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• RGB TGCT Data Access Committee

  The RGB TGCT Data Access Committee is responsible for reviewing and approving requests for access to controlled genomic data generated from testicular germ cell tumor (TGCT) patients treated at the National Cancer Institute of Mexico (INCan). The committee evaluates requests to ensure that data use complies with the informed consent provided by participants and with applicable institutional and ethical regulations.

  Dac EGAC50000000959

• Targeting vulnerabilities in IDH mutant tumours: The model matters WES study

  Introduction: Synthetic lethal interactions with IDH1 and IDH2 (IDH) mutations were identified in non-endogenous IDH mutant (IDHmut) AML and glioma models, but are absent in endogenous IDHmut chondrosarcoma cell lines. The translation into successful clinical applications has remained challenging, implying artificially created models do not fully recapitulate endogenous IDHmut tumour biology. The aim of this study was to elucidate if the model system is indeed an important factor to consider when studying therapeutic vulnerabilities in IDHmut tumours. Methods: Vector-based and CRISPR-Cas9 approaches were used to introduce or revert the IDH1 mutation in chondrosarcoma cell lines. These isogenic cell line pairs were used to examine the presence of known therapeutic vulnerabilities and their underlying biological mechanisms. Results: Vector-based IDHmut chondrosarcoma models showed the previously reported synthetic lethal interactions, but these treatment sensitivities were absent in the CRISPR-edited models. Interestingly, not all vector-based IDHmut cell lines displayed the same therapeutic vulnerabilities. Differences in treatment response were associated with multiple factors, including IDHmut protein expression and D-2-HG levels, in line with the fact that therapeutic vulnerabilities could be induced in the CRISPR-edited models by enhancing D-2-HG levels. Conclusion: Our findings demonstrate that synthetic lethal interactions observed in vector-based models are often a consequence of IDHmut protein overexpression and supra-physiological D-2-HG levels. These results highlight that relying on artificially created IDHmut models may lead to the identification of therapeutic vulnerabilities that are not present in IDHmut tumours, potentially explaining the poor translation of preclinical findings to clinical trials.

  Study EGAS50000001870

• Targeting vulnerabilities in IDH mutant tumours: The model matters RNAseq study

  Introduction: Synthetic lethal interactions with IDH1 and IDH2 (IDH) mutations were identified in non-endogenous IDH mutant (IDHmut) AML and glioma models, but are absent in endogenous IDHmut chondrosarcoma cell lines. The translation into successful clinical applications has remained challenging, implying artificially created models do not fully recapitulate endogenous IDHmut tumour biology. The aim of this study was to elucidate if the model system is indeed an important factor to consider when studying therapeutic vulnerabilities in IDHmut tumours. Methods: Vector-based and CRISPR-Cas9 approaches were used to introduce or revert the IDH1 mutation in chondrosarcoma cell lines. These isogenic cell line pairs were used to examine the presence of known therapeutic vulnerabilities and their underlying biological mechanisms. Results: Vector-based IDHmut chondrosarcoma models showed the previously reported synthetic lethal interactions, but these treatment sensitivities were absent in the CRISPR-edited models. Interestingly, not all vector-based IDHmut cell lines displayed the same therapeutic vulnerabilities. Differences in treatment response were associated with multiple factors, including IDHmut protein expression and D-2-HG levels, in line with the fact that therapeutic vulnerabilities could be induced in the CRISPR-edited models by enhancing D-2-HG levels. Conclusion: Our findings demonstrate that synthetic lethal interactions observed in vector-based models are often a consequence of IDHmut protein overexpression and supra-physiological D-2-HG levels. These results highlight that relying on artificially created IDHmut models may lead to the identification of therapeutic vulnerabilities that are not present in IDHmut tumours, potentially explaining the poor translation of preclinical findings to clinical trials.

  Study EGAS50000001871

• Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

  Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression. Systematic annotation of genome wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing and allele specific expression are each important determinants of the DCM phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. (*) numbers in parentheses represent samples that the publication is based on.

  Study EGAS00001002454

• Enhanced detection of circulating tumor DNA by fragment size analysis

  Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on sensitivity for detecting genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for non-invasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 cancer patients using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90–150 bp, and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90–150 bp improved detection of tumor DNA, with more than 2-fold median enrichment in >95% of cases, and more than 4-fold enrichment in > 10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with AUC> 0.99 compared to AUC < 0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91, compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection. This could reduce the required depth of cfDNA sequencing for clinical applications, earlier diagnosis and study of tumor biology.

  Study EGAS00001003258

• Mesothelioma_Whole_Genomes

  Genomic architecture of mesothelioma parent study is project 925. This project is set up in parallel to project 925 in order to Whole genome sequence ten of the 59 tumours in that project.

  Study EGAS00001000830

• Integrative Somatic and Germline Computational Biology to Redefine Clinical Actionability in Solid Tumors

  Neuroendocrine tumors (NETs) are rare cancers that arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic NETs (GEP-NETs) growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we performed single-cell RNA-sequencing (scRNA-seq) of fresh resections of GEP-NETs, including four pancreatic NETs, three small intestinal NETs, and one perigastric NET. We used single-cell sequencing to investigate the tumor and immune cellular landscapes of GEP-NET patients. Malignant GEP-NET gene and regulon expression was compared with normal, gastrointestinal endocrine cell differentiation and fate determination stages. We further characterized immune-immune and immune-tumor interaction networks within GEP-NETs, identifying novel therapeutic opportunities in the myeloid compartment of the microenvironment. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

  Study phs003141

• University of Texas PDX Development and Trial Center Grant

  The goal for the University Texas PDX Development and Trial Center (UTPDTC) is to optimize personalized biomarker-based cancer therapy and identify effective targeted drugs based on the molecular characteristics of each tumor. Our short-term goals are to establish a biobank of clinically, and molecularly-annotated Patient-Derived Xenografts (PDXs) and to use PDXs as a platform for preclinical drug development and biomarker discovery. The primary goal for UTPDTC investigators will be to develop PDX trial strategies for preclinical testing of single agents and drug combinations. These models will allow the determination of the optimal treatments (single drugs or combinations) that should be tested in clinical trials in increasingly individualized, molecularly defined subsets of tumors. The goal of the Patient-Derived Xenograft Core is to provide high-quality clinically relevant and molecularly annotated PDX models for the research projects proposed in the University of Texas PDX Development and Trial Center (UTPDTC) grant application and to the research activity of the NCI PDX Development and Trial Centers Research Network (PDXNet) by leveraging PDX resources at our institutions and developing new PDX models from human cancer specimens using rigorous quality standards so that the models can be used to guide clinical trial development. The PDX models developed and/or characterized by the PDX Core will be available to other cancer researchers through the PDXNet and NCI Patient-Derived Models Repository (PDMR).

  Study phs001980

• Whole genome and transcriptome analysis of medullary thyroid cancer

  Medullary thyroid cancer is the neoplasm of the calcitonin-producing parafollicular cells of the thyroid gland. The hormone calcitonin acts to lower the blood calcium level, counteracting the effects of the parathyroid hormone; it can also serve as a biomarker for the presence or recurrence of medullary thyroid cancer. Surgery is the only curative treatment for this cancer. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large sub-population of medullary thyroid cancers; however, not all patients carry oncogenic alterations of this kinase. Hence, there is a need for molecular characterization of medullary tumors on the genomic scale with the aim of identifying targetable mutations. Here, we describe the genomic profiles of two medullary thyroid cancers and report the presence of a putative oncogenic BRAF fusion in one. Such alterations previously observed in other malignancies and known targets of available drugs, can benefit patients who currently have no therapy options.

  Study EGAS00001001473

• The_impact_of_the_human_leukaemia_virus_HTLV_1_on_host_gene_expression

  PBMCs were purified from blood samples of 8 HTLV-1 infected individuals, and cryo-preserved in fetal calf serum containing 10% DMSO. DNA from each samples was extracted using Qiagen Blood & Tissue kit according to the manufacturer's protocol. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002259