Prostate Cancer in Southern Africa: Does Africa Hold Untapped Potential to Add Value to the Current Understanding of a Common Disease?

Hayes, Vanessa M.; Bornman, M. S.

doi:10.1200/jgo.2016.008862

Cited by 22 publications

(30 citation statements)

References 46 publications

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“…Representing the earliest diverged contemporary human population (13), our African participants all share an ancient KhoeSan (range, 2.5%-41.7%) along with a predominant Bantu heritage (range, 42.1%-97.5%) and therefore an exasperated inherited genomic variation, averaging 5.5 million small variants (4,432,761 SNVs and 1,131,271 indels; Table 1), 1.3-fold greater than observed for the APCRC EUR . We found the largely Europeanderived prostate cancer risk alleles (7) to be fixed (6/100) or common in SAPCS (78/100 allele frequency >0.1; 48/100 !0.5; Supplementary Table S7) and unlikely to be risk-predicting for this population, as previously suggested (14). Missense mutations in high penetrance genes were found to be common, compared with an internal dataset of nine Southern African genomes (Supplementary Table S7), and/or previously predicted as nononcogenic ( Supplementary Table S8).…”

Section: Germline Variation and Prostate Cancer Risk Allelessupporting

confidence: 68%

“…Inclusion criteria included a histopathologic Gleason score !8 prostate cancer (high-risk disease) and self-identified African ancestry, classified as Southern Bantu (n ¼ 4) or South African Coloured (n ¼ 2; Table 1). African heritage was confirmed using 103,670 autosomal ancestry informative genetic markers and ancestral fractions defined as African-Bantu (Yoruba), African-KhoeSan (Ju/'hoansi), European (CEPH-Utah), and Asian (Han Chinese), as previously described (13,14). The study was reviewed and approved by the University of Pretoria Human Research Ethics Committee (HREC #43/2010), including US Federal-wide Assurance (FWA00002567 and IRB00002235 IORG0001762).…”

Section: Patient Description Genetic Ancestries and Ethicsmentioning

confidence: 99%

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Whole-Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naïve, High-Risk Prostate Cancer

et al. 2018

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African American men are more likely than any other racial group to die from prostate cancer. The contribution of acquired genomic variation to this racial disparity is largely unknown, as genomic from Africa is lacking. Here we performed the first tumor-normal paired deep whole-genome sequencing for Africa. A direct study-matched comparison between African- and European-derived, treatment-naïve, high-risk prostate tumors for 15 cases allowed for further comparative analyses of existing data. Excluding a single hyper-mutated tumor with 55 mutations per megabase, we observed a 1.8-fold increase in small somatic variants in African- versus European-derived tumors (P-value = 1.02e-04), rising to 4-fold when compared with published tumor-matched data. Furthermore, we observed an increase in oncogenic driver mutations in African tumors (P-value = 2.92e-03); roughly 30% of impacted genes were novel to prostate cancer, and 79% of recurrent driver mutations appeared early in tumorigenesis. Although complex genomic rearrangements were less frequent in African tumors, we describe a uniquely hyper-duplicated tumor impacting 149 transposable elements. Comparable to African Americans, ERG fusions and PIK3CA mutations were absent and PTEN loss less frequent. CCND1 and MYC were frequently gained, with somatic copy number changes more likely to occur late in tumorigenesis. In addition to traditional prostate cancer gene pathways, genes regulating calcium ion-ATPase signal transduction were disrupted in African tumors. Although preliminary, our results suggest that further validation and investigation into the potential implications for elevated tumor mutational burden and tumor-initiating mutations in clinically unfavorable prostate cancer can improve patient outcomes in Africa.

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Section: Germline Variation and Prostate Cancer Risk Allelessupporting

confidence: 68%

Section: Patient Description Genetic Ancestries and Ethicsmentioning

confidence: 99%

Whole-Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naïve, High-Risk Prostate Cancer

et al. 2018

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“…Although data on prostate cancer treatment in Africa is under-reported [49], it is known that African men disproportionately suffer from prostate cancer compared to men from other parts of the world [50] and African American men have the highest rate of prostate cancer morbidity and mortality compared to men from any other race or ethnicity in the USA [51]. Socioeconomic and genetic factors are among the suggested explanations for such high burden of prostate cancer in African men [52]. There is no evidence that prostate cancer in African Americans is more virulent than in Caucasians [53].…”

Section: Drug-response Related Snps With High Mafs In Individual Popumentioning

confidence: 99%

Heterogeneity in the distribution of 159 drug-response related SNPs in world populations and their genetic relatedness

2020

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Interethnic variability in drug response arises from genetic differences associated with drug metabolism, action and transport. These genetic variations can affect drug efficacy as well as cause adverse drug reactions (ADRs). We retrieved drug-response related single nucleotide polymorphism (SNP) associated data from databases and analyzed to elucidate population specific distribution of 159 drug-response related SNPs in twenty six populations belonging to five super-populations (African, Admixed Americans, East Asian, European and South Asian). Significant interpopulation differences exist in the minor (variant) allele frequencies (MAFs), linkage disequilibrium (LD) and haplotype distributions among these populations. 65 of the drug-response related alleles, which are considered as minor (variant) in global population, are present as the major alleles (frequency �0.5) in at least one or more populations. Populations that belong to the same super-population have similar distribution pattern for majority of the variant alleles. These drug response related variant allele frequencies and their pairwise LD measure (r 2) can clearly distinguish the populations in a way that correspond to the known evolutionary history of human and current geographic distributions, while D' cannot. The data presented here may aid in identifying drugs that are more appropriate and/or require pharmacogenetic testing in these populations. Our findings emphasize on the importance of distinct, ethnicity-specific clinical guidelines, especially for the African populations, to avoid ADRs and ensure effective drug treatment.

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“…The replication of the association of chromosome 8q24 variants with increased PCa risk in African populations indicates the possible role of this genomic region in the higher burden of PCa in men of African ancestry ( Okobia et al 2011 ; Adeloye et al 2016 ). It is also found that the incidence and mortality rates are 1.6 - and 2.4 - fold greater for African Americans than for European Americans ( Hayes and Bornman 2018 ). In the USA, the incidence of PCa observed in American Indian/Alaska natives is 46.9 per 100,000, in Asian/Pacific Islanders is 52.4 per 100,000, and in Whites is 93.9 per 100,000.…”

mentioning

confidence: 99%

“…In prostate cancer (PCa), ethnicity, advanced age, and genetic history are considered important risk factors ( Chang et al 2018 ). Other risk factors such as socio-economic status, lifestyle, and environmental factors are also well documented in PCa ( Hayes and Bornman 2018 ). The 8q24 region harbors multiple risk variants for distinct cancers ( Han et al 2016 ).…”

mentioning

confidence: 99%

Population Differentiation at the PVT1 Gene Locus: Implications for Prostate Cancer

Pal

Orunmuyi

et al. 2020

G3 Genes|Genomes|Genetics

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Genetic variation in susceptibility to complex diseases, such as cancer, is well-established. Enrichment of disease associated alleles in specific populations could have implications for disease incidence and prevalence. Prostate cancer (PCa) is a disease with well-established higher incidence, prevalence, and worse outcomes among men of African ancestry in comparison to other populations. PCa is a multi-factorial, complex disease, but the exact mechanisms for its development and progression are unclear. The gene desert located on chromosome 8q24 is associated with aggressiveness of PCa. Interestingly, the non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) is present at chromosome 8q24 and is overexpressed in PCa. PVT1 gives rise to multiple transcripts with potentially different molecular and cellular functions. In an analysis of the PVT1 locus using data from the 1000 Genomes Project, we found the chromosomal region spanning PVT1 exons 4A and 4B to be highly differentiated between African and non-African populations. We further investigated levels of gene expression of PVT1 exons 4A and 4B and observed significant overexpression of these exons in PCa tissues relative to benign prostatic hyperplasia and to normal prostate tissues obtained from men of African ancestry. These results indicate that PVT1 exons 4A and 4B may have clinical implications in PCa a conclusion supported by the observation that transient and stable overexpression of PVT1 exons 4A and 4B significantly induce greater prostate epithelial cell migration and proliferation. We anticipate that further exploration of the role of PVT1 exons 4A and 4B may lead to the development of diagnostic, therapeutic, and other clinical applications in PCa.

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Prostate Cancer in Southern Africa: Does Africa Hold Untapped Potential to Add Value to the Current Understanding of a Common Disease?

Cited by 22 publications

References 46 publications

Whole-Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naïve, High-Risk Prostate Cancer

Whole-Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naïve, High-Risk Prostate Cancer

Heterogeneity in the distribution of 159 drug-response related SNPs in world populations and their genetic relatedness

Population Differentiation at the PVT1 Gene Locus: Implications for Prostate Cancer

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