Population-based germline testing of , and in breast cancer patients in the United Kingdom: Evidence to support extended testing, and definition of groups who may not require testing.

Purpose: 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 ().

Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria for -related schwannomatosis.

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.

Structures of human PTP1B variants reveal allosteric sites to target for weight loss therapy.

Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of leptin signaling whose disruption protects against diet-induced obesity in mice. We investigated whether structural characterization of human PTP1B variant proteins might reveal precise mechanisms to target for weight loss therapy. We selected 12 rare variants for functional characterization from exomes from 997 people with persistent thinness and 200,000 people from UK Biobank.

Improved sensitivity for detection of pathogenic variants in familial -related schwannomatosis.

Purpose: 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.

Health Systems in High-Performance Sport: Key Functions to Protect Health and Optimize Performance in Elite Athletes.

Enabling athletes to achieve peak performances while also maintaining high levels of health is contextually complex. We aim to describe what a 'health system' is and apply the essential functions of stewardship, financing, provision of services and resource generation to an Australian high-performance sport context. We introduce a fifth function that health systems should not detract from athletes' ability to achieve their sports goals.

Optimization of polygenic risk scores in BRCA1/2 pathogenic variant heterozygotes in epithelial ovarian cancer.

Purpose: A third of familial epithelial ovarian cancer (EOC) is explained by BRCA1/2 pathogenic variants. Polygenic risk scores (PRSs) for BRCA1/2 heterozygotes associated with EOC have been created, but impact of combination with clinical and hormonal risk factors is unclear.

Methods: We genotyped 300 cases and 355 controls and constructed modified PRSs based on those validated by Barnes et al.

Accelerated waning of the humoral response to COVID-19 vaccines in obesity.

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.

Validation of lung cancer polygenic risk scores in a high-risk case-control cohort.

Purpose: Screening with low-dose computed tomography reduces lung cancer (LC) mortality. Risk prediction models used for screening selection do not include genetic variables. Here, we investigated the performance of previously published polygenic risk scores (PRSs) for LC, considering their potential to improve screening selection.

Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent.

Purpose: Polygenic risk scores (PRSs) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi Jewish (AJ) population is assumed to be of White European (WE) origin in some commercially available PRSs despite differing effect allele frequencies (EAFs). We conducted a case-control study of WE and AJ women from the Predicting Risk of Cancer at Screening Study.

Perspectives on the implications of carrying putative pathogenic variants in the medulloblastoma predisposition genes ELP1 and GPR161.

Recent genetic sequencing studies in large series' of predominantly childhood medulloblastoma have implicated loss-of-function, predominantly truncating, variants in the ELP1 and GPR161 genes in causation of the MB subtype specifically. The latter association, along with a report of an index case with some features of Gorlin syndrome has led to speculation that GPR161 may also cause Gorlin syndrome. We show that these genes are associated with relatively low absolute risks of medulloblastoma from extrapolating lifetime risks in the general population and odds ratios from the population database gnomAD.

Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21.

Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants.

Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers.

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.

High detection rate from genetic testing in BRCA-negative women with familial epithelial ovarian cancer.

Purpose: Epithelial ovarian cancer (EOC) is associated with pathogenic variants (PVs) in homologous recombination and/or mismatch repair genes. We aimed to review the testing of women with familial EOC at our center.

Methods: Women with familial EOC (≥2 EOC in family, including index case) referred to our center between 1993 and 2021 were included.

A mechanistic mathematical model of initiation and malignant transformation in sporadic vestibular schwannoma.

Background: A vestibular schwannoma (VS) is a relatively rare, benign tumour of the eighth cranial nerve, often involving alterations to the gene NF2. Previous mathematical models of schwannoma incidence have not attempted to account for alterations in specific genes, and could not distinguish between nonsense mutations and loss of heterozygosity (LOH).

Methods: Here, we present a mechanistic approach to modelling initiation and malignant transformation in schwannoma.

Germline intergenic duplications at Xq26.1 underlie Bazex-Dupré-Christol basal cell carcinoma susceptibility syndrome.

Background: Bazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1.