Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing.

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls.

Reduced Breast and Ovarian Cancer Through Targeted Genetic Testing: Estimates Using the NEEMO Microsimulation Model.

The effectiveness and cost-effectiveness of genetic testing for hereditary breast and ovarian cancer largely rely on the identification and clinical management of individuals with a pathogenic variant prior to developing cancer. Simulation modelling is commonly utilised to evaluate genetic testing strategies due to its ability to synthesise collections of data and extrapolate over long time periods and large populations. Existing genetic testing simulation models use simplifying assumptions for predictive genetic testing and risk management uptake, which could impact the reliability of their estimates.

Sleep restriction and age effects on distinct aspects of cognition in adolescents.

Insufficient sleep negatively impacts scholastic performance in children and adolescents. Here we use a dose-response time in bed (TIB) restriction study to evaluate associations between sleep loss and multiple aspects of cognition. We evaluated changes in cognitive measures across ages 10 to 23 years and determined whether the effects of sleep loss changed across this age range.

Stromal lymphocytes are associated with upgrade of B3 breast lesions.

Various histopathological, clinical and imaging parameters have been evaluated to identify a subset of women diagnosed with lesions with uncertain malignant potential (B3 or BIRADS 3/4A lesions) who could safely be observed rather than being treated with surgical excision, with little impact on clinical practice. The primary reason for surgery is to rule out an upgrade to either ductal carcinoma in situ or invasive breast cancer, which occurs in up to 30% of patients. We hypothesised that the stromal immune microenvironment could indicate the presence of carcinoma associated with a ductal B3 lesion and that this could be detected in biopsies by counting lymphocytes as a predictive biomarker for upgrade.

Maturational trend of daytime sleep propensity in adolescents.

Study Objectives: The teenage increase in sleepiness is not simply a response to decreasing nighttime sleep duration. Daytime sleepiness increases across adolescence even when prior sleep duration is held constant. Here we determine the maturational trend in daytime sleep propensity assessed with the multiple sleep latency test (MSLT) and assess the trend's relation to pubertal maturation and changes in the sleep electroencephalogram.

Earlier Bedtime and Its Effect on Adolescent Sleep Duration.

Background And Objectives: Sleep duration decreases by ∼10 minutes per year throughout adolescence. A circadian phase delay and changes in homeostatic sleep regulation enable adolescents to stay up later. We determine if teens are able to increase sleep duration by advancing bedtime and whether this ability changes with age.

Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care.

Objective: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing.

Design, Setting, Participants: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study.

Sleep restriction effects on sleep spindles in adolescents and relation of these effects to subsequent daytime sleepiness and cognition.

Study Objectives: Limiting spindle activity via sleep restriction could explain some of the negative cognitive effects of sleep loss in adolescents. The current study evaluates how sleep restriction affects sleep spindle number, incidence, amplitude, duration, and wave frequency and tests whether sleep restriction effects on spindles change across the years of adolescence. The study determines whether sleep restriction effects on daytime sleepiness, vigilance, and cognition are related to changes in sleep spindles.

Molecular Genetic Characteristics of , a Proposed New Ovarian Cancer Predisposing Gene.

was recently identified as a new candidate ovarian cancer (OC)-predisposing gene from the genetic analysis of carriers of c.1813C>T; p.L605F in OC families.

Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants.

Background: Breast cancers (BCs) that arise in individuals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1 and BRCA2, PALB2, and RAD51C, have been shown to exhibit biallelic loss in the respective genes and be associated with triple-negative breast cancer (TNBC) and distinctive somatic mutational signatures. Tumor sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development.

Methods: Exome sequencing was performed on paired normal-breast tumor DNA from 124 carriers of germline loss-of-function (LoF) or missense variant carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-control study.

Sleep electroencephalogram evidence of delayed brain maturation in attention deficit hyperactivity disorder: a longitudinal study.

Study Objectives: This study investigates whether longitudinally measured changes in adolescent brain electrophysiology corroborate the maturational lag associated with attention deficit hyperactivity disorder (ADHD) reported in magnetic resonance imaging (MRI) studies and cross-sectional sleep electroencephalogram (EEG) data.

Methods: Semiannually nine adolescents diagnosed with ADHD (combined presentation, DSM-V criteria, mean age 12.39 ± 0.

Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression.

Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease.

Sleep restriction and age effects on waking alpha EEG activity in adolescents.

Study Objectives: To understand how sleep need changes across adolescence our laboratory is carrying out a longitudinal dose-response study on the effects of sleep duration on daytime sleepiness and performance. This report focuses on the relation of the waking alpha (8-12 Hz) electroencephalogram (EEG) to prior sleep duration, whether this relation changes with age, and whether decreased waking alpha power is related to changes in daytime sleepiness, vigilance, and executive functioning.

Methods: Study participants ( = 77) entered the study at ages ranging from 9.

Contribution of large genomic rearrangements in to familial breast cancer: implications for genetic testing.

Background: is the most important contributor to familial breast cancer after and . Large genomic rearrangements (LGRs) in and are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs in has not been systematically studied.

Estimating the proportion of pathogenic variants from breast cancer case-control data: Application to calibration of ACMG/AMP variant classification criteria.

For genes with reliable estimates of disease risk associated with loss-of-function variants, case-control data can be used to estimate the proportion of variants of typical risk effect for defined groups of variants, of relevance for variant classification. A calculation was derived for a maximum likelihood estimate of the proportion of pathogenic variants of typical effect from case-control data and applied to rare variant counts for ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D from published breast cancer studies: BEACCON (5770 familial cases and 5741 controls) and breast cancer risk after diagnostic sequencing (60,466 familial and population-based cases and 53,461 controls). There was significant evidence of pathogenic variants among rare noncoding variants, in particular deeper intronic variants, for BRCA1 (13%, p = 8.

Integration of tumour sequencing and case-control data to assess pathogenicity of RAD51C missense variants in familial breast cancer.

While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF < 0.

Unselected Women's Experiences of Receiving Genetic Research Results for Hereditary Breast and Ovarian Cancer: A Qualitative Study.

Although there is growing consensus that clinically actionable genetic research results should be returned to participants, research on recipients' experiences and best practices for return of research results is scarce. This study explored how women in a population-based study (pool) experience receiving research results about actionable pathogenic variants (PVs) for hereditary breast and ovarian cancer (HBOC) using a two-step notification process with telephone genetic counseling (TGC) support. We conducted qualitative interviews with pool participants with an HBOC PV.

A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene.

Background: Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes.

Methods: Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.

Evaluation of two population screening programmes for founder mutations in the Australian Jewish community: a protocol paper.

Introduction: People of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer. Three specific pathogenic variants, referred to as -Jewish founder mutations (B-JFM), account for >90% of pathogenic variants in people of AJ ancestry. Current practice of identifying eligible individuals for testing based on personal and/or family history has been shown to miss at least 50% of people who have one of these variants.

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present.

Longitudinal Analysis of Sleep Spindle Maturation from Childhood through Late Adolescence.

Sleep spindles are intermittent bursts of 11-15 Hz EEG waves that occur during non-rapid eye movement sleep. Spindles are believed to help maintain sleep and to play a role in sleep-dependent memory consolidation. Here we applied an automated sleep spindle detection program to our large longitudinal sleep EEG dataset (98 human subjects, 6-18 years old, >2000 uninterrupted nights) to evaluate maturational trends in spindle wave frequency, density, amplitude, and duration.