

Figure 2. (a) Gene-level alteration frequencies in CPGEA and TCGA. (b) Mirror distribution plot of FOXA1 somatic SNVs in CPGEA primary (blue, top), western primary (blue, bottom), and western metastatic (orange, bottom) cancers.

3. DNA methylation abnormalities
To complement our analysis of genetic alterations in prostate cancer, DNA methylation in the CPGEA cohort was profiled by using WGBS. As expected, prostate cancer genomes were hypomethylated relative to normal prostate tissue (Figure 3a), and 5′ untranslated regions (UTRs) and CpG islands (CGIs) were relatively hypermethylated, whereas exons, introns and repetitive elements were hypomethylated.

Figure 3. DNA methylation abnormalities and subtypes of the CPGEA prostate cancer cohort.

4. Molecular subtypes of Chinese prostate cancer
The seven molecular classes defined by TCGA using oncogenic drivers were all present in the Chinese population, in different proportions. Integrative analysis with iCluster on CNA, gene expression and DNA methylation data defined four subtypes within the CPGEA patients (Figure 3b). Among them, subtype A was unique to CPGEA and was characterized by numerous CNAs affecting genes.

5. Convergence on common oncogenic pathways
By focusing on 12 important pathways and comparing the mutational landscape between Chinese and western prostate cancer, the overall pathway-level mutation burden was similar between Chinese and western primary tumors, whereas metastatic tumors exhibited a much higher burden.

Conclusion
This study presents a comprehensive atlas of prostate cancer in Chinese men (CPGEA), which deepens our understanding of the disease by incorporating ethnic background. Comparative analysis of samples from CPGEA and western cohorts revealed marked disparities in the mutational landscape of the same disease. Although ETS fusions have long been regarded as the flagship mutation for prostate cancer, this study indisputably positions FOXA1 mutations as the most prominent signature in Chinese populations. The frequency and unique pattern of FOXA1 mutations in Chinese prostate cancer underscores the need to investigate the oncogenic mechanism of individual mutations, as well as factors that predispose Chinese individuals to them.

Reference
Li J, Xu C, Lee HJ, et al. A genomic and epigenomic atlas of prostate cancer in Asian populations[J]. Nature, 2020, 580: 93–99.

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