Biomedical subjects

Jinghui Zhang

Publications and source records attributed to Jinghui Zhang.

7 recordsLinked to original sources

PubMed2026

Integrating genetic predictors into subsequent breast cancer risk prediction in survivors of childhood cancer.

PURPOSE: Female survivors of childhood cancer are at high risk for developing breast cancer. The contributions of most general population primary breast cancer genetic predictors to this risk have not been explored. METHODS: Analyses included females who survived ≥5 years after their childhood cancer diagnosis with available array (N = 2096, subsequent breast cancer [SBC]=218) or whole-genome sequencing (WGS; N = 3292, SBC=101) data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. We computed 99 externally-validated primary breast cancer polygenic risk scores (PRS). Using deep-coverage WGS, ClinVar-annotated pathogenic/likely pathogenic (P/LP) variants in breast cancer susceptibility genes were identified. Cox proportional hazards models assessed associations with SBC risk, adjusting for treatments and genetic ancestry. RESULTS: Among 5388 female survivors (genetic ancestry, European: N = 4,752; African: N = 444; East Asian: N = 192), 319 developed SBC. Most (90.9%) PRSs were nominally associated with SBC risk (P < 0.05), but effect sizes varied substantially. PRSs with superior discriminatory ability had greater genome-wide coverage (e.g., 6.4 million-variant PRS, HR per SD = 1.71, 95% CI = 1.43 to 2.05; P = 4.2x10-9) and 7.7-fold higher odds (P = 7.0x10-4) of including variants in multiple DNA damage repair pathways compared with PRSs with weaker risk associations. Among survivors with WGS, 1.6% carried P/LP variants in clinical testing panel genes, which was associated with a 7.4-fold greater risk (95% CI = 3.16 to 17.19). Including genetic factors improved SBC risk prediction by age 40 (P < 0.001) compared to treatment exposures alone. CONCLUSIONS: Externally-validated primary breast cancer genetic susceptibility predictors are relevant for SBC risk prediction and should be prioritized for risk stratification in survivors.

Journal Article↗

PubMed2025

The landscape of structural variation in pediatric cancer.

Structural variants (SVs) account for over 60% of the driver variants in pediatric cancer, and in many cases act as the cancer initiating event. To study SVs from a pan-cancer perspective, we analyzed 1,616 pediatric cancer genomes in 16 major cancer types of hematological malignancies (n = 908), brain tumors (n = 183), and solid tumors (n = 525) and compared their profiles to those of 2,203 adult cancers. The SV burden varied ~100-fold across pediatric cancer types and demonstrated an 8- to 16-fold reduction compared to adult brain and solid tumors but was comparable in pediatric versus adult hematological malignancies. Recurrent SV hotspots occurred uniquely in pediatric acute lymphoblastic leukemias (ALLs) in proximity to RAG-mediated recombination signal sequences (RSS) and disrupted multiple immune-related loci as well as 69 genes, which often involved cryptic RSS sites. By contrast, such hotspots affected only immune-related loci but not driver genes in adult lymphoid cancers. Eight SV signatures extracted from the cohort had varying distributions across cancer types, with clustered translocations reflecting templated insertions in osteosarcoma, and medium-sized deletions (10 kb to 1 Mb) enriched in cancers with RAG-mediated deletions. Intra-patient evolutionary analysis in 13 patients with multiple spatiotemporally distinct samples revealed that RAG-mediated recombination in leukemia and complex rearrangements in solid tumors occurred both early in disease initiation and continuously during later diversification, contributing to clonal heterogeneity. Finally, we found that both driver genes and fragile sites were the two genomic regions most frequently disrupted by SVs. The unique and diverse SV landscapes that emerged from this comprehensive analysis expand the scope of RSS-mediated mutagenesis in pediatric ALL and will be a valuable resource for guiding future functional studies and the design of clinical genomic testing in pediatric cancer.

Journal Article↗

PubMed2019

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Child↗

PubMed2003

Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals.

Two potential breast cancer susceptibility genes, encoding the BRCA1-interacting proteins ZNF350 (or ZBRK1) and BRIP1 (or BACH1), have been identified in yeast two-hybrid screens. We sequenced these genes in probands from 21 families with potentially inherited breast/ovarian cancer, all of which were negative for BRCA1/BRCA2 mutations. Families had at least one case of male breast cancer, two cases of ovarian cancer, or three or more cases of breast and ovarian cancer. In addition, 58 early-onset (before age 35) breast cancer cases and 30 reference individuals were analyzed. Of 17 variants detected in ZBRK1, a missense mutation Val524Ile was identified in the proband of one high-risk family, but no other family members were available for testing. Of 25 variants identified in BRIP1, in addition to four common silent or missense mutations, we identified Gln540Leu, a non-conservative amino acid change, in a single familial proband with inflammatory breast cancer, but this mutation was not present in her three relatives with breast cancer. Haplotype analysis suggests that all ZBRK1 SNPs fall within a single block with two SNPs capturing 92% of the haplotype diversity, while the BRIP1 SNPs fall in two blocks, with five SNPs capturing 89% of the haplotype diversity. Based on sequencing of ZBRK1 and BRIP1 in 21 BRCA1/2-negative probands from inherited breast/ovarian cancer families, it appears unlikely that mutations in these genes account for a significant fraction of inherited breast cancer. Further analysis in unselected cases will be required to know whether the identified variants play a role in genetic predisposition to breast cancer in the general population. Hum Mutat 22:121-128, 2003. Published 2003 Wiley-Liss, Inc.

BRCA1 Protein↗

PubMed2002

HapScope: a software system for automated and visual analysis of functionally annotated haplotypes.

We have developed a software analysis package, HapScope, which includes a comprehensive analysis pipeline and a sophisticated visualization tool for analyzing functionally annotated haplotypes. The HapScope analysis pipeline supports: (i) computational haplotype construction with an expectation-maximization or Bayesian statistical algorithm; (ii) SNP classification by protein coding change, homology to model organisms or putative regulatory regions; and (iii) minimum SNP subset selection by either a Brute Force Algorithm or a Greedy Partition Algorithm. The HapScope viewer displays genomic structure with haplotype information in an integrated environment, providing eight alternative views for assessing genetic and functional correlation. It has a user-friendly interface for: (i) haplotype block visualization; (ii) SNP subset selection; (iii) haplotype consolidation with subset SNP markers; (iv) incorporation of both experimentally determined haplotypes and computational results; and (v) data export for additional analysis. Comparison of haplotypes constructed by the statistical algorithms with those determined experimentally shows variation in haplotype prediction accuracies in genomic regions with different levels of nucleotide diversity. We have applied HapScope in analyzing haplotypes for candidate genes and genomic regions with extensive SNP and genotype data. We envision that the systematic approach of integrating functional genomic analysis with population haplotypes, supported by HapScope, will greatly facilitate current genetic disease research.

Algorithms↗

PubMed2002

The Celera Discovery System.

The Celera Discovery System (CDS) is a web-accessible research workbench for mining genomic and related biological information. Users have access to the human and mouse genome sequences with annotation presented in summary form in BioMolecule Reports for genes, transcripts and proteins. Over 40 additional databases are available, including sequence, mapping, mutation, genetic variation, mRNA expression, protein structure, motif and classification data. Data are accessible by browsing reports, through a variety of interactive graphical viewers, and by advanced query capability provided by the LION SRS search engine. A growing number of sequence analysis tools are available, including sequence similarity, pattern searching, multiple sequence alignment and Hidden Markov Model search. A user workspace keeps track of queries and analyses. CDS is widely used by the academic research community and requires a subscription for access. The system and academic pricing information are available at http://cds.celera.com.

Animals↗

PubMed2002

The effect of nitric oxide/endothelins system on the hepatic ischemia/reperfusion injury.

The relationship between the hepatic ischemia/reperfusion (I/R) injury and the balance of nitric oxide/endothelins (NO/ET) was studied. The changes of the ratio of NO/ET and the hepatic injury were observed in a rat hepatic I/R model pretreated with several tool drugs. In the acute phase of hepatic I/R injury, the ratio of plasma NO/ET was reduced from 1.58 +/- 0.20 to 0.29 +/- 0.05 (P < 0.01) and the hepatic damage deteriorated. NO donor L-Arg and ET receptor antagonist TAK-044 could alleviate the hepatic I/R injury to some degree, whereas NO synthase inhibitor L-NAME aggravated the damage. It was concluded that the hepatic I/R injury might be related with the disturbance of the NO/ET balance. Regulation of this balance might have an effect on the I/R injury.

Animals↗