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Fulltext Determination of genetic aberrations and novel transcripts involved in the pathogenesis of oligodendroglioma using array comparative genomic hybridization and next generation sequencing

Hassanudin SA, Ponnampalam SN, Amini MN

Oncol Lett, 2019 Feb;17(2):1675-1687.
PMID: 30675227 DOI: 10.3892/ol.2018.9811

The aim of the present study was to determine the genetic aberrations and novel transcripts, particularly the fusion transcripts, involved in the pathogenesis of low-grade and anaplastic oligodendroglioma. In the present study, tissue samples were obtained from patients with oligodendroglioma and additionally from archived tissue samples from the Brain Tumor Tissue Bank of the Brain Tumor Foundation of Canada. Six samples were obtained, three of which were low-grade oligodendroglioma and the other three anaplastic oligodendroglioma. DNA and RNA were extracted from each tissue sample. The resulting genomic DNA was then hybridized using the Agilent CytoSure 4×180K oligonucleotide array. Human reference DNA and samples were labeled using Cy3 cytidine 5'-triphosphate (CTP) and Cy5 CTP, respectively, while human Cot-1 DNA was used to reduce non-specific binding. Microarray-based comparative genomic hybridization data was then analyzed for genetic aberrations using the Agilent Cytosure Interpret software v3.4.2. The total RNA isolated from each sample was mixed with oligo dT magnetic beads to enrich for poly(A) mRNA. cDNAs were then synthesized and subjected to end-repair, poly(A) addition and connected using sequencing adapters using the Illumina TruSeq RNA Sample Preparation kit. The fragments were then purified and selected as templates for polymerase chain reaction amplification. The final library was constructed with fragments between 350-450 base pairs and sequenced using deep transcriptome sequencing on an Illumina HiSeq 2500 sequencer. The array comparative genomic hybridization revealed numerous amplifications and deletions on several chromosomes in all samples. However, the most interesting result was from the next generation sequencing, where one anaplastic oligodendroglioma sample was demonstrated to have five novel fusion genes that may potentially serve a critical role in tumor pathogenesis and progression.
Unusual cause of neuropathy: extensive dural spread of primary cervical osteosarcoma

Ponnampalam SN, Tan WY, Wazir NN, George J

Acta Radiol Short Rep, 2012;1(1):1-3.
PMID: 23986826 DOI: 10.1258/arsr.2012.110028

We report a very rare case of a high grade osteosarcoma of the cervical spine in a 62-year-old woman. She presented with a relatively short history of a swelling in the posterior neck and cervical lymphadenopathy. This was associated with hoarseness of the voice, significant weight loss, and right upper arm radicular symptoms initially, progressing to paraplegia. Based on MR and CT imaging of the neck and an excision biopsy of an enlarged right supraclavicular lymph node, the histology revealed a high grade primary osteosarcoma of the cervical spine.
Fulltext A blood-based gene expression and signaling pathway analysis to differentiate between high and low grade gliomas

Ponnampalam SN, Kamaluddin NR, Zakaria Z, Matheneswaran V, Ganesan D, Haspani MS, et al.

Oncol Rep, 2017 Jan;37(1):10-22.
PMID: 28004117 DOI: 10.3892/or.2016.5285

The aims of the present study were to undertake gene expression profiling of the blood of glioma patients to determine key genetic components of signaling pathways and to develop a panel of genes that could be used as a potential blood-based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples. In this study, blood samples were obtained from glioma patients, non-glioma and control subjects. Ten samples each were obtained from patients with high and low grade tumours, respectively, ten samples from non-glioma patients and twenty samples from control subjects. Total RNA was isolated from each sample after which first and second strand synthesis was performed. The resulting cRNA was then hybridized with the Agilent Whole Human Genome (4x44K) microarray chip according to the manufacturer's instructions. Universal Human Reference RNA and samples were labeled with Cy3 CTP and Cy5 CTP, respectively. Microarray data were analyzed by the Agilent Gene Spring 12.1V software using stringent criteria which included at least a 2-fold difference in gene expression between samples. Statistical analysis was performed using the unpaired Student's t-test with a p<0.01. Pathway enrichment was also performed, with key genes selected for validation using droplet digital polymerase chain reaction (ddPCR). The gene expression profiling indicated that were a substantial number of genes that were differentially expressed with more than a 2-fold change (p<0.01) between each of the four different conditions. We selected key genes within significant pathways that were analyzed through pathway enrichment. These key genes included regulators of cell proliferation, transcription factors, cytokines and tumour suppressor genes. In the present study, we showed that key genes involved in significant and well established pathways, could possibly be used as a potential blood-based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples.
Fulltext Effectiveness of structured teaching programme on transmission and prevention of human immunodeficiency virus/acquired immune deficiency syndrome among adolescent girls in Lowry Memorial High School, Bengaluru

Stephen N, Gusen NJ, Kumzhi PR, Gaknung B, Auta DA, Bulndi LB, et al.

Indian J Sex Transm Dis AIDS, 2018 03 26;41(1):73-82.
PMID: 33062987 DOI: 10.4103/ijstd.IJSTD_102_17

Background: Adolescence is a critical stage in human development. Most young people become sexually active during adolescence and are more likely to have multipartner and unprotected sex with high-risk behavior that predisposes them to sexually transmitted infections such as human immunodeficiency virus (HIV).
Objectives: The objective of the study was to evaluate the effectiveness of a structured teaching programme on transmission and prevention of HIV/acquired immune deficiency syndrome (HIV/AIDS) among adolescent girls.
Methods: An evaluative research approach was adopted, in which a preexperimental, one group pre- and post-test research design was used to evaluate the effectiveness of the structured teaching programme on transmission and prevention of HIV/AIDS among adolescent girls studying at Lowry Memorial High School, Bengaluru. A self-administered structured questionnaire was used for data collection. Data were presented in frequency tables and statistical graphs (bar charts) and analyzed using descriptive statistics (mean, standard deviation) and inferential statistical methods (Chi-square and paired "t"-tests) using SPSS version 21.
Results: The findings of the study revealed that the mean percentage difference in the pre- and post-test knowledge scores was statistically significant at 5% level (P < 0.05). The overall mean post-test knowledge score of adolescent girls on transmission and prevention of HIV/AIDS was 88.83%. It is apparently higher compared to the pretest knowledge score, which was 67.67% with enhancement of 21.16%. This implies that the structured teaching programme was effective in gaining knowledge of adolescent girls regarding transmission and prevention of HIV/AIDS.
Conclusion: Our study suggests that structured teaching programme enhanced the knowledge of the adolescent girls on transmission and prevention of HIV/AIDS. We, therefore, recommend that structured teaching programmes on transmission and prevention of HIV/AIDS should be encouraged among adolescents and youths to reduce the spread of HIV infection.
Fulltext Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Matejcic M, Saunders EJ, Dadaev T, Brook MN, Wang K, Sheng X, et al.

Nat Commun, 2019 01 17;10(1):382.
PMID: 30655571 DOI: 10.1038/s41467-019-08293-z

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
Fulltext Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Matejcic M, Saunders EJ, Dadaev T, Brook MN, Wang K, Sheng X, et al.

Nat Commun, 2018 Nov 05;9(1):4616.
PMID: 30397198 DOI: 10.1038/s41467-018-06863-1

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p
Fulltext Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Papadimitriou N, Dimou N, Tsilidis KK, Banbury B, Martin RM, Lewis SJ, et al.

Nat Commun, 2020 01 30;11(1):597.
PMID: 32001714 DOI: 10.1038/s41467-020-14389-8

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.
Fulltext Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study

Adams CD, Richmond R, Ferreira DLS, Spiller W, Tan V, Zheng J, et al.

Cancer Epidemiol Biomarkers Prev, 2019 Jan;28(1):208-216.
PMID: 30352818 DOI: 10.1158/1055-9965.EPI-18-0079

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).
METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.
RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.
CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.
IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
Fulltext Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Huynh-Le MP, Fan CC, Karunamuni R, Thompson WK, Martinez ME, Eeles RA, et al.

Nat Commun, 2021 02 23;12(1):1236.
PMID: 33623038 DOI: 10.1038/s41467-021-21287-0

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p
Fulltext Genome-wide association study of prostate cancer-specific survival

Szulkin R, Karlsson R, Whitington T, Aly M, Gronberg H, Eeles RA, et al.

Cancer Epidemiol Biomarkers Prev, 2015 Nov;24(11):1796-800.
PMID: 26307654 DOI: 10.1158/1055-9965.EPI-15-0543

BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.
METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).
RESULTS: We observed no significant association between genetic variants and prostate cancer survival.
CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study.
IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.
Fulltext Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Seyed Khoei N, Jenab M, Murphy N, Banbury BL, Carreras-Torres R, Viallon V, et al.

BMC Med, 2020 09 03;18(1):229.
PMID: 32878631 DOI: 10.1186/s12916-020-01703-w

BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.
METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P
Fulltext Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, et al.

Am J Hum Genet, 2023 Jul 06;110(7):1200-1206.
PMID: 37311464 DOI: 10.1016/j.ajhg.2023.05.010

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.
Fulltext Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry

Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, et al.

medRxiv, 2023 May 15.
PMID: 37292833 DOI: 10.1101/2023.05.12.23289860

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.
Fulltext Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Dadaev T, Saunders EJ, Newcombe PJ, Anokian E, Leongamornlert DA, Brook MN, et al.

Nat Commun, 2018 06 11;9(1):2256.
PMID: 29892050 DOI: 10.1038/s41467-018-04109-8

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
Fulltext Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Schumacher FR, Al Olama AA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.

Nat Genet, 2018 07;50(7):928-936.
PMID: 29892016 DOI: 10.1038/s41588-018-0142-8

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.
Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Schumacher FR, Olama AAA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.

Nat Genet, 2019 02;51(2):363.
PMID: 30622367 DOI: 10.1038/s41588-018-0330-6

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
Fulltext Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, et al.

Nat Genet, 2021 Jan;53(1):65-75.
PMID: 33398198 DOI: 10.1038/s41588-020-00748-0

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Fulltext Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, et al.

Cancer Discov, 2016 Sep;6(9):1052-67.
PMID: 27432226 DOI: 10.1158/2159-8290.CD-15-1227

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.
SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, et al.

Nat Genet, 2021 Mar;53(3):413.
PMID: 33473200 DOI: 10.1038/s41588-021-00786-2
Fulltext Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, et al.

Nat Genet, 2023 Dec;55(12):2065-2074.
PMID: 37945903 DOI: 10.1038/s41588-023-01534-4

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

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