Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers

Abstract

Background African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub-Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation. Methods Using whole genome sequencing and best practice workflows, we performed a comprehensive analysis of SVs for 180 (predominantly Gleason score ≥ 8) prostate tumours derived from 115 African, 61 European and four ancestrally admixed patients. We investigated the landscape and relationship of somatic SVs in driving ethnic disparity (African versus European), with a focus on African men from southern Africa. Results Duplication events showed the greatest ethnic disparity, with a 1.6- (relative frequency) to 2.5-fold (count) increase in African-derived tumours. Furthermore, we found duplication events to be associated with CDK12 inactivation and MYC copy number gain, and deletion events associated with SPOP mutation. Overall, African-derived tumours were 2-fold more likely to present with a hyper-SV subtype. In addition to hyper-duplication and deletion subtypes, we describe a new hyper-translocation subtype. While we confirm a lower TMPRSS2-ERG fusion-positive rate in tumours from African cases (10% versus 33%), novel African-specific PCa ETS family member and TMPRSS2 fusion partners were identified, including LINC01525, FBXO7, GTF3C2, NTNG1 and YPEL5. Notably, we found 74 somatic SV hotspots impacting 18 new candidate driver genes, with CADM2, LSAMP, PTPRD, PDE4D and PACRG having therapeutic implications for African patients. Conclusions In this first African-inclusive SV study for high-risk PCa, we demonstrate the power of SV interrogation for the identification of novel subtypes, oncogenic drivers and therapeutic targets. Identifying a novel spectrum of SVs in tumours derived from African patients provides a mechanism that may contribute, at least in part, to the observed ethnic disparity in advanced PCa presentation in men of African ancestry.

Optical genome mapping reveals balanced and unbalanced genetic changes associated with tumor‐forming potential in an early‐stage prostate cancer epithelial subline (M2205)

“…In this study, the region of complexity on chromosome 8 showed genes that were disrupted by the abnormalities ( DEPTOR, ENPP2, EXT1, F13A1A, SLC51B, TOP1 , and TRAPPC9 ), and allowed for the recognition of two gene fusion events ( DEPTOR::TRAPPC9 and EXT1::BC052578 ). The complex structural findings involving chromosome 8 are of particular interest because: (1) this is a change that was acquired coincident with the tumor‐forming ability of this subline; and (2) this region (8q24) has been reported to have a nonrandom association with prostate cancer in Black patients (Gong et al., 2022; Han et al., 2016; Jaratlerdsiri et al., 2018; Walavalkar et al., 2020). Gains/amplification of MYC have been associated with prostate cancer, being more frequently noted in late‐stage tumors derived from African men (Jaratlerdsiri et al., 2018; Jenkins et al., 1997; Shim et al., 2022; Silva et al., 2016).…”

African inclusion in prostate cancer genomic studies provides the first glimpses into addressing health disparities through tailored clinical care

“…On 31 August 2022, we published two papers simultaneously in Nature and Genome Medicine, aimed at providing a first glimpse into the genomic contribution to PCa health disparity for men from Sub‐Saharan Africa. 3 , 4 Generating deep sequenced blood and matched tumour genome data for 183 largely treatment naïve and clinicopathologically aggressive disease‐presenting patients, besides 53 Australians and seven Brazilians, the study included 123 South Africans. Through ancestral interrogation of inherited variation, patients were further genetically classified as African ( n = 113; all South African), European ( n = 61; 53 Australian, five South African, and three Brazilian) or Admixed ( n = 9; five South African and four Brazilian).…”

“…Till now, we have had no understanding of the knowledge gained from extensive PCa genome sequencing efforts, which would be of clinical relevance to men from Sub‐Saharan Africa. On 31 August 2022, we published two papers simultaneously in Nature and Genome Medicine, aimed at providing a first glimpse into the genomic contribution to PCa health disparity for men from Sub‐Saharan Africa 3,4 . Generating deep sequenced blood and matched tumour genome data for 183 largely treatment naïve and clinicopathologically aggressive disease‐presenting patients, besides 53 Australians and seven Brazilians, the study included 123 South Africans.…”

Survival Outcomes by Race and Ethnicity in Veterans With Nonmetastatic Castration-Resistant Prostate Cancer

“…In addition, Black men with local-stage disease face a higher risk of progression after treatment . Many explanations have been proposed, with various molecular, genetic, environmental, and even psychological factors suggested as causes of these disparities …”

“…12 Many explanations have been proposed, with various molecular, genetic, environmental, and even psychological factors suggested as causes of these disparities. [13][14][15][16][17][18][19][20][21][22][23] Prostate cancer is a notably heterogeneous disease, with the implications for a patient's quality of life, survival, and need and type of treatment all depending on the disease stage and biological characteristics. Patients with newly diagnosed low-risk disease can be simply monitored for disease progression; this approach spares them from the adverse effects of treatment without affecting their survival.…”