Publications by authors named "George J Burghel"
Background: The NHS Jewish BRCA Testing Programme is offering germline and genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population.Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline.
View Article and Find Full Text PDFPurpose: To assess the contribution of germline pathogenic variants (PVs) in population-based series of breast cancers and the best strategy to improve detection rates.
Methods: Three cohort studies were utilized, including a hospital-based series identified from new UK mainstream testing criteria (group-1), offering testing to all women (group-2-BReast CAncer [BRCA]-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (group-3-Predicting Risk of Cancer at Screening). DNA samples from women with breast cancer were sequenced for PVs in , , and Partner and Localiser of BRCA2 ().
Background: High-grade serous ovarian cancer (HGSOC) can be treated with platinum-based neoadjuvant chemotherapy (NACT) and delayed primary surgery (DPS). Histopathological response to NACT can be assessed using Böhm's chemotherapy response score (CRS). We investigated whether germline BRCA1/2 (gBRCA1/2) genotype associated with omental CRS phenotype.
View Article and Find Full Text PDFPurpose: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.
View Article and Find Full Text PDFBackground: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity.
Methods: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds.
Background: Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly -related schwannomatosis (SWN), but when BVS are absent, this can also indicate -related or -related SWN.
View Article and Find Full Text PDFPurpose: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain.
Methods: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study.
Article Synopsis
- New diagnostic criteria for NF2-related schwannomatosis were established in 2022, leading to an updated prevalence study in the UK, which focused on the rate of de novo NF2 cases.
- A total of 1,084 living NF2 patients were identified, indicating a prevalence of 1 in 61,332, with a striking 72% of cases being de novo, many of which were mosaic.
- The findings also revealed that nonsense variants were most common (24.8%), while missense variants had a higher familial association (56%), emphasizing the importance of patient databases for accurate genetic counseling.
Article Synopsis
- This study investigates the role of inversions—structural variants that involve the rearrangement of DNA—in genetic diseases, using data from 33,924 families involved in the 100,000 Genomes Project.
- Researchers identified 47 ultra-rare rearrangements, including de novo inversions, in genes linked to disease, with analyses correlating genetic findings to clinical outcomes in some cases, including a specific diagnosis for three family members.
- The findings suggest that while inversions are less common in genetic diseases compared to other structural variants, they can significantly contribute to the etiology in approximately 1 in 750 families with rare conditions.
Article Synopsis
- Male breast cancer (MBC) is relatively rare, with 1 in 1000 men affected, and shows a higher likelihood of genetic risk factors compared to female breast cancer.
- The study analyzed germline testing for high-risk gene variants across 204 families with at least one MBC case, finding that 25% had pathogenic variants, particularly linked to specific genes.
- Results indicated that higher scores on the Manchester Scoring System correlate with a higher detection rate of these variants, suggesting it is a useful tool for assessing genetic risk in such families.
Background: Reanalysis of exome/genome data improves diagnostic yield. However, the value of reanalysis of clinical array comparative genomic hybridisation (aCGH) data has never been investigated. Case-by-case reanalysis can be challenging in busy diagnostic laboratories.
View Article and Find Full Text PDFIn the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref.
View Article and Find Full Text PDFHereditary Breast and Ovarian Cancer (HBOC) is a genetic condition associated with increased risk of cancers. The past decade has brought about significant changes to hereditary breast and ovarian cancer (HBOC) diagnostic testing with new treatments, testing methods and strategies, and evolving information on genetic associations. These best practice guidelines have been produced to assist clinical laboratories in effectively addressing the complexities of HBOC testing, while taking into account advancements since the last guidelines were published in 2007.
View Article and Find Full Text PDFPurpose: To determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familial -related schwannomatosis.
Methods: We conducted genetic screening of a cohort of 168 second-generation individuals meeting the clinical criteria for -related schwannomatosis. In addition to the current clinical screening techniques, targeted next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification analysis, we applied additional genetic screening techniques, including karyotype and RNA analysis.
Patients diagnosed with epithelial ovarian cancer may undergo reflex tumour / testing followed by germline testing in patients with a positive tumour test result. This testing model relies on tumour / tests being able to detect all types of pathogenic variant. We analysed germline and tumour test results from patients treated for epithelial ovarian cancer at our specialist oncological referral centre.
View Article and Find Full Text PDFArticle Synopsis
- The study examines the integration of genomic data across NHS laboratories in England and Wales, highlighting variations in data structure, quality, and ease of local assembly for cancer susceptibility gene testing.
- A survey of 51 clinical scientists revealed significant differences in how variant data is transferred, formatted, and classified within Laboratory Information Management Systems (LIMS) across the participating labs.
- The findings indicate that current workflows are often inefficient and prone to errors due to their manual nature, suggesting that implementing recommended improvements could streamline data submission processes for better national and international collaboration.
Background: The identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC.
Methods: Outcomes of germline , and _c.
Article Synopsis
- The study aimed to explore the occurrence of germline pathogenic variants (PVs) in women diagnosed with bilateral breast cancer.
- A total of 764 women underwent testing for specific variants, revealing varying detection rates, particularly higher in triple-negative and specific ER+HER2 cancers.
- Results indicate that the estrogen receptor (ER) status of the first breast cancer significantly predicts the ER status of the second tumor, especially in patients with certain PVs.
Purpose: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown.
Patients And Methods: Phase II trial with two entry points (EP1, EP2).
Women diagnosed with non-mucinous high-grade epithelial ovarian cancer (EOC) in England are often reflex-tested for germline and tumour / variants. The value of germline testing in women diagnosed aged ≥80 is questionable. We performed an observational study of all women diagnosed with non-mucinous high-grade EOC who underwent germline and tumour testing by the North West of England Genomic Laboratory Hub.
View Article and Find Full Text PDFArticle Synopsis
- - NF2-related schwannomatosis is a genetic condition that leads to the formation of multiple benign tumors, primarily schwannomas, due to inherited or new mutations in the NF2 gene.
- - The study highlights that over half of the new mutations in the NF2 gene (54%) occur at just six specific CpG sites, despite these sites making up less than 10% of all nonsense mutation positions.
- - Among these six CpG variants, one specific variant (c.586C>T; p.(Arg196Ter)) shows a significantly higher occurrence of new mutations compared to others, suggesting possible differences in how mutations arise during cellular reproduction.
Article Synopsis
- * Individual-level data from 16,722 patients, with the earliest submission dating back to 2000, revealed that over 60% of NHS MMR analyses were captured in the NDRS, with colorectal cancer being the most common cancer studied.
- * The NDRS dataset represents a comprehensive collection of clinical and genomic patient information, which can support ongoing research and potentially lead to the creation of a national genomic disease registry.
Purpose: To investigate frequency of germline pathogenic variants (PVs) in women with ductal carcinoma in situ (DCIS) and grade 1 invasive breast cancer (G1BC).
Methods: We undertook analysis in 311 women with DCIS and 392 with G1BC and extended panel testing (non-/) in 176/311 with DCIS and 156/392 with G1BC. We investigated PV detection by age at diagnosis, Manchester Score (MS), DCIS grade and receptor status.