Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records.

OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018.

BACKGROUND: Sebaceous carcinomas (SC) may be associated with the cancer predisposition syndrome Muir-Torre/Lynch syndrome (MTS/LS), identifiable by SC mismatch repair (MMR) screening; however, there is limited data on MMR status of SC. OBJECTIVE: To describe the epidemiology of SC, copresentation of other cancers, and population level frequency of MMR screening in SC. METHODS: A population-based retrospective cohort study of SC patients in the National Cancer Registration and Analysis Service in England. RESULTS: This study included 1077 SC cases (739 extraocular, 338 periocular). Age-standardized incidence rates (ASIR) were higher in men compared with women, 2.74 (95% CI, 2.52-9.69) per 1,000,000 person-years for men versus 1.47 person-years (95% CI, 1.4-1.62) for women. Of the patients, 19% (210/1077) developed at least one MTS/LS-associated malignancy. MMR immunohistochemical screening was performed in only 20% (220/1077) of SC tumors; of these, 32% (70/219) of tumors were MMR deficient. LIMITATIONS: Retrospective design. CONCLUSIONS: Incorporation of MMR screening into clinical practice guidelines for the management of SC will increase the opportunity for MTS/LS diagnoses, with implications for cancer surveillance, chemoprevention with aspirin, and immunotherapy treatment targeted to MTS/LS cancers.

Identification of people with Lynch syndrome from those presenting with colorectal cancer in England: baseline analysis of the diagnostic pathway.

It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017 state that all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation of the agreed diagnostic pathway at a baseline point 2 years post-publication of official guidelines. Using real-world data collected and curated by the National Cancer Registration and Analysis Service (NCRAS), we retrospectively followed up all people diagnosed with CRC in England in 2019. Nationwide laboratory diagnostic data incorporated somatic (tumour) testing for dMMR (via immunohistochemistry or microsatellite instability), somatic testing for MLH1 promoter methylation and BRAF status, and constitutional (germline) testing of MMR genes. Only 44% of CRCs were screened for dMMR; these figures varied over four-fold with respect to geography. Of those CRCs identified as dMMR, only 51% underwent subsequent diagnostic testing. Overall, only 1.3% of patients with colorectal cancer had a germline MMR genetic test performed; up to 37% of these tests occurred outside of NICE guidelines. The low rates of molecular diagnostic testing in CRC support the premise that Lynch syndrome is underdiagnosed, with significant attrition at all stages of the testing pathway. Applying our methodology to subsequent years' data will allow ongoing monitoring and analysis of the impact of recent investment. If the diagnostic guidelines were fully implemented, we estimate that up to 700 additional people with LS could be identified each year.

Botulinum A toxin in the treatment of neurogenic detrusor overactivity: a consolidated field of application.

Several studies show promising results in terms of both clinical and urodynamic improvements, supporting the efficacy, safety and tolerability of botulinum toxin serotype A (BoNT-A) for managing neurogenic detrusor overactivity (DO). DO due to spinal cord injuries represents the most frequently treated dysfunction, where the efficacy appears to be high, with beneficial effects on quality of life. Data on the management of DO in patients with multiple sclerosis, cerebrovascular accidents and Parkinson's disease are scarce or absent; thus, the suitability of BoNT-A in the treatment neurogenic DO of other diseases of central nervous origin requires further investigation. Indeed, good quality, randomized controlled trials are still needed to identify not only the most appropriate patients to treat, but also the appropriate dose, administration technique, frequency of treatment and any eventual long-term complications. Thus, the use of intravesical BoNT-A in the control of neurogenic DO appears to be promising, but the drug is still in phase 3 clinical development, and further high-quality research is essential.

PREP1 tumor suppressor protects the late-replicating DNA by controlling its replication timing and symmetry.

The synthesis of middle-to-late-replicating DNA can be affected independently of the rest of the genome by down-regulating the tumor suppressor PREP1 (PKNOX1). Indeed, DNA combing shows that PREP1 down-regulation affects DNA replication rate, increases the number of simultaneously firing origins and the asymmetry of DNA replication, leading to DNA damage. Genome-wide analysis of replication timing by Repli-seq shows that, upon PREP1 down-regulation, 25% of the genome is replicated earlier in the S-phase. The targeted DNA sequences correspond to Lamin-Associated Domains (LADs), and include late-replicating (LRRs) and temporal transition regions (TTRs). Notably, the distribution of PREP1 DNA binding sites and of its target genes indicates that DNA replication defects are independent of the overall PREP1 transcriptional activity. Finally, PREP1 down-regulation causes a substantial decrease in Lamin B1 levels. This suggests that DNA is released from the nuclear lamina earlier than in the control cells and is available for replication, thus explaining timing defects and DNA damage.This is the first evidence that the replication timing of a specific fraction of the human genome is affected by PREP1 tumor suppressor. This previously unknown function might significantly contribute to the genomic instability observed in human tumors.

Body mass index and lower urinary tract symptoms in women.

INTRODUCTION: The prevalence of obesity has been rising sharply in industrialised countries over the past decade. As the Body Mass Index (BMI) is recognized as an accurate and objective measurement of individual body mass, this study investigated whether BMI is associated with lower urinary tract symptoms in women. MATERIALS AND METHODS: This retrospective study analysed a database of 750 female patients who were referred to the Uro-Gynaecology Unit from 2002 to 2004 because of urinary and sexual disturbances. Patients were divided into four classes (I, II, III, IV). Each class was analysed as a function of the following variables: type and grade of urinary incontinence, number of daily pads, irritative symptoms, sexual activity, micturitional urgency or detrusor hyperactivity, urine leakage during urodynamics testing while coughing or performing Valsava's manoeuvre, dysuria, abdominal straining, stop-go micturition, feeling of incomplete bladder emptying, feeling of perineal heaviness, hypovalid stream, constipation, grade and type of urogenital prolapse. RESULTS: In BMI class I did not complain of urinary incontinence. 155 70.8% referred urinary leakage while coughing or under physical effort. In Class II BMI 78.9% referred urinary incontinence. The incidence rose as the BMI increased. In BMI class III, 95.1% referred urinary incontinence and all 16 patients in BMI class IV were incontinent. CONCLUSIONS: Obese women are more prone to urinary incontinence which has a negative impact on the patient's quality of life and depression status. Mental status as well as anatomic deficits may explain the relationship between obesity and incontinence.