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• X chromosomal genetic variants are associated with childhood obesity

  Current genetic association studies are usually focused on autosomal variants only, and the sex chromosomes are often neglected. In recent years, a number of statistical techniques and strategies have been widely described making much easier overcoming X-chromosome technical hurdles and including this region within genetic studies. Tenomodulin (TNMD) is a Xq22 chromosome anti angiogenic locus which has been recently linked to different obesity-related phenotypes. These results have not been replicated to date. Given these facts, we have conducted a genetic association analysis in Spanish children population including seven TNMD SNPs as potential candidate markers for obesity and metabolic dysfunctions. Additionally genotypes for another locus located in the X chromosome, the SLC6A14, have been included in the dataset. A total of 915 DNA samples from 258 normal weight, 177 overweight and 480 obese Spanish children (438 males, 477 females) were genotyped for seven TNMD SNPs and one SLC6A14 SNP. Associations with anthropometric measurements and glucose metabolism were investigated.

  Study EGAS00001002738

• Complete Genomics paired end sequencing; Ovarian cancer

  We sequenced the genomes from a monozygotic twin discordant for schizophrenia and a tumor-normal pair of an ovarian cancer patient. Using whole-genome twin data to discriminate between correctly identified single nucleotide variants (SNVs) and errors a strategy for the accurate detection of SNVs was developed. By applying stringent sequencing quality measures, excluding error-prone regions and selecting SNVs identified by different mapping and variation calling algorithms, error rates were ~37-fold reduced. This enabled us to identify the first discordant SNVs in monozygotic twins using whole-genome sequencing. In addition, by showing that novel SNVs are highly enriched in errors, accurate estimates of the number of novel and rare SNVs occurring in unrelated Caucasian individuals were obtained. Finally, somatic mutations in coding and regulatory sequences were reliably identified in the highly rearranged ovarian tumor. Overall, our data demonstrate that strategies to reduce error rates in whole-genomes are required for disease gene discovery.

  Study EGAS00001000158

• Neuroblastoma relapse trio series from the AMC

  The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed RAS-MAPK pathway mutations. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

  Study EGAS00001001183

• MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

  Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas1. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients2. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

  Study EGAS00001004544

• whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.

  Study EGAS00001000709

• Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

  Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C-allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6x10-14) greater metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

  Study EGAS00001001875

• Real-time response profiling through serial plasma analyses during FOLFOX treatment in patients with colorectal cancer

  Response evaluation of cancer therapeutics relies on the assessment of the change in tumor burden, which is performed in accordance with defined criteria every 8-12 weeks. However, predictive factors for response are not available for the majority of patients with advanced stage colorectal cancer. Here we show that measurement of circulating tumor DNA (ctDNA) levels during one of the most commonly administered drug regimens, i.e. FOLFOX, allows an early, real-time assessment of treatment response. During the 48-hour FOLFOX application, we serially assessed plasma DNA and observed that ctDNA levels initially decreased during the first 23 hours. In patients with stable disease or partial response, ctDNA levels remained low, whereas in patients with progressive disease, ctDNA levels increased at the end of the treatment cycle predicting clinical and radiologic response correctly. Hence, ctDNA monitoring during treatment may contribute to an early outcome prediction with significant implications for the management of patients.

  Study EGAS00001004213

• Whole-exome sequencing and microRNA profiling predicted relapse risk of stage I lung adenocarcinomas

  Despite the advance in precision therapy, about 20% of stage I non-small cell lung cancer patients suffer a relapse after surgical resection. To develop molecular signatures for relapse prediction of stage I lung adenocarcinoma (LUAD), we conduct comprehensive analyses of multiplatform molecular profiling from 113 treatment-naïve stage I Taiwanese LUAD patients. We identify 16 nonsynonymous non-sporadic point mutations (NSPOPMs) harbored at EGFR, KRAS, TP53, CTNNB1 and 6 other genes, and find that the Non-EGFR NSPOPMs were associated with early relapse in a dose-dependent manner via variant allele fraction (VAF). We define a score, maxVAF, to aggregate the VAFs of these NSPOPMs by the maximum value. MicroRNA expression analysis shows a strong correlation between miR-31 and maxVAF. Combining maxVAF with miR-31 led to a powerful risk prediction for surgically resected stage I patients (hazard ratio = 8.65, P = 0.001). Our study opens up more options for precision management of stage I LUAD patients.

  Study EGAS00001004461

• Systematic comparative analysis of single-nucleotide variants detection methods from single-cell RNA sequencing data

  Systematic interrogation of single nucleotide variations (SNVs) is one of the most promising approaches to delineate the cellular heterogeneity and phylogenetic relationships at the single cell level. While SNV detection from abundant single cell RNA sequencing (scRNA-seq) data is applicable and cost-effective in identifying expressed variants, inferring sub-clones, and deciphering genotype-phenotype linkages, there is a lack of computational methods specifically developed for SNV calling in scRNA-seq. Although variant callers for bulk RNA-seq have been sporadically used in scRNA-seq, the performances of different tools have not been assessed. Here, we performed a systematic comparison of seven tools including SAMtools, the GATK pipeline, CTAT, FreeBayes, MuTect2, Strelka2 and VarScan2, using both simulation and scRNA-seq datasets, and identified multiple elements influencing their performance. Our study provided the first benchmarking to evaluate the performances of different SNV detection tools for scRNA-seq data.

  Study EGAS00001003883

• Combined clinical and gene expression score identifies high-risk individuals among follicular lymphoma patients on immunotherapy

  Follicular lymphoma (FL) is usually an indolent malignant B-cell lymphoma, but at least 30% of the patients experience transformation to Diffuse Large B-cell Lymphoma (DLBCL) with inferior survival. Early identification of patients with poor prognosis is essential for tailoring treatment. Here, we describe a network-based integrative analysis of 168 FL-biopsies from 127 patients with long clinical follow-up and transformation status. A distinct shift in expression towards a DLBCL expression phenotype is observed in BTK associated genes in cases with transformation. This shift is present years prior to transformation. An integrated score combining the BTK score and a clinical index is proposed, termed the BTK-FLIPI score. It identifies patients (16%) with very poor prognosis, with median time to progression 21.7 months (95% CI: 14.3-42.6) versus 70.9 months (95% CI: 41.5-95.0) for the remainder. The results suggest BTK as a potential target for treatment of high-risk FL-patients.

  Study EGAS00001002566