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Introduction There is a clinical need to develop novel and better biomarkers to monitor patients with neuroendocrine neoplasms (NENs). Circulating cell free tumor derived DNA (ctDNA), a form of liquid biopsy, is finding clinical utility in an ever increasing number of malignancies however has not been widely tested in patients with NENs. Aims Our aim was to identify and track plasma ctDNA in a cohort of patients with NENs using a personalized, patient specific approach. Materials and methods A total of 35 serial plasma samples were collected from 9 patients with metastatic, well differentiated NENs (6 small intestinal and 1 lung, 1 ovarian and 1 pelvic; range 2-5 plasma samples per patient) over the space of 2-25 months. For each patient, NEN specific somatic mutations (single nucleotide variants and insertions/deletions) were identified through whole exome sequencing of paired tumor-leucocyte DNA and were used to design a bespoke multi-variant Ampliseq™ HD ctDNA panel (5-20 variants per patient) for targeted next generation sequencing. Imaging and treatment were provided as per usual clinical care. Results ctDNA was detectable in 6/9 patients and in 19/35 plasma samples. A rise in the number of ctDNA target variants and/or variant allele frequency was seen in 4/6 patients who experienced disease progression. Two of these patients received peptide receptor radionuclide therapy after which ctDNA disappeared in one patient and substantially reduced in the other, which correlated with treatment response. The 3 patients who did not have detectable ctDNA at any time point all had grade 1 small intestinal NENs with stable disease during the observation period. Discussion Our data provide exciting evidence for the feasibility of using ctDNA as a biomarker in NENs. By targeting multiple individualized variants using next generation sequencing, we have demonstrated that ctDNA can track changes in disease burden and can monitor response to treatment in patients. Of equal importance, ctDNA was not detectable in patients with quiescent disease. This could help identify patients who do not need intensive monitoring. Targeting bespoke, multiple variants per patient is a novel and powerful approach for NENs, especially given their heterogenous genetic landscape. This study provides important early evidence that ctDNA may be a clinically useful biomarker for detection and surveillance of NENs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.

Bohring–Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.

The increasing understanding of the genome is recognised as being one of the main determinants of future improvement in healthcare. The availability of genetic data from a large number of individuals increases the ability to investigate questions across many rare and common diseases and in different populations, and also provides more information for understanding clinical care outcomes for an individual. A number of large scale genome sequencing initiatives have been launched in the last few years to try and capitalise on this potential. Within Europe, the UK has led the way with the 100,000 Genomes Project. This project looks at the genome sequences of patients with rare diseases or cancer. More recently France announced plans to invest EUR 670 million in a genomics and personalised medicine programme. In the US, the Precision Medicine Initiative aims at large-scale research by gathering one million or more volunteers to extend precision medicine to all diseases. Meanwhile, China has announced plans to invest nearly USD 10 billion in its own precision medicine initiative. These projects demonstrate the commitment at a national level and raise the question “What benefits would be realised by undertaking a million genome initiative in a coordinated effort across European countries?” A coordinated, pan-European MEGA project would garner crucial genetic information that could have an immeasurable benefit when it comes to the health of current and future EU citizens.

Han Brunner and colleagues report the identification of de novo nonsense mutations in ASXL1 in individuals with Bohring-Opitz syndrome, which is characterized by intellectual disability, distinctive facial features and multiple congenital malformations. Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1 , which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.

Next-generation sequencing methods now allow rapid and cost-effective sequencing of DNA on a scale not previously possible. This offers great opportunities for the research of Mendelian disorders, but also significant challenges. The sequencing of exomes, or whole genomes, has emerged as a powerful clinical research tool, with targeted gene analyses generally being preferred in the clinical diagnostic setting. These methods have been employed here with the aim of identifying novel genetic causes of inherited heart disorders and to gain insights into the utility and limitations of these techniques for clinical diagnosis in these disorders. Data produced from the introduction of a targeted multi-gene next-generation sequencing test into clinical practice has been studied. Variation within the mitochondrial genome has been analysed to assess the importance of mitochondrial DNA variants in patients with hypertrophic cardiomyopathy. The m.4300A>G mutation is identified as an important cause of this disorder, with other previously cardiomyopathy-associated and novel variants also identified. Such multi-gene tests can facilitate interpretable and phenotype-relevant results, but at the expense of limiting more extensive data acquisition. Whole-genome sequencing has been performed in five families with different autosomal dominant inherited heart disease phenotypes of unknown genetic aetiology. In two of these likely pathogenic variants were identified, one in the gene encoding titin (TTN) and the other in the calcium channel subunit gene CACNA1C. In vitro studies were undertaken to support the pathogenicity of the TTN variant and understand the functional effects of this. In the other three families either multiple candidate gene variants were identified or no clear candidate variant was identified. This highlights the difficulties in interpreting these results, even in carefully selected families. Overall, although the research benefits of exome or genome studies are evident, the interpretation and validation of genetic variant data produced remains highly challenging for clinical diagnosis.

Discusses with experts why most of us sometimes tell lies, while some people are pathological liars. Beyond this is the phenomenon of compulsive lying which affects people who lie so habitually that they no longer control it, plus career liars and sporting liars.

Britain has 73 MEPs (Members of the European Parliament) but they attract little attention, and most of that is bad. Interviews one of the most active MEPs, Charles Tannock, and discusses the real problems of waste and bureaucracy.

Reports on the £14.8 billion Crossrail tunnel boring project in London, which is Europe's largest construction project. The boring machine is operating under Hyde Park and has to avoid the existing underground railway installations.

Interviews Lindy Jones, whose memoir \"The Voice in My Head is Perfect\" describes her experiences as a sufferer from motor neurone disease (MND). The disease also affects Professor Stephen Hawking, but Jones, and the MND Association's external affairs director Farah Nazeer, say that it is often misunderstood and neglected.

Interviews Professor Mark Nixon, who is a leading expert in developing biometric techniques to identify people, using CCTV, in order to prevent crime; some example are given of criminals caught by these techniques. He talks about the hostility which such surveillance arouses among civil liberties groups, and about the importance of gait analysis, which is the study of people's body shape and how they walk; other ways of recognising people biometrically include eye colour patterns, facial recognition, footfall, and ears.