Reconstructing Prehistoric African Population Structure.

We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.

African-specific molecular taxonomy of prostate cancer.

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African-European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene-environment interaction-defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa-we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Charting a landmark-driven path forward for population genetics and ancient DNA research in Africa.

Population history-focused DNA and ancient DNA (aDNA) research in Africa has dramatically increased in the past decade, enabling increasingly fine-scale investigations into the continent's past. However, while international interest in human genomics research in Africa grows, major structural barriers limit the ability of African scholars to lead and engage in such research and impede local communities from partnering with researchers and benefitting from research outcomes. Because conversations about research on African people and their past are often held outside Africa and exclude African voices, an important step for African DNA and aDNA research is moving these conversations to the continent. In May 2023 we held the DNAirobi workshop in Nairobi, Kenya and here we synthesize what emerged most prominently in our discussions. We propose an ideal vision for population history-focused DNA and aDNA research in Africa in ten years' time and acknowledge that to realize this future, we need to chart a path connecting a series of "landmarks" that represent points of consensus in our discussions. These include effective communication across multiple audiences, reframed relationships and capacity building, and action toward structural changes that support science and beyond. We concluded there is no single path to creating an equitable and self-sustaining research ecosystem, but rather many possible routes linking these landmarks. Here we share our diverse perspectives as geneticists, anthropologists, archaeologists, museum curators, and educators to articulate challenges and opportunities for African DNA and aDNA research and share an initial map toward a more inclusive and equitable future.

Human origins in a southern African palaeo-wetland and first migrations.

Anatomically modern humans originated in Africa around 200 thousand years ago (ka)1-4. Although some of the oldest skeletal remains suggest an eastern African origin2, southern Africa is home to contemporary populations that represent the earliest branch of human genetic phylogeny5,6. Here we generate, to our knowledge, the largest resource for the poorly represented and deepest-rooting maternal L0 mitochondrial DNA branch (198 new mitogenomes for a total of 1,217 mitogenomes) from contemporary southern Africans and show the geographical isolation of L0d1'2, L0k and L0g KhoeSan descendants south of the Zambezi river in Africa. By establishing mitogenomic timelines, frequencies and dispersals, we show that the L0 lineage emerged within the residual Makgadikgadi-Okavango palaeo-wetland of southern Africa7, approximately 200 ka (95% confidence interval, 240-165 ka). Genetic divergence points to a sustained 70,000-year-long existence of the L0 lineage before an out-of-homeland northeast-southwest dispersal between 130 and 110 ka. Palaeo-climate proxy and model data suggest that increased humidity opened green corridors, first to the northeast then to the southwest. Subsequent drying of the homeland corresponds to a sustained effective population size (L0k), whereas wet-dry cycles and probable adaptation to marine foraging allowed the southwestern migrants to achieve population growth (L0d1'2), as supported by extensive south-coastal archaeological evidence8-10. Taken together, we propose a southern African origin of anatomically modern humans with sustained homeland occupation before the first migrations of people that appear to have been driven by regional climate changes.

A review and comparative study of cancer detection using machine learning: SBERT and SimCSE application.

BACKGROUND: Using visual, biological, and electronic health records data as the sole input source, pretrained convolutional neural networks and conventional machine learning methods have been heavily employed for the identification of various malignancies. Initially, a series of preprocessing steps and image segmentation steps are performed to extract region of interest features from noisy features. Then, the extracted features are applied to several machine learning and deep learning methods for the detection of cancer. METHODS: In this work, a review of all the methods that have been applied to develop machine learning algorithms that detect cancer is provided. With more than 100 types of cancer, this study only examines research on the four most common and prevalent cancers worldwide: lung, breast, prostate, and colorectal cancer. Next, by using state-of-the-art sentence transformers namely: SBERT (2019) and the unsupervised SimCSE (2021), this study proposes a new methodology for detecting cancer. This method requires raw DNA sequences of matched tumor/normal pair as the only input. The learnt DNA representations retrieved from SBERT and SimCSE will then be sent to machine learning algorithms (XGBoost, Random Forest, LightGBM, and CNNs) for classification. As far as we are aware, SBERT and SimCSE transformers have not been applied to represent DNA sequences in cancer detection settings. RESULTS: The XGBoost model, which had the highest overall accuracy of 73 ± 0.13 % using SBERT embeddings and 75 ± 0.12 % using SimCSE embeddings, was the best performing classifier. In light of these findings, it can be concluded that incorporating sentence representations from SimCSE's sentence transformer only marginally improved the performance of machine learning models.

Detection of somatic structural variants from short-read next-generation sequencing data.

Somatic structural variants (SVs), which are variants that typically impact >50 nucleotides, play a significant role in cancer development and evolution but are notoriously more difficult to detect than small variants from short-read next-generation sequencing (NGS) data. This is due to a combination of challenges attributed to the purity of tumour samples, tumour heterogeneity, limitations of short-read information from NGS and sequence alignment ambiguities. In spite of active development of SV detection tools (callers) over the past few years, each method has inherent advantages and limitations. In this review, we highlight some of the important factors affecting somatic SV detection and compared the performance of seven commonly used SV callers. In particular, we focus on the extent of change in sensitivity and precision for detecting different SV types and size ranges from samples with differing variant allele frequencies and sequencing depths of coverage. We highlight the reasons for why some SV callers perform well in some settings but not others, allowing our evaluation findings to be extended beyond the seven SV callers examined in this paper. As the importance of large SVs become increasingly recognized in cancer genomics, this paper provides a timely review on some of the most impactful factors influencing somatic SV detection that should be considered when choosing SV callers.

Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer.

BACKGROUND: Germline testing for prostate cancer is on the increase, with clinical implications for risk assessment, treatment, and management. Regardless of family history, NCCN recommends germline testing for patients with metastatic, regional, very-high-risk localized, and high-risk localized prostate cancer. Although African ancestry is a significant risk factor for aggressive prostate cancer, due to a lack of available data no testing criteria have been established for ethnic minorities. PATIENTS AND METHODS: Through deep sequencing, we interrogated the 20 most common germline testing panel genes in 113 Black South African males presenting with largely advanced prostate cancer. Bioinformatic tools were then used to identify the pathogenicity of the variants. RESULTS: After we identified 39 predicted deleterious variants (16 genes), further computational annotation classified 17 variants as potentially oncogenic (12 genes; 17.7% of patients). Rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (2 patients), and TP53 Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, whereas patients with FANCA Arg504Cys and RAD51C Arg260Gln reported a family history of prostate cancer. Overall, rare pathogenic and early-onset or familial-associated oncogenic variants were identified in 6.9% (5/72) and 9.2% (8/87) of patients presenting with a Gleason score ≥8 or ≥4 + 3 prostate cancer, respectively. CONCLUSIONS: In this first-of-its-kind study of southern African males, we provide support of African inclusion for advanced, early-onset, and familial prostate cancer genetic testing, indicating clinical value for 30% of current gene panels. Recognizing current panel limitations highlights an urgent need to establish testing guidelines for men of African ancestry. We provide a rationale for considering lowering the pathologic diagnostic inclusion criteria and call for further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel.

Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone.

The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.

Optical mapping reveals a higher level of genomic architecture of chained fusions in cancer.

Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response. These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative chromosomes. Although methods exist for detecting individual fusions, they are generally unable to reconstruct complex chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase-length genome maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping (Bionano Genomics) of a well-studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147 chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular relevance to human cancer.

Metagenomic and metatranscriptomic analysis of human prostate microbiota from patients with prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the most common malignant neoplasm among men in many countries. Since most precancerous and cancerous tissues show signs of inflammation, chronic bacterial prostatitis has been hypothesized to be a possible etiology. However, establishing a causal relationship between microbial inflammation and PCa requires a comprehensive analysis of the prostate microbiome. The aim of this study was to characterize the microbiome in prostate tissue of PCa patients and investigate its association with tumour clinical characteristics as well as host expression profiles. RESULTS: The metagenome and metatranscriptome of tumour and the adjacent benign tissues were assessed in 65 Chinese radical prostatectomy specimens. Escherichia, Propionibacterium, Acinetobacter and Pseudomonas were abundant in both metagenome and metatranscriptome, thus constituting the core of the prostate microbiome. The biodiversity of the microbiomes could not be differentiated between the matched tumour/benign specimens or between the tumour specimens of low and high Gleason Scores. The expression profile of ten Pseudomonas genes was strongly correlated with that of eight host small RNA genes; three of the RNA genes may negatively associate with metastasis. Few viruses could be identified from the prostate microbiomes. CONCLUSIONS: This is the first study of the human prostate microbiome employing an integrated metagenomics and metatranscriptomics approach. In this Chinese cohort, both metagenome and metatranscriptome analyses showed a non-sterile microenvironment in the prostate of PCa patients, but we did not find links between the microbiome and local progression of PCa. However, the correlated expression of Pseudomonas genes and human small RNA genes may provide tantalizing preliminary evidence that Pseudomonas infection may impede metastasis.

Metagenomic analysis reveals a rich bacterial content in high-risk prostate tumors from African men.

BACKGROUND: Inflammation is a hallmark of prostate cancer (PCa), yet no pathogenic agent has been identified. Men from Africa are at increased risk for both aggressive prostate disease and infection. We hypothesize that pathogenic microbes may be contributing, at least in part, to high-risk PCa presentation within Africa and in turn the observed ethnic disparity. METHODS: Here we reveal through metagenomic analysis of host-derived whole-genome sequencing data, the microbial content within prostate tumor tissue from 22 men. What is unique about this study is that patients were separated by ethnicity, African vs European, and environments, Africa vs Australia. RESULTS: We identified 23 common bacterial genera between the African, Australian, and Chinese prostate tumor samples, while nonbacterial microbes were notably absent. While the most abundant genera across all samples included: Escherichia, Propionibacterium, and Pseudomonas, the core prostate tumor microbiota was enriched for Proteobacteria. We observed a significant increase in the richness of the bacterial communities within the African vs Australian samples (t = 4.6-5.5; P = .0004-.001), largely driven by eight predominant genera. Considering core human gut microbiota, African prostate tissue samples appear enriched for Escherichia and Acidovorax, with an abundance of Eubacterium associated with host tumor hypermutation. CONCLUSIONS: Our study provides suggestive evidence for the presence of a core, bacteria-rich, prostate microbiome. While unable to exclude for fecal contamination, the observed increased bacterial content and richness within the African vs non-African samples, together with elevated tumor mutational burden, suggests the possibility that bacterially-driven oncogenic transformation within the prostate microenvironment may be contributing to aggressive disease presentation in Africa.

TMPRSS2-ERG fusions linked to prostate cancer racial health disparities: A focus on Africa.

BACKGROUND: The androgen-regulated gene TMPRSS2 to the ETS transcription factor gene ERG fusion is the most common genomic alteration acquired during prostate tumorigenesis and biased toward men of European ancestry. In contrast, African American men present with more advanced disease, yet their tumors are less likely to acquire TMPRSS2-ERG. Data for Africa is scarce. METHODS: RNA was made available for genomic analyses from 181 prostate tissue biopsy cores from Black South African men, 94 with and 87 without pathological evidence for prostate cancer. Reverse transcription polymerase chain reaction was used to screen for the TMPRSS2-ERG fusion, while transcript junction coordinates and isoform frequencies, including novel gene fusions, were determined using targeted RNA sequencing. RESULTS: Here we report a frequency of 13% for TMPRSS2-ERG in tumors from Black South Africans. Present in 12/94 positive versus 1/87 cancer negative prostate tissue cores, this suggests a 92.62% predictivity for a positive cancer diagnosis (P = 0.0031). At a frequency of almost half that reported for African Americans and roughly a quarter of that reported for men of European ancestry, acquisition of TMPRSS2-ERG appears to be inversely associated with aggressive prostate cancer. Further support was provided by linking the presence of TMPRSS2-ERG to low-grade disease in younger patients (P = 0.0466), with higher expressing distal ERG fusion junction coordinates. CONCLUSIONS: Only the second study of its kind for the African continent, we support a link between TMPRSS2-ERG status and prostate cancer racial health disparity beyond the borders of the United States. We call for urgent evaluation of androgen deprivation therapy within Africa.

Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer.

BACKGROUND: Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. METHODS: Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. RESULTS: We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). CONCLUSIONS: Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis.

Spectrum of mitochondrial genomic variation and associated clinical presentation of prostate cancer in South African men.

BACKGROUND: Prostate cancer incidence and mortality rates are significantly increased in African-American men, but limited studies have been performed within Sub-Saharan African populations. As mitochondria control energy metabolism and apoptosis we speculate that somatic mutations within mitochondrial genomes are candidate drivers of aggressive prostate carcinogenesis. METHODS: We used matched blood and prostate tissue samples from 87 South African men (77 with African ancestry) to perform deep sequencing of complete mitochondrial genomes. Clinical presentation was biased toward aggressive disease (Gleason score >7, 64%), and compared with men without prostate cancer either with or without benign prostatic hyperplasia. RESULTS: We identified 144 somatic mtDNA single nucleotide variants (SNVs), of which 80 were observed in 39 men presenting with aggressive disease. Both the number and frequency of somatic mtDNA SNVs were associated with higher pathological stage. CONCLUSIONS: Besides doubling the total number of somatic PCa-associated mitochondrial genome mutations identified to date, we associate mutational load with aggressive prostate cancer status in men of African ancestry.

Complete Khoisan and Bantu genomes from southern Africa.

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.

Complex patterns of genomic admixture within southern Africa.

Within-population genetic diversity is greatest within Africa, while between-population genetic diversity is directly proportional to geographic distance. The most divergent contemporary human populations include the click-speaking forager peoples of southern Africa, broadly defined as Khoesan. Both intra- (Bantu expansion) and inter-continental migration (European-driven colonization) have resulted in complex patterns of admixture between ancient geographically isolated Khoesan and more recently diverged populations. Using gender-specific analysis and almost 1 million autosomal markers, we determine the significance of estimated ancestral contributions that have shaped five contemporary southern African populations in a cohort of 103 individuals. Limited by lack of available data for homogenous Khoesan representation, we identify the Ju/'hoan (n = 19) as a distinct early diverging human lineage with little to no significant non-Khoesan contribution. In contrast to the Ju/'hoan, we identify ancient signatures of Khoesan and Bantu unions resulting in significant Khoesan- and Bantu-derived contributions to the Southern Bantu amaXhosa (n = 15) and Khoesan !Xun (n = 14), respectively. Our data further suggests that contemporary !Xun represent distinct Khoesan prehistories. Khoesan assimilation with European settlement at the most southern tip of Africa resulted in significant ancestral Khoesan contributions to the Coloured (n = 25) and Baster (n = 30) populations. The latter populations were further impacted by 170 years of East Indian slave trade and intra-continental migrations resulting in a complex pattern of genetic variation (admixture). The populations of southern Africa provide a unique opportunity to investigate the genomic variability from some of the oldest human lineages to the implications of complex admixture patterns including ancient and recently diverged human lineages.

Clinical presentation of prostate cancer in black South Africans.

BACKGROUND: Compared with White Americans, Black American men are at a significant increased risk of presenting with prostate cancer (PCa) and associated mortality, suggesting a link to African-ancestry. However, PCa status within Africa is largely unknown. We address the clinical presentation of PCa within Black South African men. METHODS: Over 1,000 participants with or without PCa have enrolled in the Southern African Prostate Cancer Study (SAPCS). Using genome-wide profiling we establish a unique within Africa population substructure. Adjusting for age, clinical variables were assessed, compared against Black Americans and between rural and urban localities while addressing potential socio-demographic confounders. RESULTS: We report a significant difference in the distribution of prostate specific antigen (PSA) levels skewed towards higher PSA levels in the PCa cases (83.0% present with a PSA ≥ 20 µg/L; median PSA = 98.8 µg/L) relative to men with no detectable PCa (18.5% present with a PSA ≥ 20 µg/L; median PSA = 9.1 µg/L). Compared with Black Americans, Black South Africans presented with significantly more aggressive disease defined by Gleason score >7 (17% and 36%, respectively) and PSA ≥ 20 µg/L (17.2% and 83.2%, respectively). We report exasperated disease aggression defined by Gleason score >7 (P = 0.0042) and poorly differentiated tumor grade (P < 0.0001) within rural versus urban localities. CONCLUSION: Black South African men present with higher PSA levels and histopathological tumor grade compared with Black Americans, which is further escalated in men from rural localities. Our data suggests that lack of PSA testing may be contributing to an aggressive PCa disease phenotype within South African men.

Genetic diversity and population structure of the endangered marsupial Sarcophilus harrisii (Tasmanian devil).

The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction because of a contagious cancer known as Devil Facial Tumor Disease. The inability to mount an immune response and to reject these tumors might be caused by a lack of genetic diversity within a dwindling population. Here we report a whole-genome analysis of two animals originating from extreme northwest and southeast Tasmania, the maximal geographic spread, together with the genome from a tumor taken from one of them. A 3.3-Gb de novo assembly of the sequence data from two complementary next-generation sequencing platforms was used to identify 1 million polymorphic genomic positions, roughly one-quarter of the number observed between two genetically distant human genomes. Analysis of 14 complete mitochondrial genomes from current and museum specimens, as well as mitochondrial and nuclear SNP markers in 175 animals, suggests that the observed low genetic diversity in today's population preceded the Devil Facial Tumor Disease disease outbreak by at least 100 y. Using a genetically characterized breeding stock based on the genome sequence will enable preservation of the extant genetic diversity in future Tasmanian devil populations.

The impact of telomere length on prostate cancer aggressiveness, genomic instability and health disparities.

The telomere repetitive TTAGGG motif at the ends of chromosomes, serves to preserve genomic integrity and chromosomal stability. In turn, genomic instability is a hallmark of cancer-implicating telomere disturbance. Prostate cancer (PCa) shows significant ancestral disparities, with men of African ancestry at the greatest risk for aggressive disease and associated genomic instability. Yet, no study has explored the role of telomere length (TL) with respect to ancestrally driven PCa health disparities. Patient- and technically-matched tumour-blood whole genome sequencing data for 179 ancestrally defined treatment naïve PCa patients (117 African, 62 European), we assessed for TL (blood and tumour) associations. We found shortened tumour TL to be associated with aggressive PCa presentation and elevated genomic instabilities, including percentage of genome alteration and copy number gains, in men of African ancestry. For European patients, tumour TL showed significant associations with PCa driver genes PTEN, TP53, MSH2, SETBP1 and DDX11L1, while shorter blood TL (< 3200 base pairs) and tumour TL (< 2861 base pairs) were correlated with higher risk for biochemical recurrence. Concurring with previous studies linking TL to PCa diagnosis and/or prognosis, for the first time we correlated TL differences with patient ancestry with important implications for future treatments targeting telomere dysfunction.