Report of the ICES\NAFO Joint Working Group on Deep-water Ecology (WGDEC), 11–15 March 2013, Floedevigen, Norway.

On 11 February 2013, the joint ICES/NAFO WGDEC, chaired by Francis Neat (UK) and attended by ten members met at the Institute for Marine Research in Floedevi-gen, Norway to consider the terms of reference (ToR) listed in Section 2. WGDEC was requested to update all records of deep-water vulnerable marine eco-systems (VMEs) in the North Atlantic. New data from a range of sources including multibeam echosounder surveys, fisheries surveys, habitat modelling and seabed imagery surveys was provided. For several areas across the North Atlantic, WGDEC makes recommendations for areas to be closed to bottom fisheries for the purposes of conservation of VMEs

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection

An Acoustic Survey of Orange Roughy Aggregations to the West and North of the Porcupine Bank

The survey was carried out over a 14 day period from the 5th – 20th February 2005 onboard the 65m RV Celtic Explorer. The main focus of this pilot survey was to acoustically survey orange roughy (Hoplostethus atlanticus) spawning aggregations.Funder: Marine Institut

A Decade of the Oesophageal Cancer Clinical and Molecular Stratification Consortium: OCCAMS

Multi-centre collaboration is essential to achieve the sample sizes required for robust and informative research studies for less common medical conditions. Substantial logistical and governance support is needed to ensure that the clinical and molecular data generated are high quality and can benefit the international research community and patients.The Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium was created in 2009 as a collaboration across the United Kingdom to better understand oesophageal adenocarcinoma (OAC). The aims of OCCAMS are: to develop a bioresource of samples with clinical data from oesophageal and gastro-oesophageal junction (GOJ) adenocarcinoma patients; to identify clinical, demographic, and molecular factors affecting development and progression of OAC; to promote use of these data and the OCCAMS network for clinical trials to improve management of this cancer; and to share data with internal and external academic and commercial parties for the benefit of patients.At the time of writing, OCCAMS has collected and curated a bioresource derived from 4,440 oesophageal cancer patients, representing over 44,000 individual samples with detailed clinical and epidemiological annotations, from 27 UK centres (Figure 1). OCCAMS was a key contributor to the International Cancer Genome Consortium (ICGC), ICGC 25K and ICGC ARGO projects, as well as the Pan-Cancer Analysis of Whole Genomes (PCAWG) study. OCCAMS has also contributed to the Cancer Research UK Grand Challenge Mutographs project and projects run by Genomics England.We have continued to extend the OCCAMS genomic resource and are increasingly complementing this with other -omics data including single cell technologies and 3D organoids. The OCCAMS Steering Committee was created at inception and consists of members of the core OCCAMS infrastructure team and representatives from every site that contributes to the consortium. Proposals for new research projects are formally submitted using a proforma for discussion at regular meetings of the steering committee. This structure allowed OCCAMS to control the use of finite resources, such as blood and tissue, whilst encouraging researchers to apply to use the resource. It also allowed similar projects to be combined, or aligned, to reduce academic wastage and maximise the quality of the scientific output. Bespoke cohorts can be created for a specific project via the Cambridge-based OCCAMS team, and clinical and -omics data are provided so that specific research can be conducted. Sequencing reads and methylation array data have been made available to the wider research community via the International Cancer Genome Consortium and/or the European Genome-phenome Archive (EGA), to take advantage of existing governance structures. Molecular and clinical data, as well as patient-derived organoids, from OCCAMS have been extensively exploited to understand various aspects of OAC biology within and outside the Consortium. In total, we have established 33 collaborations within OCCAMS and 14 with external groups, including European and US partners from academia and industry, resulting in 34 research publications. There are further studies still underway, which will provide further research outputs for this cancer, which has poor outcomes. Some scientific outputs of OCCAMS to date are described in table 1.Our key overall lesson drawn from OCCAMS is that multicentre consortia can collect data and tissue (including fresh frozen) from huge numbers of patients, even when studying a cancer like OAC, which has a relatively low incidence. However, care must be taken to create robust and detailed databases, with metadata, to make sure that the clinical information being recorded is accurate and relevant to the molecular questions being asked. Accurate patient outcomes should be linked to national registries. Ethical approval should encompass all the data and tissue required and include agreement from the patient to track patient outcomes across relevant national registries as well as to share data and resources with academic collaborators. During the course of OCCAMS we amended the consent to allow data sharing with commercial collaborators with a specific tick box so that patients can opt in or out. This was included to ensure maximal opportunity for clinical translation of the findings; the majority of patients have consented for commercial as well as academic collaboration.We allowed flexibility as to which samples each centre collected, for example whether samples were fresh frozen or formalin-fixed paraffin-embedded, or whether ctDNA was double spun on site or collected in Streck tubes. This allowed more centres to get involved, which often led to their infrastructure being expanded to collect a wider range of sample types. This encouraged inclusivity of OCCAMS membership, maximising buy in from the UK clinical community. Clear, standardised protocols were needed to reduce sample wastage and maximise quality. As the number of molecular analyses using OCCAMS samples increased there was careful consideration of how all the data, which included demographic, clinical, whole genome sequencing, and RNAseq, could be linked. Linkage increases the value of this data and enhances the ability to generate new insights into disease. The steering group coordinated the academic output of this resource, driving forward research. A sense of community was created by holding yearly in-person meetings to share new findings and discuss future projects, with competitions to encourage junior clinical researchers to access the data. The goal was to create a sense of ownership for the clinical researchers who contributed patient data to OCCAMS, as this encouraged use of the data for molecular projects and for understanding the clinical features of OAC. A multicentre collaboration must focus on the patient. Throughout this project we had strong patient representation to ensure that our research focus was relevant and that all materials were clear and consistent. This included discussion between patients and researchers about research priorities as well as co-production of patient facing materials and patient led sessions at our annual symposium. The exchange between patients, public and researchers, especially those new to the field, led to a heightened appreciation of why research in this disease is so important. New discoveries will lead to improved patient outcomes only when the potential clinical impact of the science is constantly borne in mind. <br/

Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics

Esophageal adenocarcinoma (EAC) incidence is increasing while 5-year survival rates remain less than 15%. A lack of experimental models has hampered progress. We have generated clinically annotated EAC organoid cultures that recapitulate the morphology, genomic, and transcriptomic landscape of the primary tumor including point mutations, copy number alterations, and mutational signatures. Karyotyping of organoid cultures has confirmed polyclonality reflecting the clonal architecture of the primary tumor. Furthermore, subclones underwent clonal selection associated with driver gene status. Medium throughput drug sensitivity testing demonstrates the potential of targeting receptor tyrosine kinases and downstream mediators. EAC organoid cultures provide a pre-clinical tool for studies of clonal evolution and precision therapeutics

The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic

Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma

Background: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. Methods: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging. Results: TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1–2; median overall survival (OS) not reached) and non-responders (TRG 3–5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P &lt; 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P &lt; 0·001). Conclusion: A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1–2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders.</p