Long-term renal function in children with Wilms Tumour and constitutional WT1 pathogenic variant

BACKGROUND: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. METHODS: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. RESULTS: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4–74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3–16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. CONCLUSIONS: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation

Anticipated health behaviour changes and perceived control in response to disclosure of genetic risk of breast and ovarian cancer: a quantitative survey study among women in the UK

BACKGROUND: Genetic risk assessment for breast cancer and ovarian cancer (BCOC) is expected to make major inroads into mainstream clinical practice. It is important to evaluate the potential impact on women ahead of its implementation in order to maximise health benefits, as predictive genetic testing without adequate support could lead to adverse psychological and behavioural responses to risk disclosure. OBJECTIVE: To examine anticipated health behaviour changes and perceived control to disclosure of genetic risk for BCOC and establish demographic and person-specific correlates of adverse anticipated responses in a population-based sample of women. DESIGN: Cross-sectional quantitative survey study carried out by the UK Office for National Statistics in January and March 2014. SETTING: Face-to-face computer-assisted interviews conducted by trained researchers in participants’ homes. PARTICIPANTS: 837 women randomly chosen from households across the UK identified from the Royal Mail’s Postcode Address File. OUTCOME MEASURES: Anticipated health behaviour change and perceived control to disclosure of BCOC risk. RESULTS: In response to a genetic test result, most women (72%) indicated ‘I would try harder to have a healthy lifestyle’, and over half (55%) felt ‘it would give me more control over my life’. These associations were independent of demographic factors or perceived risk of BCOC in Bonferroni-corrected multivariate analyses. However, a minority of women (14%) felt ‘it isn’t worth making lifestyle changes’ and that ‘I would feel less free to make choices in my life’ (16%) in response to BCOC risk disclosure. The former belief was more likely to be held by women who were educated below university degree level (P<0.001) after adjusting for other demographic and person-specific correlates. CONCLUSION: These findings indicate that women in the UK largely anticipate that they would engage in positive health behaviour changes in response to BCOC risk disclosure

Health care professionals' attitudes towards population-based genetic testing and risk-stratification for ovarian cancer: A survey study

BACKGROUND: Ovarian cancer is usually diagnosed at a late stage when outcomes are poor. Personalised ovarian cancer risk prediction, based on genetic and epidemiological information and risk stratified management in adult women could improve outcomes. Examining health care professionals’ (HCP) attitudes to ovarian cancer risk stratified management, willingness to support women, self-efficacy (belief in one’s own ability to successfully complete a task), and knowledge about ovarian cancer will help identify training needs in anticipation of personalised ovarian cancer risk prediction being introduced. METHODS: An anonymous survey was distributed online to HCPs via relevant professional organisations in the UK. Kruskal-Wallis tests and pairwise comparisons were used to compare knowledge and self-efficacy scores between different types of HCPs, and attitudes toward population-based genetic testing and risk stratified management were described. Content analysis was undertaken of free text responses concerning HCPs willingness to discuss risk management options with women. RESULTS: One hundred forty-six eligible HCPs completed the survey: oncologists (31%); genetics clinicians (30%); general practitioners (22%); gynaecologists (10%); nurses (4%); and ‘others’. Scores for knowledge of ovarian cancer and genetics, and self-efficacy in conducting a cancer risk consultation were generally high but significantly lower for general practitioners compared to genetics clinicians, oncologists, and gynaecologists. Support for population-based genetic testing was not high (<50%). Attitudes towards ovarian cancer risk stratification were mixed, although the majority of participants indicated a willingness to discuss management options with patients. CONCLUSIONS: Larger samples are required to investigate attitudes to population-based genetic testing for ovarian cancer risk and to establish why some HCPs are hesitant to offer testing to all adult female patients. If ovarian cancer risk assessment using genetic testing and non-genetic information including epidemiological information is rolled out on a population basis, training will be needed for HCPs in primary care to enable them to provide appropriate support to women at each stage of the process

Attitude towards and factors affecting uptake of population based BRCA testing in the Ashkenazi Jewish population: a cohort study

Objective To evaluate factors affecting unselected‐population‐based‐BRCA‐testing in Ashkenazi‐Jews (AJ). Design Cohort‐study set within recruitment to the GCaPPS‐trial (ISRCTN73338115). Setting North‐London AJ‐population. Population or Sample AJ women/men >18‐years, recruited through self‐referral. Methods AJ‐women/men underwent pre‐test counselling for BRCA‐testing through recruitment clinics (clusters). Consenting individuals provided blood‐sample for BRCA‐testing. Socio‐demographic/family‐history/knowledge/psychological well‐being data along‐with benefits/risks/cultural‐influences (18‐item‐questionnaire measuring ‘attitude’) were collected. 4‐item likert‐scales analysed initial ‘interest’ and ‘intention‐to‐test’ pre‐counselling. Uni‐&‐multivariable logistic‐regression‐models evaluated factors affecting uptake/interest/intention‐to undergo BRCA‐testing. Statistical inference was based on cluster robust standard‐errors and joint Wald‐tests for significance. Item‐Response‐Theory and graded‐response‐models modelled responses to 18‐item questionnaire. Main Outcome Measures Interest, intention, uptake, attitude towards BRCA‐testing. Results 935 (women=67%/men=33%; mean‐age=53.8(S.D=15.02) years) individuals underwent pre‐test genetic‐counselling. Pre‐counselling 96% expressed interest but 60% indicated clear intention‐to undergo BRCA‐testing. Subsequently 88% opted for BRCA‐testing. BRCA‐related knowledge (p=0.013) and degree‐level education(p=0.01) were positively and negatively (respectively) associated with intention‐to‐test. Being married/cohabiting had four‐fold higher‐odds for BRCA‐testing uptake (p=0.009). Perceived benefits were associated with higher pre‐counselling odds for interest and intention‐to undergo BRCA‐testing. Reduced uncertainty/reassurance were the most important factors contributing to decision‐making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional‐impact/inability to prevent cancer/marriage‐ability/ethnic‐focus/stigmatization) were significantly associated with lower‐odds of uptake‐of BRCA‐testing, and discriminated between acceptors and decliners. Male‐gender/degree‐level‐education (p=0.001) had weaker, while having children had stronger (p=0.005) attitudes towards BRCA‐testing. Conclusions BRCA‐testing in the AJ‐population has high acceptability. Pre‐test counselling increases awareness of disadvantages/limitations of BRCA‐testing, influencing final cost‐benefit perception and decision‐making on undergoing testing. This article is protected by copyright. All rights reserved

Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term outcomes

© 2019 Royal College of Obstetricians and Gynaecologists Objective: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. Design: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. Setting: North London Ashkenazi-Jewish (AJ) population. Population/Sample: AJ women/men. Methods: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. Inclusion criteria: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. Interventions: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. Main outcome measures: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. Results: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97–4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89–2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74–2.26%). Conclusion: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. Tweetable abstract: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life

Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations.

BACKGROUND: Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. METHODS: A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. INCLUSION CRITERIA: Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier. Ashkenazi Jewish men/women underwent pre-test genetic counselling prior to BRCA1/2 testing in the Genetic Cancer Prediction through Population Screening trial (ISRCTN73338115). Genetic counselling clinics (clusters) were randomised to traditional counselling (TC) and DVD-based counselling (DVD-C) approaches. DVD-C involved a DVD presentation followed by shorter face-to-face genetic counselling. Outcome measures included genetic testing uptake, cancer risk perception, increase in knowledge, counselling time and satisfaction (Genetic Counselling Satisfaction Scale). Random-effects models adjusted for covariates compared outcomes between TC and DVD-C groups. One-sided 97.5% CI was used to determine non-inferiority. SECONDARY OUTCOMES: relevance, satisfaction, adequacy, emotional impact and improved understanding with the DVD; cost-minimisation analysis for TC and DVD-C approaches. RESULTS: 936 individuals (clusters=256, mean-size=3.6) were randomised to TC (n=527, clusters=134) and DVD-C (n=409, clusters=122) approaches. Groups were similar at baseline, mean age=53.9 (SD=15) years, women=66.8%, men=33.2%. DVD-C was non-inferior to TC for increase in knowledge (d=-0.07; lower 97.5% CI=-0.41), counselling satisfaction (d=-0.38, 97.5% CI=1.2) and risk perception (d=0.08; upper 97.5% CI=3.1). Group differences and CIs did not cross non-inferiority margins. DVD-C was equivalent to TC for uptake of genetic testing (d=-3%; lower/upper 97.5% CI -7.9%/1.7%) and superior for counselling time (20.4 (CI 18.7 to 22.2) min reduction (p<0.005)). 98% people found the DVD length and information satisfactory. 85-89% felt it improved their understanding of risks/benefits/implications/purpose of genetic testing. 95% would recommend it to others. The cost of genetic counselling for DVD-C=£7787 and TC=£17 307. DVD-C resulted in cost savings=£9520 (£14/volunteer). CONCLUSIONS: DVD-C is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to TC. TRIAL REGISTRATION NUMBER: ISRCTN 73338115

A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. ΔMLH1, ΔMSH6, and ΔMSH2 signatures were similar to each other but distinct from ΔPMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies

A Pathogenic Mosaic TP53 Mutation in Two Germ Layers Detected by Next Generation Sequencing.

Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described

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. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene