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.

Background Mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome is one of the most well‐known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi‐systemic phenotype that predominantly features neurological manifestations––stroke‐like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses. Methods A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed. Results Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke‐like episodes. Heteroplasmy is higher in a tissue other than blood in most cases. Conclusion The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered.

Diurnal oscillations in human cardiac electrophysiology are thought to be under the control of the endogenous circadian clock. The incidence of arrhythmic events in patients with Long QT syndrome (LQTS) varies diurnally. The diurnal variation in QT interval has previously been identified as a potential for error in clinical trials which utilise ECG measurement. We performed a systematic review of clinical trials for LQTS to identify practice around specification of timing information for point electrocardiogram (ECG) measurements, analysis of continual ECG recordings ≥24 h, and drug delivery. Despite guidelines having been issued around the analysis of 24-h ECG recordings, we identify a lack of usage of detailed time of day information in trial design for LQTS studies, which has the potential to affect the interpretation of the results of drug trials. We identify that, in contrast, clinical trials for QT prolonging drugs demonstrate increased incorporation of time of day information of both QT analysis and drug dosing. We provide a visual portal to allow trial designers and clinicians to better understand timing of common cardiac-targeting drugs, and to bear this concept in mind in the design of future clinical trials.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by a generous grant from the Newnham College Senior Members Research Support fund. Introduction Inherited cardiac arrhythmias (ICAs) are a major cause of sudden cardiac death (SCD) in the young. ICAs are caused by variants in genes encoding ion channels that predispose individuals to life-threatening arrhythmic events. Early diagnosis to facilitate implementation of effective clinical interventions that greatly reduce SCD risk is critical. ICAs have traditionally been considered monogenic diseases. However, the genomic architecture of ICAs is likely a continuum, ranging from monogenic and near-monogenic (strong genetic factor influenced by a few genetic modifiers) to oligogenic (cumulative effects of coinheritance of many genetic modifiers). The circadian clock, which is predicted to control the expression of one third of the protein-coding genome, has been implicated in contributing to ICAs because the incidence of arrhythmic events in ICA patients oscillates with a period of 24 hours. We therefore hypothesised that it may contribute to oligogenic disease. Purpose To identify variants that may contribute to ICAs and that are located in cis-regulatory motifs that are both functionally predicted to be binding sites for clock transcription factors and located in the promoters of ICA-associated genes predicted to exhibit diurnal rhythmic expression. Methods Genes associated with ICAs and predicted to be rhythmically expressed were identified and the region 1kb upstream of their transcription start sites screened for mammalian circadian motifs. Whole genome sequencing data from participants with ICAs in The 100,000 Genomes Project was interrogated for variants within these motifs. Results Two variants in the SCN5A promoter were significantly associated with Brugada syndrome (BrS) (OR = 2.77, p-value <2.2E-16; OR = 2.11, p-value = 6.23E-14). The variants were found in high linkage disequilibrium (D’=0.988, p-value <2.2E-16). This 2-variant haplotype was enriched in BrS patients who did (OR = 2.43, p-value = 7.07E-08; OR = 1.32, p-value = 0.0204) and did not (OR = 3.00, p-value <2.2E-16; OR = 1.78, p-value = 8.30E-09) have a likely genomic cause, implying that it may be a genetic modifier of BrS. This haplotype in the homozygous state was significantly enriched in individuals with BrS in whom a likely genomic cause had not been identified, suggesting it may be an autosomal recessive cause (OR = 0.102, Fisher’s p-value = 0.0120). Conclusion This haplotype has previously been reported to modulate BrS severity in a large family with a pathogenic SCN5A variant and has demonstrated a trend towards reduced SCN5A expression in murine cardiomyocytes – a molecular mechanism that slows cardiac conduction, predisposing individuals to BrS. Therefore, this 2-variant haplotype, or 1 variant therein, in the SCN5A promoter is a putative genetic modifier and autosomal recessive cause of BrS. Future work includes functional assay in human cardiomyocytes to characterise its molecular consequences on SCN5A expression and the circadian clock.

No abstract