Dafydd Gareth Evans

The University of Manchester · Centre for Genetic Medicine

Background/Objectives: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or microsatellite instability (MSI) testing, but concordance...

Background Breast cancer is the most common form of cancer in women. Adult weight gain and modifiable health behaviors, including smoking, alcohol intake, and lack of physical activity, are well-known risk factors. Most weight gain in women occurs between the ages of 18 and 35 years. Digital interventions have the potential to address logistical ch...

Background Whether carriers of BRCA1 or BRCA2 (BRCA1/2) pathogenic variants (PVs) have increased risks of childhood, adolescent, and young adult (CAYA) cancers is controversial. We aimed to evaluate this risk and to inform clinical care of young BRCA1/2 PV carriers and genetic testing for CAYA cancer patients. Methods Using data from 47,117 indivi...

Background High-grade serous ovarian cancer (HGSOC) can be treated with platinum-based neoadjuvant chemotherapy (NACT) and delayed primary surgery (DPS). Histopathological response to NACT can be assessed using Böhm’s chemotherapy response score (CRS). We investigated whether germline BRCA1/2 (g BRCA1/2 ) genotype associated with omental CRS phenot...

The variability in vestibular schwannoma growth rates greatly complicates clinical treatment. Management options are limited to radiological observation, surgery, radiotherapy and, in specific cases, bevacizumab therapy. As such, there is a pressing requirement for growth restricting drugs for vestibular schwannoma. This study explored potential pr...

Background The incorporation of breast density and a polygenic risk score (PRS) into breast cancer risk prediction models can alter previously communicated risk estimates. Previous research finds that risk communication does not usually change personal risk appraisals. This study aimed to examine how women from the family history risk study apprais...

Background Genetic testing to identify germline high-risk pathogenic variants in breast cancer susceptibility genes is increasingly part of the breast cancer diagnostic pathway. Novel patient-centred pathways may offer opportunity to expand capacity and reduce turnaround time. Methods We recruited 1140 women with unselected breast cancer to underg...

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings ind...

Purpose Mammographic density is associated with the risk of developing breast cancer and can be predicted using deep learning methods. Model uncertainty estimates are not produced by standard regression approaches but would be valuable for clinical and research purposes. Our objective is to produce deep learning models with in-built uncertainty est...

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 NF2-related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1-related or LZTR...

Purpose: Breast density is associated with the risk of developing cancer and can be automatically estimated using deep learning models from digital mammograms. Our aim is to evaluate the capacity and reliability of such models to predict density from low-dose mammograms taken to enable risk estimates for younger women. Approach: We trained deep...

Germline genetic testing for pathogenic variants (PVs) in breast cancer (BC) genes is currently triggered by algorithms that assess the likelihood of PVs in specific patient populations.1 Testing in patients with BC in England was updated in April 2022, making it more widely avail- able, including all women diagnosed <40 years, except those with gr...

Background Breast cancer is the most frequent female malignancy in the UK. Around 20% of cases are linked to weight gain, excess weight and health behaviours. We designed a weight gain prevention, health behaviour intervention for young women at increased risk. Methods The study comprised a single arm observational study over 2 months testing acce...

Recent exome-wide association studies have explored the role of coding variants in breast cancer risk, highlighting the role of rare variants in multiple genes including BRCA1, BRCA2, CHEK2, ATM and PALB2, as well as new susceptibility genes e.g., MAP3K1. These genes, however, explain a small proportion of the missing heritability of the disease. M...

Objectives New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also asses...

Simple Summary BRCA genetic testing is available for UK Jewish individuals through the National Health Service or private providers. This study evaluated how well UK organisations (UKO), UK Jewish community organisations (JCO), and genetic testing providers (GTP) provide information about BRCA online. Google was used to find relevant websites and a...

Objectives: High mammographic density (MD) and excess weight are associated with increased risk of breast cancer. Weight loss interventions could reduce risk, but classically defined percentage density measures may not reflect this due to disproportionate loss of breast fat. We investigate an artificial intelligence-based density method, reporting...

Objectives To report the long‐term outcomes from a longitudinal psychosocial study that forms part of the ‘Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls’ (IMPACT) study. The IMPACT study is a multi‐national study of targeted prostate cancer (PrCa) screening in i...

Background No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic...

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of r...

Purpose. To improve breast cancer risk prediction for young women, we have developed deep learning methods to estimate mammographic density from low dose mammograms taken at approximately 1/10th of the usual dose. We investigate the quality and reliability of the density scores produced on low dose mammograms focussing on how image resolution and l...

Background Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate,...

Background Menopausal hormone therapy (MHT) can alleviate menopausal symptoms but has been associated with an increased risk of breast cancer. MHT prescription should be preceded by individualised risk/benefit evaluation; however, data outlining the impact of family history alongside different MHT therapeutic approaches are lacking. Aim To quantif...

BACKGROUND Genetic testing to identify germline high-risk pathogenic variants in breast cancer susceptibility genes is an important step in the breast cancer diagnostic pathway. To expand capacity and reduce turnaround time, testing is increasingly offered within mainstream oncology services, rather than via referral to clinical genetics. However,...

Background: Women with breast cancer and a BRCA1 mutation face a high risk of contralateral breast cancer. For this reason, many women with a unilateral breast cancer opt for bilateral mastectomies. Some will have a contralateral prophylactic mastectomy as a second surgery. However, it is not clear to what extent this operation impacts breast cance...

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 3...

Objective To explore the impact of molecular subtype in endometrial cancer (EC) on CD8+T cell densities. Furthermore, this work will test the assumption that all mismatch repair deficient (MMRd) tumours are immunologically similar which would enable current trial data to be generalised to all MMRd ECs. Methods and analysis All tumours were charact...

Background No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting five-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genet...

Importance In young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown. Objective To determine whether time between most...

Study objective: To update a published early economic evaluation of exemplar risk-stratified national breast screening programmes (stratified-NBSP). Method: An existing validated decision-analytic model, using discrete event simulation (the Gray-model), was used to structure the pathways for 3 stratified-NBSP (risk-1; risk-2; risk-3) compared with...

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...

Objectives: Mammographic density is associated with increased risk of developing breast cancer. Automated estimation of density in women below normal screening age would enable earlier risk stratification. We are piloting the use of low dose mammograms combined with models that can make accurate mammographic density estimates. Methods: Three models...

Background Male breast cancer (MBC) affects around 1 in 1000 men and is known to have a higher underlying component of high and moderate risk gene pathogenic variants (PVs) than female breast cancer, particularly in BRCA2 . However, most studies only report overall detection rates without assessing detailed family history. Methods We reviewed germ...

NF2 -related Schwannomatosis ( NF2 SWN) is a rare tumour-predisposition syndrome characterised by the growth of multiple central and peripheral nervous system neoplasms. The drivers of NF2 SWN are pathogenic variants in the tumour suppressor gene NF2 , encoding the protein Merlin, leading to development of bilateral vestibular schwannoma (VS) in >9...

Background: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate...

Background 1 in 40 UK Jewish individuals carry a pathogenic variant in BRCA1/BRCA2 . Traditional testing criteria miss half of carriers, and so population genetic testing is being piloted for Jewish people in England. There has been no qualitative research into the factors influencing BRCA awareness and testing experience in this group. This study...

Purpose There is no guidance surrounding postoperative venous thromboembolism (VTE) prophylaxis using pharmacological agents (chemoprophylaxis) in patients undergoing skull base surgery. The aim of this study was to compare VTE and intracranial haematoma rates after skull base surgery in patients treated with/without chemoprophylaxis. Methods Revi...

Background Weight and health behaviours impact on breast cancer risk. We describe trends in weight and health behaviours in women at entry to a specialist breast cancer family history clinic in Manchester, UK, and changes after clinic entry. Methods Questionnaires were completed at clinic entry (1987–2019, n = 10,920), and updated in 2010–11 ( n =...

In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of health...

Introduction/Background Risk-reducing surgery, medical prevention, and breast cancer (BC) surveillance offer the opportunity to manage BC and ovarian cancer (OC) risk in BRCA1/BRCA2/PALB2/RAD51C/RAD51D/BRIP1 cancer-susceptibility-gene (CSG) carriers, but their cost-effectiveness remains poorly addressed. We aimed to estimate the cancers and deaths...

Introduction/Background PROTECTOR (ISRCTN25173360) evaluates outcomes of pre-menopausal women at increased ovarian cancer(OC) risk, who choose risk-reducing early-salpingectomy (RRES) and delayed-oophorectomy (DO), salpingo-oophorectomy (RRSO), or no surgery. No qualitative study has explored quality-of-life and satisfaction after RRESDO. This stud...

Background Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1 / BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS)....

BACKGROUND Breast cancer is the most common form of cancer in women. Adult weight gain and modifiable health behaviors, including smoking, alcohol intake, and lack of physical activity, are well-known risk factors. Most weight gain in women occurs between the ages of 18 and 35 years. Digital interventions have the potential to address logistical ch...

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 fema...

Importance Pathogenic variants (PVs) in BRCA1 , BRCA2 , PALB2 , RAD51C , RAD51D , and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1 , BRCA2 , PALB2 , RAD51C , and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer th...

Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70–100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there a...

Background Uptake to anastrozole for breast cancer prevention is low, partly due to women’s concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass....

Purpose To determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familial NF2 -related schwannomatosis. Methods We conducted genetic screening of a cohort of 168 second-generation individuals meeting the clinical criteria for NF2 -related schwannomatosis. In addition to the curre...

Introduction Breast cancer incidence starts to increase exponentially when women reach 30–39 years, hence before they are eligible for breast cancer screening. The introduction of breast cancer risk assessment for this age group could lead to those at higher risk receiving benefits of earlier screening and preventive strategies. Currently, risk ass...

Background Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation ‘NF’) are rare hereditary tumour predisposition syndromes. Due to the low prevalence, variability in the range and severity of manifestations, as well as limited treatment options, these conditions require innovative...

Simple Summary Approximately 10–15% of patients with epithelial ovarian cancer have an inherited (germline) BRCA1 or BRCA2 mutation. Following a diagnosis of epithelial ovarian cancer, patients are routinely tested for germline and/or somatic (tumour) BRCA1/2 mutations. Our study shows that if germline BRCA1/2 testing is only performed for patients...

IMPORTANCE: In young-onset breast cancer, a diagnosis within 5-10 years of childbirth associates with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with breast cancer at younger ages, but the impact of childbirth on mortality is unknown. OBJECTIVE: Determine whether time between recent ch...

Background The identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC. Methods Outcomes of germlin...

Objectives Develop an endometrial cancer risk prediction model and externally validate it for UK primary care use. Design Cohort study. Setting The UK Biobank was used for model development and a linked primary (Clinical Practice Research Datalink, CPRD) and secondary care (HES), mortality (ONS) and cancer register (NRCAS) dataset was used for ex...

Accurate prediction of individual breast cancer risk paves the way for personalised prevention and early detection. The incorporation of genetic information and breast density has been shown to improve predictions for existing models, but detailed image-based features are yet to be included despite correlating with risk. Complex information can be...

Background Introducing breast density and polygenic risk scores into breast cancer prediction models results in greater precision and can involve alterations to previously communicated risk estimates and preventative management. This study explored how women from a UK family history risk and prevention clinic view, experience and understand a chang...

Adult-onset idiopathic inflammatory myopathy (IIM) is associated with an increased cancer risk within the 3 years preceding and following IIM onset. Evidence- and consensus-based recommendations for IIM-associated cancer screening can potentially improve outcomes. This International Guideline for IIM-Associated Cancer Screening provides recommendat...

Purpose:-To assess the contribution of germline pathogenic variants (PVs) in a population- based series of breast cancers and the best strategy to improve detection rates. Methods:-Three cohort studies were utilised, including a hospital-based series identified from new UK mainstream testing criteria (Group-1), offering testing to all women (Group-...

Introduction Neurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enabl...

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcino-genesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with...