A5066680610- BRCA gene mutations in cancer
- Cancer Genomics and Diagnostics
- PARP inhibition in cancer therapy
- Neurofibromatosis and Schwannoma Cases
- Ovarian cancer diagnosis and treatment
- Meningioma and schwannoma management
- Genetic factors in colorectal cancer
- Bone Tumor Diagnosis and Treatments
- Lung Cancer Treatments and Mutations
- Genomics and Rare Diseases
- RNA modifications and cancer
- Cystic Fibrosis Research Advances
- Genomic variations and chromosomal abnormalities
- Renal cell carcinoma treatment
- CRISPR and Genetic Engineering
- Renal and related cancers
- RNA and protein synthesis mechanisms
- Chromatin Remodeling and Cancer
- Tracheal and airway disorders
- Sarcoma Diagnosis and Treatment
- Colorectal Cancer Treatments and Studies
- Neonatal Respiratory Health Research
- Colorectal Cancer Screening and Detection
- Molecular Biology Techniques and Applications
- RNA Research and Splicing
University of California, Santa Cruz
2016-2024
University of Manchester
2012-2024
United States Air Force Academy
2024
Manchester University NHS Foundation Trust
2012-2023
St Mary's Hospital
2012-2022
St Mary's Hospital
2001-2022
St. Mary's Hospital
2007-2022
Manchester Academic Health Science Centre
2009-2022
Institut thématique Génétique, génomique et bioinformatique
2021
Bioinformatics Institute
2021
There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best manage the risk of in syndrome. The Manchester International Consensus Group was convened April 2017 address this unmet need. aim develop clear and comprehensive guidance regarding management sequelae based on existing evidence expert opinion medical professionals patients.
<b><i>Background:</i></b> Four sets of clinical diagnostic criteria for neurofibromatosis 2 (NF2) have been developed by groups expert clinicians, but sensitivity has never formally assessed. The differ people without bilateral vestibular schwannomas, which are pathognomonic NF2. <b><i>Objective: </i></b> To empirically evaluate the four existing <b><i>Methods: study was based on 163 403 in United Kingdom NF2 registry (41%) who presented schwannomas. authors applied to each person at initial...
Blood samples from 125 unrelated families with classical type 2 neurofibromatosis (NF2) bilateral vestibular schwannomas have been analysed for mutations in the NF2 gene. A further 17 fulfilling modified criteria also analysed. Causative identified 54 (43%) and six (35%) of those criteria. Forty-two cases 38 truncating had an average age at onset symptoms 19 years diagnosis 22.4 years. Fifty-one 16 splice site (15 six), missense (18 large deletions five) 27.8 33.4 Subjects were significantly...
The validation and verification of laboratory methods procedures before their use in clinical testing is essential for providing a safe useful service to clinicians patients. This paper outlines the principles context human molecular genetic testing. We describe implementation processes, types tests key components, suggest some relevant statistical approaches that can be used by individual laboratories ensure are conducted defined standards.
<h3>Background:</h3> Schwannomatosis is a rare condition characterised by multiple schwannomas and lack of involvement the vestibular nerve. A recent report identified bi-allelic mutations in <i>SMARCB1/INI1</i> gene single family with schwannomatosis. We aimed to establish contribution <i>SMARCB1</i> <i>NF2</i> genes sporadic familial schwannomatosis our cohort. <h3>Methods:</h3> performed DNA sequence dosage analysis 28 cases 15 families <h3>Results:</h3> germline 5 (33.3%) 2 (7.1%)...
<b>Background:</b> Neurofibromatosis type 2 (NF2) is almost unique among inherited disorders in the frequency of mosaicism first affected generation. However, implications this on transmission risks have not been fully elucidated. <b>Methods:</b> The expanded database 460 families with NF2 and 704 individuals was analysed for to offspring. <b>Results:</b> 64 mosaic patients, a projected rate 33% sporadic classical bilateral vestibular schwannoma at presentation 60% those presenting...
Objectives Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap neurofibromatosis-2 (NF2), but the underlying epidemiology poorly understood. We present birth incidence prevalence allowing for NF2. Methods NF2 cases were ascertained from Manchester region England (population=4.8 million) across UK. Point calculated regional statistics. Genetic analysis was also performed on , LZTR1 SMARCB1 blood...
Abstract We recently reported SMARCE1 mutations as a cause of spinal clear cell meningiomas. Here, we have identified five further cases with non‐ NF2 meningiomas and six cranial Three the three were tumours. screened them for investigated copy number changes in all point mutation‐negative samples. two novel individuals Copy analysis large deletion 5′ end unrelated probands Testing affected unaffected relatives one these same female siblings their father, providing evidence incomplete...
To determine the specificity of current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to requirement unilateral vestibular schwannoma (VS) and at least other NF2-related tumors.We interrogated our Manchester NF2 database, which contained 205 individuals meeting who initially presented with a VS. Of these, 83 (40.7%) went on develop contralateral We concentrated genetic analysis group 70 fulfilled additional nonintradermal schwannomas.Overall, 5/70 (7%) VS...
To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for variants lymphocyte DNA and where available tumor DNA. The proportion individuals proven or presumed mosaic variant was assessed allele frequencies identified evaluated using next-generation sequencing.The rate proven/presumed 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic...
Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent mortality colonoscopic surveillance aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports screening EC; however, the expected proportion test positives, optimal strategy is uncertain. Previous studies from insurance-based...
PurposeWhere multiple in silico tools are concordant, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework affords supporting evidence toward pathogenicity or benignity, equivalent to a likelihood ratio ~2. However, limited availability "clinical truth sets" prior use tool training limits their utility evaluation performance.MethodsWe created set 9,436 missense variants classified as deleterious tolerated clinically validated...
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients different variants of the disease. Correlation between gene mutation patient phenotype suggested exist. However, several independent studies have shown that fraction various phenotypes...
<h3>Background</h3> Meningiomas have been reported to occur in approximately 50% of neurofibromatosis type 2 (NF2) patients. The <i>NF2</i> gene is commonly biallelically inactivated both schwannomas and meningiomas. spectrum mutations consists mainly truncating (nonsense frameshift) mutations. A smaller number patients missense mutations, which are associated with a milder disease phenotype. <h3>Methods</h3> This study analysed the cumulative incidence gender effects as well...
<h3>Background</h3> Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype–phenotype correlations are well established in NF2, little known about effects of mutation type or location within the gene on mortality. Improvements NF2 diagnosis management have occurred, but their effect patient survival unknown. <h3>Methods</h3> We evaluated clinical...
Pathogenic variants in BRCA1 or BRCA2 are identified ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes alternative mutational mechanisms altering have not explained the missing heritability. Here, we report a dominantly inherited 5′ UTR variant associated epigenetic silencing due to promoter hypermethylation two and methylation ten CpG dinucleotides who cancer but do germline pathogenic...
Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) expression correlates with malignancy, but its role(s) in pathogenesis remains enigmatic. We interrogated the IGF2BP3-RNA interaction network pancreatic ductal adenocarcinoma (PDAC) cells. Using a combination of genome-wide approaches, we have identified 164 direct targets IGF2BP3. These transcripts encode proteins enriched for functions such as cell migration, proliferation, and adhesion. Loss IGF2BP3 reduced PDAC invasiveness...