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.
Description:
ADDITIONAL FILE 1: FIGURE S1. Concordant SV call generation from Manta
and GRIDSS. FIGURE S2. Summary of SVs in each type, compared to other
studies. FIGURE S3. CIRCOS plot of hyper-SV mutated tumours. FIGURE S4. The spread of SV breakpoints and samples in each 1 Mbp genomic bin. FIGURE S5. TMPRSS2-ERG fusion with interstitial region retention.
TABLE S1. Clinical and pathological characteristics of 180 prostate cancer
patients included in this study. TABLE S2. Biallelic assessment of CDK12
in hyper-duplicated samples. TABLE S3. Biallelic assessment of BRCA2 in
hyper-deleted samples.
ADDITIONAL FILE 2: TABLE S4. Summary of gene fusions identified from SVs.
ADDITIONAL FILE 3: TABLE S5. SV calls resulting in gene fusions.
DATA AND MATERIALS AVAILABILITY : The datasets analysed in this study were obtained and accessible through
Jaratlerdsiri et al [6], with sequence data deposited in the European GenomePhenome Archive (EGA; https://ega-archive.org) under overarching accession
EGAS00001006425 and including the Southern African Prostate Cancer Study
(SAPCS) Dataset (EGAD00001009067) and Garvan/St Vincent’s Prostate Cancer
Database (EGAD00001009066). The computational code used to analyse SV
subtypes, SV hotspots and gene fusions is available on GitHub [68].