Decision making for health-related research outcomes that alter diagnosis: A model from paediatric brain tumours.

Aims: The question of how to handle clinically actionable outcomes from retrospective research studies is poorly explored. In neuropathology, this problem is exacerbated by ongoing refinement in tumour classification. We sought to establish a disclosure threshold for potential revised diagnoses as determined by the neuro-oncology speciality.

Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

Background: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone.

Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study.

Objective: To evaluate patient preference for short (gist) or detailed/extensive decision aids (DA) for genetic testing at ovarian cancer (OC) diagnosis.

Design: Cohort study set within recruitment to the Systematic Genetic Testing for Personalised Ovarian Cancer Therapy (SIGNPOST) study (ISRCTN: 16988857).

Setting: North-East London Cancer Network (NELCN) population.

UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: , , and .

Germline pathogenic variants (GPVs) in the cancer predisposition genes , , , , , , , and are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in , , , and , there are few guidelines on how to manage the more moderate OC risk in patients with GPV in , , and , with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of and R as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in and .

Background: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO).

Methods: Our study recruited 875 female -heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO.

Unselected Population Genetic Testing for Personalised Ovarian Cancer Risk Prediction: A Qualitative Study Using Semi-Structured Interviews.

Unselected population-based personalised ovarian cancer (OC) risk assessments combining genetic, epidemiological and hormonal data have not previously been undertaken. We aimed to understand the attitudes, experiences and impact on the emotional well-being of women from the general population who underwent unselected population genetic testing (PGT) for personalised OC risk prediction and who received low-risk (<5% lifetime risk) results. This qualitative study was set within recruitment to a pilot PGT study using an OC risk tool and telephone helpline.

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline and parallel somatic testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Results from London Regional Clinical Genetics services over a 5-year period on germline testing in women diagnosed with breast cancer at <30 years.

Background: The most common cancer diagnosed in germline pathogenic variant (PV) carriers is premenopausal breast cancer. An increased rate of breast tumour HER2 positivity has been reported in this group. Screening for breast/other cancers is recommended in PV carriers.

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study.

Background: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer.

Prostate Cancer Risk by BRCA2 Genomic Regions.

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location.

Population Study of Ovarian Cancer Risk Prediction for Targeted Screening and Prevention.

Unlabelled: Unselected population-based personalised ovarian cancer (OC) risk assessment combining genetic/epidemiology/hormonal data has not previously been undertaken. We aimed to perform a feasibility study of OC risk stratification of general population women using a personalised OC risk tool followed by risk management. Volunteers were recruited through London primary care networks.

Association of Genomic Domains in and with Prostate Cancer Risk and Aggressiveness.

Pathogenic sequence variants (PSV) in or () are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 and 171 male PSV carriers with prostate cancer, and 3,388 and 2,880 male PSV carriers without prostate cancer. PSVs in the 3' region of (c.

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.

Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.

Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study.

Background: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies.

Objective: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.

Design, Setting, And Participants: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With or Mutations.

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for and mutation carriers.

Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 and 3525 mutation carriers) and a prospective cohort (2276 and 1610 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families.

Rothmund-Thomson Syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene.

Background: Poikiloderma is defined as a chronic skin condition presenting with a combination of punctate atrophy, areas of depigmentation, hyperpigmentation and telangiectasia. In a variety of hereditary syndromes such as Rothmund-Thomson syndrome (RTS), Clericuzio-type poikiloderma with neutropenia (PN) and Dyskeratosis Congenita (DC), poikiloderma occurs as one of the main symptoms. Here, we report on genotype and phenotype data of a cohort of 44 index patients with RTS or related genodermatoses.

Gene-gene interactions in breast cancer susceptibility.

There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.

BRCA1, BRCA2 and CHEK2 c.1100 delC mutations in patients with double primaries of the breasts and/or ovaries.

Background: Previous publications and utilisation of risk models for BRCA1 and BRCA2 mutation identification suggests that multiple primary disease in an individual is a strong predictor of a BRCA1/2 mutation and that this is more predictive than the same cancers occurring in close relatives.

Methods: This study assessed the pathological mutation detection rates for BRCA1, BRCA2 and the CHEK2c.1100 delC mutation in 2022 women with breast cancer, including 100 with breast/ovary double primary and 255 with bilateral breast cancer.

Update on genetic predisposition to breast cancer.

It has been evident for some time that individuals from some families exhibit a genetic predisposition to breast cancer. Since the discovery of the first breast cancer susceptibility gene, BRCA1 in the 1990s, much work has been carried out to identify further breast cancer susceptibility genes. This has led to the identification of another high-penetrance gene, BRCA2, a number of moderate-penetrance genes and, more recently, common low-penetrance genes and loci.