Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome

PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes

The role of virtual consultations in cancer genetics: challenges and opportunities introduced by the COVID-19 pandemic

The COVID-19 pandemic changed the delivery of healthcare within the United Kingdom. A virtual model of care, utilising telephone and video consultations, was rapidly imposed upon cancer genetics teams. This large-scale change in service delivery has led to new opportunities that can be harnessed to improve patient care. There is a clear potential to mitigate geographical barriers, meet increasing patient expectations of implementing virtual consultations, reduce hospital carbon footprints, and decrease hospital costs while increasing efficiency. However, there are also significant challenges introduced by this model of care. Virtual healthcare consultations introduce another new level of digital exclusion for patients and clinicians. There are also potential challenges for maintaining patient confidentiality, and limited utility in circumstances where a physical exam may be warranted. For clinicians, there may be impacts on empathetic responses delivered and challenges in workflow and workload. Virtual consultations are likely to continue being a feature of cancer genetics services. A flexible approach is needed to allow for virtual and traditional models of care to work together and best meet patients’ needs. Cancer genetics services should harness the opportunities provided by virtual processes to improve patient care, whilst collaborating with patient groups and other stakeholders to carefully examine and address the challenges that virtual consultations introduce

Towards establishing consistency in triage in a tertiary specialty

Clinical Genetics services provide a diagnostic, counselling and genetic testing service for children and adults affected by, or at risk of, a genetic condition, most of which are rare, and/or genetically heterogeneous. Appropriate triage of referrals is crucial to ensure that the most urgent referrals are seen as quickly as possible, without negatively impacting the waiting times of less urgent cases. We aimed to examine triage practice in six Clinical Genetic centres across the United Kingdom and Ireland. Thirteen simulated referrals were drafted based on common referrals to Clinical Genetics. Copies of each referral were forwarded to each centre, where 10 nominated clinicians were asked to triage each referral. Triaged referrals were returned to the coordinating author for analysis. An electronic questionnaire was contemporaneously completed by clinical leads in each unit to gather local demographic details and local operating procedures relevant to triage. Widespread inconsistencies were noted both within and between units, with respect to the acceptance of referrals to the services, prioritisation and designated clinic type. Referral rates, staffing levels and waiting lists varied widely between units. Inconsistencies observed between units are likely influenced by a number of factors, including staffing levels, referral rates and average family size. Inconsistency within units likely reflects the complex nature of many Clinical Genetic referrals, and triage guidelines should help improve decision-making in this setting

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network

Investigating the impact of genomic profiling on breast cancer risk prediction, treatment and outcome

It has, for many years, been acknowledged that “breast cancer” is an umbrella term for many genetically and immunophenotypically distinct malignancies of the breast. Treatment paradigms are shifting in direct response to increasing understanding of the molecular mechanisms underlying this complex set of diseases. Breast cancer, like all other cancers, is “genetic”; triggered by a pathogenic variant in a tumour suppressor or proto-oncogene, or by pathogenic silencing or up-regulation of such genes by copy number variation, epigenetics or variation of regulatory elements. Such variation may occur at the level of the germline or of the soma. The genetic architecture of breast cancer has been well defined, with susceptibility loci categorised as high-, medium- or low-risk depending on the associated disease penetrance. The aim of this study was to explore the utility of molecular profiling of the germline of patients with breast cancer for known and putative high- and low-risk susceptibility loci, and of the tumours of such individuals, and to investigate the association of germline and somatic variation on risk estimation, phenotype, prognostication, treatment planning and outcome. A mixed methods study was undertaken. The referral patterns of clinicians and uptake of patients with respect to BRCA1/BRCA2 testing, as well as phenotype associated with pathogenic mutations in these high-risk genes were examined by observational cohort studies. Surveillance of these high-risk individuals was assessed by patient surveys. A number of case-control studies were undertaken to identify novel cancer susceptibility loci, or to explore the association of putative loci with disease, by targeted sequencing of the 3’ UTRs and miRNA binding sites of cancer predisposition genes, Sanger sequencing, Sequenome, and Taqman genotyping. Functional assays were undertaken to examine the biological impact of one of the variants of interest identified. A longitudinal cohort study was undertaken to examine the influence of tumour gene expression profiling on therapeutic decision-making in patients with breast cancer. 31 families with confirmed pathogenic variants in BRCA1 or BRCA2 in the West of Ireland were identified. A recurrent large genomic rearrangement in BRCA1 (deletion exons 1-23) was found to occur more frequently in patients in this region than elsewhere in Ireland. Patients with such pathogenic variants may be successfully repatriated to National Breast Screening services for surveillance, as it was confirmed that 87-91% of individuals receiving surveillance through this pathway receive at least recommended screening. A variant in the non-coding region of BRCA1 was also shown to associate with severe disease. A novel variant in the PCM1 gene was identified in patients with ovarian cancer, but did not associate with breast cancer in our cohort. A variant at 12p11 was confirmed to be associated with breast cancer risk in Irish patients. A variant in KRAS was postulated to be associated with disease risk, and was shown to confer differential propensity to colony formation in vitro in response to alterations in the hormonal milieu. It was observed that gene expression analysis of tumours was taken up with high acceptability by Irish patients and clinicians, and treatment decisions were modified accordingly. This work has demonstrated the potential clinical utility of tumour and germline assessment in defining patient risk, prognosis and treatment. However, further larger-scale studies are required to confirm the postulated associations of rare low-penetrance alleles with disease. The potential translational utility of the findings of this work is promising, but increased funding in genetics in the clinical setting is required to ensure patients can avail of genomic profiling where appropriate.2022-01-2

Assessing awareness of colorectal cancer symptoms and screening in a peripheral colorectal surgical unit: a survey based study

Background: The National Screening Program for colorectal cancer is scheduled to commence in the near future. Previous studies on the topic of colorectal cancer and screening have highlighted paucity in public awareness of epidemiology, symptoms and signs of colorectal cancer. The aim of this study was to assess understanding of colorectal cancer and screening in a representative sample of the local catchment population of Mayo General Hospital. Methods: A prospective cohort study was instituted utilising an anonymous survey, which was distributed at consecutive general surgical out-patient clinics over a one month period prior to initiation of the screening program. Data collected included demographics, presenting complaint type and duration, and general knowledge of colorectal cancer facts. Attitudes towards screening were also evaluated. Results: Eighty-eight of the one hundred and thirty six patients sampled were female (65%). Thirty-six per cent of the sample was within the screening target age-group (55–74), with mean age 53years (+/−18). Most respondents recognised bleeding per rectum as a possible symptom of colorectal cancer. A significant proportion, however, incorrectly selected less sinister symptoms as concerning, while only fifty per cent correctly cited weight loss. Family history was acknowledged as a risk factor by fifty-seven per cent with age and gender cited less often (29%, 4%), while forty-seven per cent incorrectly cited stress as a risk. Screening was defined as testing of symptomatic patients or those with a positive family history by eighty-one per cent of respondents, with only nineteen per cent associating screening with an asymptomatic cohort. Strikingly, twenty-five per cent of patients would decline screening. Conclusions: There remains poverty of awareness regarding colorectal cancer. More public health initiatives are required to help improve understanding of the disease process, and to improve public compliance with the screening initiative

Clinical use of the oncotype dx genomic test to guide treatment decisions for patients with invasive breast cancer

Implementation of the Oncotype DX assay has led to a change in the manner in which chemotherapy is utilized in patients with early stage, estrogen receptor (ER)-positive, node-negative breast cancer; ensuring that patients at highest risk of recurrence are prescribed systemic treatment, while at the same time sparing low-risk patients potential adverse events from therapy unlikely to influence their survival. This test generates a recurrence score between 0 and 100, which correlates with probability of distant disease recurrence. Patients with low-risk recurrence scores (0-17) are unlikely to derive significant survival benefit with adjuvant chemotherapy and hormonal agents derived from using adjuvant hormonal therapy only. Conversely, adjuvant chemotherapy has been shown to significantly improve survival in patients with high-risk recurrence scores (>= 31). Trials are ongoing to determine how best to manage patients with recurrence scores in the intermediate range. This review outlines the introduction and impact of Oncotype DX testing on practice; ongoing clinical trials investigating its utility; and challenging clinical scenarios where the absolute recurrence score may require careful interpretation. We also performed a bibliometric analysis of publications on the topics of breast cancer and Oncotype DX as a surrogate marker of acceptability and incorporation of the assay into the management of patients with breast cancer