Yong-Jie Lu

Queen Mary, University of London | QMUL · Barts Cancer Institute

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separ...

Background Treatment decisions in prostate cancer (PCa) rely on disease stratification between localised and metastatic stages, but current imaging staging technologies are not sensitive to micro-metastatic disease. Circulating tumour cells (CTCs) status is a promising tool in this regard. The Parsortix® CTC isolation system employs an epitope-inde...

Given that cancer mortality is usually a result of late diagnosis, efforts in the field of early detection are paramount to reducing cancer-related deaths and improving patient outcomes. Increasing evidence indicates that metastasis is an early event in patients with aggressive cancers, often occurring even before primary lesions are clinically det...

Background: Treatment decisions in prostate cancer (PCa) rely on disease stratification between localised and metastatic stages, but current imaging staging technologies are not sensitive to micro-metastatic disease. Circulating tumour cells (CTCs) status is a promising tool in this regard. The Parsortix® CTC isolation system employs an epitope-ind...

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 fin...

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-m...

With the growing recognition of RNA modification as a hallmark of cancer, N ¹ -methyladenosine (m ¹ A) methylation has been reported as a key mechanism of post-transcriptional regulation. However, the molecular mechanisms underlying m ¹ A modification in bladder cancer (BLCA) progression remain unclear. In the current study, we aimed to explore the...

Background Docetaxel improves overall survival (OS) in castration-resistant prostate cancer (PCa) (CRPC) and metastatic hormone-sensitive PCa (mHSPC). However, not all patients respond due to inherent and/or acquired resistance. There remains an unmet clinical need for a robust predictive test to stratify patients for treatment. Liquid biopsy of ci...

Circular RNA (circRNA), a type of noncoding RNAs, has been demonstrated to act vital roles in tumorigenesis and cancer deterioration. While tumor-associated macrophages (TAMs) involved in tumor malignancy, the interactions between circRNAs and TAMs in prostate cancer (PCa) remains unclear. In the present study, we found that hsa_circ_0094606 (subse...

Background Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue ( n = 51), including benign pros...

Background Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. Objective To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic fact...

P53 suppresses tumorigenesis through multiple cellular functions/mechanisms, including genomic stability surveillance. Recently, it has also be reported for its role in cancer immune response modulation. Deficiency in DNA repair pathways lead to the accumulation of genomic alterations and tumor mutation burden and in consequence resulting in the ac...

Background Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associ...

Purpose Bladder cancer (BLCA) is one of the most common cancers worldwide. In a large proportion of BLCA patients, disease recurs and/or progress after resection, which remains a major clinical issue in BLCA management. Therefore, it is vital to identify prognostic biomarkers for treatment stratification. We investigated the efficiency of CpG methy...

Introduction: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve ass...

Recent advances in sample preparation enable label-free mass spectrometry (MS)-based proteome profiling of small numbers of mammalian cells. However, specific devices are often required to downscale sample processing volume from the standard 50-200 μL to sub-μL for effective nanoproteomics, which greatly impedes the implementation of current nanopr...

A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00786-2.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS 1 ) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS 2 (PHS 1 , adapted for OncoArray) in a multi-ethnic...

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 datas...

Simple Summary There is a tremendous amount of gene expression information available for prostate cancer, but very few tools exist to combine the disparate datasets generated across sample types and technical platforms. We present a method of integrating different types of expression data from different study cohorts to increase analytic power, and...

Castration-resistant prostate cancer (CRPC) is the major cause of death from prostate cancer. Biomarkers to improve early detection and prediction of CRPC especially using non-invasive liquid biopsies could improve outcomes. Therefore, we investigated the plasma exosomal miRNAs associated with CRPC and their potential for development into non-invas...

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, bringi...

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, bringi...

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG...

P53 suppresses tumorigenesis through multiple cellular functions/mechanisms. Recently, Janic A, et al. reported that DNA repair pathways are critical mediators of p53-dependent tumor suppression. We showed, by mining cBioPortal data of a range of human cancers, that the tendency of mutual exclusivity of mutations in p53 and DNA repair genes only ex...

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported Europe...

Background: Prostate cancer causes substantial morbidity and mortality worldwide. Recently, a polygenic hazard score (PHS1)--the weighted sum of 54 single-nucleotide polymorphism (SNP) genotypes--was developed and validated to predict age of aggressive prostate cancer onset in Caucasians. We evaluated the performance of the PHS for prediction of ag...

Circulating tumor cells (CTCs), with their close association with cancer metastasis, the most aggressive feature of solid tumors, represent an important aspect of “liquid biopsy,” which provides minimally- or noninvasive approaches for cancer detection and disease status monitoring. CTC analysis has shown the potential clinical applications in seve...

Fluorescence in situ hybridization (FISH) method enables in situ genetic analysis of both metaphase and interphase cells from different types of material, including cell lines, cell smears, and fresh and paraffin-embedded tissue. Despite the growing number of commercially available FISH probes, still for large number of gene loci or chromosomal reg...

Purpose: PSA testing results in unnecessary biopsy and over-diagnosis with consequent over-treatment. Tissue biopsy is an invasive procedure, associated with significant morbidity. More accurate non- or minimum-invasive diagnostic approaches should be developed to avoid unnecessary prostate biopsy and over-diagnosis. We investigated the potential...

Prostate cancer (PCa) ranks as the second most frequent cancer and the fifth leading cause of cancer death in men worldwide. Androgen-derivation theray is the rincial treatment for locally advanced and metastatic disease. Although a majority of atients initially resond well to ADT, most will rogress to castration-resistant rostate cancer (CRPC), wh...

Background: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosit...

p>Prostate cancer (PCa) ranks as the second most frequent cancer and the fifth leading cause of cancer death in men worldwide. Androgen-deprivation therapy is the principal treatment for locally advanced and metastatic disease. Although a majority of patients initially respond well to ADT, most will progress to castration-resistant prostate cancer...

Genome-wide association study–identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a...

Background: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity...

With the mechanistic understanding of immune checkpoints and success in checkpoint blockade using antibodies for the treatment of certain cancers, immunotherapy has become one of the hottest areas in cancer research, with promise of long‐lasting therapeutic effect. Currently, however, only a proportion of cancers have a good response to checkpoint...

Testicular germ cell tumors (TGCTs) are the commonest tumors in young men. With the advancement of chemotherapies, most TGCTs are successfully cured, even when diagnosed at an advanced and metastatic stage. However, a proportion of often young patients, median age 35-40, with advanced disease are not cured and will inevitably die. Therefore, there...

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.

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.

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide...

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-t...

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...

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: T...

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 Eur...

Objectives: To determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain in penile cancer has prognostic value and association with histopathological parameters, HPV and clinical outcome. Methods: PIK3CA copy number status (CNS) was assessed with fluorescence in-situ hybridisation in tis...

We performed an in-depth and well-powered investigation of genetic variation across the cancer susceptibility region at chromosome 8q24 (127.6-129.0 Mb) to search for novel risk variants associated with prostate cancer (PCa) risk in the European ancestry population. We combined genotyped and imputed data from the PRACTICAL/ELLIPSE OncoArray and iCO...

Background Therapeutic targeting of the PI3K-AKT-mTOR pathway may benefit patients with advanced penile squamous cell carcinoma (PSCC). Objectives To determine the prevalence of PIK3CA copy number gain and correlate this with the activity status of PI3K-AKT-mTOR pathway in pre-malignant penile intraepithelial neoplasia (PeIN) and invasive PSCC. M...

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-a...

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 finemap 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-a...

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 Eur...

Motivation: The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistica...

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previ...

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for...

Objectives To determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain is common and could prove a useful marker for the activation status of the PI3K-AKT-mTOR pathway in penile squamous cell carcinoma (PSCC). Methods Fresh frozen tissue and archival blocks were collected from 24 PSCC pat...

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 Eur...

Anti-apoptotic Bcl-2 is frequently activated in human malignant cells to promote cell survival and inhibit cell death. Replication-selective oncolytic adenoviruses deleted in the functional Bcl-2 homologue E1B19K potently synergise with apoptosis-inducing chemotherapeutic drugs, including mitoxantrone for prostate cancer. Here, we demonstrate that...

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgk...

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss...

Summary characteristics of the genomes and somatic copy number alterations (SCNAs). Left side: Samples classified by disease status i.e. samples from prostatectomies from patients free of metastatic disease (PT) or samples from patients with metastatic disease (M). Right side: Prostatectomy samples where there was at least six months follow up (n =...

Genes with mutations in extended MRA, GISTIC, and homozygous loss regions. Possible haploinsufficiency targets are identified as genes where there are at least three mutations and a normal allele retained. (XLSX)

Copy number alteration segments detected by ASCAT that overlap with deletion MRAs. Each deletion is represented as a distinct colour as shown in the key. Deletions are as follows: neutral LOH (loss of one allele with duplication of the remaining allele); hemizygous deletion LOH (loss of one allele); homozygous loss (loss of the two alleles); and ot...

A platform comparison of ASCAT profiles on a single sample. (a) one profile from SNP6.0 and (b) one from NGS data. (PDF)

Classification of somatic copy number alterations. (DOCX)

Minimal regions of deletions and amplifications with linked genes. This table includes: Comparison of MRAs, extended MRAs and GISTIC-detected regions; amplifications and deletions found in previous prostate cancer studies.; percentage of the minimal regions of alterations that are conserved regions; and clinical correlations and ETS associations of...

Mutations in lncRNAs and conserved RNAs located within the minimal regions of somatic copy number alteration. lncRNAs were examined that were defined by the MiTranscriptome project as being either cancer-associated or containing conserved regions. (XLSX)

GISTIC regions of deletion and amplification. q-values: The q-value of the peak region. Residual q-values: The q-value of the peak region after removing (“peeling off”) amplifications or deletions that overlap other, more significant peak regions in the same chromosome. Wide Peak Limits: The “wide peak” boundaries most likely to contain the targete...

Structural rearrangements in regions of deletion involving genes found to be in or close to minimal regions of alteration. (XLSX)

Structural rearrangements in regions of deletion involving genes found to be in or close to GISTIC detected regions. (XLSX)

Summary of cases and copy number platforms. (DOCX)

Example copy number plots (BAF and logR) for four tumour samples (and associated controls) for each of the 24 novel MCRs that we have identified. The black lines indicate the segment detected by ASCAT and the blue lines indicate the MCR region. (PDF)

Diagrammatic explanation on minimal and extended MRA. (PDF)

Hierarchical clustering of 103 prostate cancer samples with multiscale bootstrap resampling. The data are binary values corresponding to the presence/absence (1/0) of regions of copy number gain and loss in each of the tumour samples. p-values were calculated via hierarchical cluster analysis with multiscale bootstrap resampling of 1000 using Ward’...