Updates in Prostate Cancer Research and Screening in Men at Genetically Higher Risk

Purpose of Review Prostate cancer (PrCa) is the most common cancer in men in the western world and is a major source of morbidity and mortality. Currently, general population PrCa screening is not recommended due to the limitations of the prostate-specific antigen (PSA) test. As such, there is increasing interest in identifying and screening higher-risk groups. The only established risk factors for PrCa are age, ethnicity, and having a family history of PrCa. A significant proportion of PrCa cases are caused by genetic factors. Recent Findings Several rare germline variants have been identified that moderately increase risk of PrCa, and targeting screening to these men is proving useful at detecting clinically significant disease. The use of a “polygenic risk score” (PRS) that can calculate a man’s personalized risk based on a number of lower-risk, but common genetic variants is the subject of ongoing research. Research efforts are currently focusing on the utility of screening in specific at-risk populations based on ethnicity, such as men of Black Afro-Caribbean descent. Whilst most screening studies have focused on use of PSA testing, the incorporation of additional molecular and genomic biomarkers alongside increasingly sophisticated imaging modalities is being designed to further refine and individualise both the screening and diagnostic pathway. Approximately 10% of men with advanced PrCa have a germline genetic predisposition leading to the opportunity for novel, targeted precision treatments. Summary The mainstreaming of genomics into the PrCa screening, diagnostic and treatment pathway will soon become standard practice and this review summarises current knowledge on genetic predisposition to PrCa and screening studies that are using genomics within their algorithms to target screening to higher-risk groups of men. Finally, we evaluate the importance of germline genetics beyond screening and diagnostics, and its role in the identification of lethal PrCa and in the selection of targeted treatments for advanced disease.

Considerations in Management for Trans and Gender Diverse Patients with Inherited Cancer Risk

Purpose of Review To best support all patients with inherited cancer risk, we must broaden our scope of practice to consider the needs of the transgender and gender diverse (trans) community. We considered best practice for supporting trans patients including tailored risk assessments and management recommendations. Recent Findings There is limited literature considering trans patient care in cancer genetics. Small case studies have highlighted how medical transition and cancer risk–reducing options intersect with the need for individualised care. Studies have also shown that cancer genetics professionals do not feel prepared to support trans patients. Summary Patient-centred care for trans patients relies on a multidisciplinary team (MDT) engaged in shared decision-making. National guidelines are needed to standardise access to appropriate discussions around risk-reducing options and screening. International collaborative research is required to provide empiric data on the impact of gender-affirming treatments on cancer risk, and more experiential data is needed from trans patients accessing cancer genetics services. Finally, education and training in this area should be formally embedded for all cancer genetics professionals.

Horizon Scanning in Cancer Genomics: How Advances in Genomic Medicine Will Change Cancer Care Over the Next Decade

Purpose of Review Advances in genomic medicine have the potential to revolutionise cancer patient care by driving forwards the clinical practice of precision oncology. This review aims to outline how genomic medicine advances may alter the care of cancer patients and their families over the next 10 years. Recent Findings The translation of oncogenomic advances into the clinical environment will likely be facilitated by the increasing availability of next-generation sequencing technologies and the increasing genomic literacy of healthcare professionals. The implementation of the centralised, nationwide NHS Genomic Medicine Service promises to improve equity of cancer care and to facilitate personalisation of almost every stage of the care pathway, from informing population screening and how we diagnose cancer to delivering prognoses and surveillance. Advances in cancer pharmacogenomics, and other “omics” technologies, have a tremendous potential to optimise patient care. Genomic medicine advances will also enhance the care offered to cancer patients’ families. Summary Genomic medicine advances are likely to transform almost every aspect of a cancer patient’s care pathway. Cancer care will profoundly improve over the next decade, increasing UK cancer survival rates and improving patient outcomes.

The Role of RNA-Sequencing as a New Genetic Diagnosis Tool

Purpose of Review Whole exome sequencing (WES) and whole-genome sequencing (WGS) are frontline approaches for the genetic diagnosis of rare diseases. However, WES/WGS fails in up to 75% of cases. Transcriptomics via RNA-sequencing (RNA-Seq) is a novel approach that aims to increase the diagnostic yield in rare diseases. Recent Findings Recent publications focus on the success of RNA-Seq for increasing diagnosis rates in WES/WGS-negative patients in up to 36% of cases, across a range of different diseases, sample sizes, and tissue types. Summary RNA-Seq is beneficial for aiding prioritisation of causative variants currently not detected or often overlooked by WES/WGS alone. An improvement in diagnostic yields has been demonstrated using multiple source tissues, with muscle and fibroblasts being the most representative, but the more accessible blood still demonstrating diagnostic success, particularly in neuromuscular disorders. The introduction of RNA-Seq to the genetic diagnosis toolbox promises to be a useful complementary tool to WES/WGS for improving genetic diagnosis in patients with rare disease.

From Beyond the Grave: Use of Medical Information from the Deceased to Guide Care of Living Relatives

Purpose of Review In order to inform patients of their genetic risks, access to the medical records and/or stored samples of their relatives is often helpful. We consider some of the obstacles to such access when these relatives are deceased and suggest how they might be navigated. Recent Findings We explore an issue first highlighted in 2004 by Lucassen et al. (Br Med J 328:952–953, 2004) and re-evaluate it in the wake of novel technologies and mainstreaming of genomic medicine. We find that it is still an issue in practice despite professional guidelines advocating access to familial information (Joint Committee on Genomics in Medicine 2019) and that the Human Tissue Act 2004 is often wrongly constructed as a reason to block access. Access is often obstructed by failing to adopt the necessary relational concept of autonomy that applies in genetic medicine as reported by Horton and Lucassen (Curr Genet Med Rep 7:85–91, 2019) and by considering confidentiality to be absolute, even after death. In response to a recent legal case about the confidentiality of genetic test results, and their disclosure to family members (ABC v St George’s Healthcare NHS Trust 2020), Dove et al. (J Med Ethics 45:504–507, 2019) suggested that a duty to consider the interests of genetic relatives could co-exist alongside a duty of confidentiality to a patient. In this way, healthcare professionals can use professional judgement about the relative value of genetic information to family members. This is equally relevant in accessing deceased relatives’ information. A recent systematic review found a high level of acceptability of postmortem use of genetic data for medical research amongst participants and their relatives, and it is reasonable to assume that this acceptability would extend to clinical practice as reported by Bak et al. (Eur J Hum Genet 28:403–416, 2020). Summary Within clinical practice, access to medical records/samples of deceased relatives is often obstructed unnecessarily, potentially resulting in harm to the living relatives seeking advice. Consent to such access is important but need not be the bureaucratic hurdle that is often imposed.

Utility of RNA Sequencing Analysis in the Context of Genetic Testing

Purpose of Review RNA analysis is beginning to be integrated into clinical laboratory genomics, and a review of its current uses and limitations is warranted. Here, we summarize the scope and utility of RNA analysis in the context of clinical genetic testing, including considerations for genetic counseling. Recent Findings RNA analysis is a powerful approach for interpreting some variants of uncertain significance, for analyzing splicing alterations, for providing additional functional evidence for sequence and structural variants, and for discovering novel variants. However, a review of RNA sequencing methods has noted variability in both laboratory processes and findings. Genetic counseling related to RNA analysis has to take into account nonstandardized laboratory processes, sample-type limitations, and differences in variant-interpretation outcomes. Summary RNA analysis is an important complement to DNA testing, although limitations still exist. Maximizing the utility of RNA analysis will require appropriate patient referrals and standardization of laboratory processes as the practice continues to expand the ability to identify and resolve molecular diagnoses.

Genetics of Amyotrophic Lateral Sclerosis

Purpose of Review Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) spectrum disorder is a rare fatal disease with strong genetic influences. The implementation of short-read sequencing methodologies in increasingly large patient cohorts has rapidly expanded our knowledge of the complex genetic architecture of the disease. We aim to convey the broad history of ALS gene discovery as context for a focused review of 11 ALS gene associations reported over the last 5 years. We also summarize the current level of genetic evidence for all previously reported genes. Recent Findings The history of ALS gene discovery has occurred in at least four identifiable phases, each powered by different technologies and scale of investigation. The most recent epoch, benefitting from population-scale genome data, large international consortia, and low-cost sequencing, has yielded 11 new gene associations. We summarize the current level of genetic evidence supporting these ALS genes, highlighting any genotype-phenotype or genotype-pathology correlations, and discussing preliminary understanding of molecular pathogenesis. This era has also raised uncertainty around prior ALS-associated genes and clarified the role of others. Summary Our understanding of the genetic underpinning of ALS has expanded rapidly over the last 25 years and has led directly to the clinical application of molecularly driven therapies. Ongoing sequencing efforts in ALS will identify new causative and risk factor genes while clarifying the status of genes reported in prior eras of research.