Search Results - EGA European Genome-Phenome Archive

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy and is characterized by a striking degree of heterogeneity. We enrolled a total of 1001 DLBCL patients and comprehensively defined the landscape of genetic mutations, copy number alterations and expression through whole-exome and transcriptome sequencing. We identified 150 genetic drivers of DLBCL including many novel, clinically relevant genes (e.g. SPEN, SETD1B and KLHL14). Genetic drivers were highly enriched among essential genes identified by CRISPR screening in DLBCL cell lines including those of immediate potential therapeutic relevance such as MTOR, SYK, SF3B1 and XPO1. RHOA emerged as a critical driver gene from our genetic analysis and CRISPR screen; we further delineated its functional role in vitro and in vivo models to define its role as an essential oncogene in DLBCL. Our work thus identifies the functional landscape of genetic drivers and their clinical and therapeutic relevance in DLBCL patients.

Study EGAS00001002606

Comparative genomics research for Chinese colorectal cancer

In order to clarify the mechanisms of genesis and development of colorectal carcinoma, in this study, we performed comparative genomics research in Chinese colorectal cancer at various clinical stage via whole exon sequencing or whole genome sequencing. Comparative bioinformatical analysis was perform to find the difference on somatic single-nucleotide variants, short insert/deletion variants, genomic structural variants, and copy number variants between cancer tissue and normal tissue, or among cancer tissues at various clinical stages.

Study EGAS00001002607

Reduced Representation Bisulfite Sequencing (RRBS) in various tissues to discover DNA methylation markers for the diagnosis of breast and ovarian cancer.

Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. In addition, monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence.In order to discover the most relevant CpG regions, we used RRBS and analysed several tissue samples: 11 prospectively collected invasive epithelial ovarian cancer samples (high grade serous n=8, low grade serous n=1, endometrioid n=1, mucinous n=1, mean age = 54.7 years), 8 prospectively collected invasive ductal breast cancer samples (2/8 triple negative; mean age = 56.6 years), one benign tumor (papillary serous cystadenoma, age = 86 years), 18 non-neoplastic tissue samples (breast n=7 and adnexal n=11, mean age = 60.2 years), two non-neoplastic endometrial tissues (mean age = 68 years) and twenty three white blood cell samples (mean age = 57.8 years) were assessed by RRBS. Genome wide methylation analysis was performed by Reduced Representation Bisulfite Sequencing (RRBS) at GATC Biotech. DNA was digested with MspI followed by size selection of the library, providing enhanced coverage for the CpG-rich regions. The digested DNA was adapter ligated, bisulfite modified and PCR amplified. The libraries were sequenced on Illumina’s HiSeq 2500. Analysis of the first samples sequenced with 100bp paired-end mode showed that the library insert size was small. Therefore, the remaining samples were sequenced with 50 bp paired-end mode. Using Genedata Expressionist® for Genomic Profiling v9.1, we established a bioinformatics pipeline for the detection of cancer specific differentially methylated regions (DMRs). The most promising DMRs were taken forward for the development and validation of serum based clinical assays.

Study EGAS00001002609

Somatic_Variation_Angiosarcoma

Through whole genome sequencing, this study will explore the mutational profiles and signatures within an angiosarcoma tumour from a patient with xeroderma pimentosum. Very little information is known about this tumour type and it has not previously been studied within the context of xerogerma pigmentosum.

Study EGAS00001002610

The genomic landscape of cutaneous squamous cell carcinoma from immunosuppressed and immunocompetent patients reveals common drivers and a novel mutational signature associated with chronic azathioprine exposure

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Combining whole exome analyses from 40 primary cSCC tumours, comprising 20 well differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients, coupled with integration of independent gene expression studies has allowed the identification of commonly mutated genes and altered pathways and processes. Mutational signature analysis revealed the presence of a novel signature (signature 32), which was found exclusively in the tumours from immunosuppressed patients who had been exposed to azathioprine. Characterisation of a panel of 15 keratinocyte cancer cell lines derived from tumours from immunocompetent and immunosuppressed patients reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a resource for the validation of tumour drivers and therapeutic targets.

Study EGAS00001002612

Capture Hi-C on MM

In situ promoter capture Hi-C on multiple myeloma cell line KMS11 in experimental triplicates. Hi-C libraries were prepared as previously described (Rao et al., 2014, http://dx.doi.org/10.1016/j.cell.2014.11.021). Promoter capture was based on 32,313 biotinylated 120-mer RNA baits (Agilent). Hi-C libraries were sequenced using Illumina HiSeq 2000 technology. The files are in FASTQ format.

Study EGAS00001002614

Clonal evolution study of Intrahepatic cholangiocarcinoma in Zhongshan Hospital

Clonal evolution study of Intrahepatic cholangiocarcinoma

Study EGAS00001002625

Somatic_mutation_and_clonal_evolution_in_the_human_pancreas___WGS

In this study we aim to characterise the landscape of mutation and clonal selection in the human pancreas. The study combines targeted sequencing and whole-genome sequencing of microbiopsies from the pancreas. The range of patients studied will include healthy individuals, both smokers and non-smokers, and patients with pancreatic ductal adenocarcinoma.

Study EGAS00001002626

Ultra-Fast Patient-Derived Xenografts Identify Functional and Spatial Tumour Heterogeneities that Drive Therapeutic Resistance

Treatment of patients with advanced cancers increasingly relies on agents targeting specific molecular or cellular aberrations. These expensive therapies often fail because of pre-existing drug resistance. Intra-tumoural molecular and micro-environmental heterogeneity resistance can create resistance in one or more subclones of a tumour, leading to spatio-functional heterogeneity. We created a rapid approach for quantifying tumour functional phenotypes based on tumour-implantation into the chorioallantoic membrane of chick embryos. We apply this technique to 43 separate biopsies from 6 patients with renal cell carcinoma (RCC) with 36 replicates per biopsy, achieving a 93.6% engraftment rate (1449/1548). Challenging these models with sunitinib, an anti-angiogenic therapy frequently used in RCC allowed us to quantify spatio-functional heterogeneity in individual patients. Prediction of de novo drug resistance in advanced cancer patients would facilitate precision medicine by tailoring systemic therapies and improve clinical trial design outcome measures. We describe a patient-derived xenograft platform where fresh patient tumour samples are implanted into the chorioallantoic membrane (CAM) of chick embryos at high engraftment efficiencies, permitting large scale “tumour avatar” studies to guide the selection of drugs and to predict clinical drug resistance outcomes in renal cell carcinoma (RCC) patients. Applying this “tumour avatar” model in a co-clinical trial on RCC patients, we observe intra-tumoural functional heterogeneity with sunitinib treatment, revealing the presence of drug-resistant clones prior to the initiation of therapy. Multi-regional exome Matched DNA sequencing of the primary tumour and metastases revealed DNA mutational signatures associated with sunitinib resistance at baseline and after treatment. These These studies demonstrate a rapid and affordable method of findings confirm the existence of genetic and surveying functional tumour heterogeneities heterogeneity.

Study EGAS00001002627

Mutational spectrum of highly differentiated, fusion-negative rhabdomyosarcoma (set 1).

Pediatric PAX-FOXO1 fusion-negative rhabdomyosarcoma represents a diverse spectrum of tumors. In this study, the mutational spectrum of 22 fusion-negative rhabdomyosarcomas with high, rhabdomyoma-like levels of differentiation was evaluated using OncoPanel v.2 (OPv2), an Agilent SureSelect custom designed bait set consisting of the coding regions of 504 cancer-relevant genes. Corresponding normal tissue was not available. Discarded normal human skeletal muscle, obtained from 7 donors without tumor history, were also included in the sequencing run.

Study EGAS00001002630

HDAC inhibitors in synovial sarcoma cells

Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb-group targets were reactivated including tumor suppressor CDKN2A, and pro-apoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and pro-apoptotic factors BIK, BIM and BMF were important to apoptosis induction following HDAC-inhibition in synovial sarcoma

Study EGAS00001002637

Identification of a Fumarate-Hydratase Deficient-like RCC Subtype with Convergent Pathway Alterations

The development of molecularly targeted therapies builds upon the identification of tumor clades with shared molecular abnormalities. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial syndrome resulting from germline mutation of the two-hit tumor suppressor gene, Fumarate Hydratase (FH). HLRCC renal tumors present often in young adults, exhibit unique histological features and are particularly aggressive. HLRCC is uncommon and poorly understood, and whether there are sporadic renal tumors with similar characteristics, is unclear. Notably, FH can also be inactivated somatically in RCC, and should be included among FH-deficient (FHD) kidney tumors. We identified a tumor clade without FH mutations but with similar morphological and molecular characteristics as well as aggressive clinical behavior, which we name FHDL (FHD-like). We show that FHD/FHDL tumors represent a unique subtype of CIMP (CpG Island Methylator Phenotype) with the highest levels of overall genome methylation and CDKN2A silencing. FHD/FHDL tumors are characterized by convergent activation of the Hippo pathway as determined by frequent and mutually exclusive mutations in NF2 and PTPN14. AKR1B10, an NRF2 target, was upregulated in FHD/FHDL tumors as well as GATA3, which suggests a shared origin in the renal medulla and is consistent with topological studies. There is loss of 5-hydroxymethylcytosine in both FHD and FHDL tumors. These data define a group of particularly aggressive renal cancers with shared molecular features and potential targets for therapeutic intervention.

Study EGAS00001002646

Detection of clinically relevant genetic and transcriptomic landscape in DLBCL uniformly treated by R-CHOP

Recent studies using next-generation sequencing strategies have described the landscape of genetic alterations in diffuse large B-cell lymphoma (DLBCL). However, little is known about the clinical relevance of recurrent mutations and copy number alterations and their transcriptional footprints. This study examines the frequency, interaction and clinical impact of recurrent genetic aberrations in DLBCL using high-resolution technologies in a large population-based cohort.

Study EGAS00001002657

WGS of 32 paired SRCC samples

Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however with no systematical investigation for prognostic genomic features. We systematically investigated the clinical characteristics of 1,868 Chinese gastric cancer patients, and found that signet-ring cell content was significantly related to multiple clinical characteristics and treatment outcomes. Next, we performed whole genome sequencing for 32 SRCC patients with > 80% signet-ring cells in tumor, and identified frequent5 CLDN18-ARHGAP26/6 fusion (25%). With additional 797 patients for validation, we notice that prevalence of CLDN18-ARHGAP26/6 fusion is positively associated with signet-ring cell content (P = 4.1 x 10 -9 ), younger age at diagnosis (P = 4.2 x 10 -10 ), female/male ratio (P = 1.7 x 10 -9 ), and advanced TNM stage (P = 1.7 x 10 -5 ). Importantly, patients with CLDN18-ARHGAP26/6 fusion had a worse survival outcomes (P = 0.03), and got no benefit0 from platinum/fluoropyrimidines based chemotherapy (P = 0.92) compared to fusion-free patients (P = 0.001), which is consistent with the fact of oxaliplatin/fluoropyrimidine resistance acquired in CLDN18-ARHGAP26 introduced gastric cancer cell lines. Overall, this study provides new insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.

Study EGAS00001002668

We performed whole-exome sequencing of 20 samples (10 actinic keratosis and 10 cutaneous squamous cell carcinoma) to investigate a potential relationship between DNA methylation-based subtypes and genetic mutation patterns (Rodriguez-Paredes et al., Nat Commun 2017)

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer type and arises from keratinocytes. Most cSCC progress from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain only partially understood. Here we have used Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status of about 850.000 CpGs in epidermal preparations from healthy skin, AK and cSCC. Importantly, we found that the premalignant AK samples displayed classical features of cancer methylomes and were highly similar to cSCC methylomes. Further analysis identified typical features of stem cell methylomes, such as a reduced DNA methylation age, non-CpG methylation and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature was detected only in one half of the AK and cSCC samples, while the other half showed keratin and enhancer methylation patterns that were more closely related to the control epidermis. These findings suggest the existence of two distinct subclasses of AK and cSCC that originate from distinct keratinocyte differentiation stages.

Study EGAS00001002670

The identification of genetic vulnerabilities in head and neck cancers for the development of novel treatments.

The global cancer burden is expected to double by the year 2030 and this will disproportionately affect the Asian continent. Head and neck squamous cell carcinoma (HNSCC) is endemic in Asia. It is the sixth most common cancer worldwide and the second most common in Malaysia, with approximately 600,000 new cases per year globally. Longterm survival remains less than 50%, underscoring the need for better therapeutic strategies. In this proposal we aim to bring new technological advancements in the identification of critical genes in HNSCC and the identification of compounds for the development of new therapies in HNSCC. We propose to genomically characterise 16 unique Asian H&N cancer cell lines, to classify sub groups where identification of essential genes that can be targeted for tumor control can be applied in a more rational way. Further, we propose to use zebrafish, an established drug discovery platform to identify promising pathway-specific compounds that could be further studied using CRISPR/Cas9 lethality screens and biological models to better identify novel therapeutic strategies to combat this major health problem in Asia.

Study EGAS00001002682

Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling

Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts. Enhancer regions revealed novel oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, increased survival and slowed proliferation in mouse and neurosphere patient-derived models of ependymomas. This study represents one of the largest enhancer mapping study of any cancer type to date, and provides a framework for target and drug discovery for other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

Study EGAS00001002696

Alternative splicing isoforms in patient-derived hepatocellular carcinoma cells

The aim of this study was to obtain a landscape of alternative splicing (AS) in human hepatocellular carcinoma (HCC). We applied hybrid sequencing by integrating Pacbio long-read and Illumina short-read RNA sequencing data from 8 patient-derived HCC cell lines, and used an immortalized hepatocyte cell line as reference. This study revealed features of annotated and novel splice variants in HCC cells, including transcript length, AS type and protein changes. We also identified novel isoforms and tumor specific isoforms, which may represent potential biomarkers and targets for therapeutic development.

Study EGAS00001002697

Gut microbiome modulates response to anti PD1 immunotherapy in metastatic melanoma patients

There is a growing appreciation of the role of the microbiome in cancer, and evidence in pre-clinical models that the gut microbiome may modulate responses to immune checkpoint blockade though this has not been well-characterized in patients. We analyzed the oral (n=86)and gut (n=43) 16S microbiome in melanoma patients on PD-1 blockade. Significant differences were noted in the diversity and composition of the gut microbiome between responders and non-responders in patients with a fecal microbiome sample, with significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria) in R. Metagenomic studies (n=25) revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling demonstrated enhanced systemic and anti-tumor immunity in patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplant from responding patients. Together, these data have important implications for treatment with immune checkpoint blockade in cancer. The fastq files associated with this dataset are stored at ENA under the following accession numbers: PRJEB22894 (Fecal 16S), PRJEB22874 (Oral 16S), PRJEB22895 (Murine 16S), PRJEB22893 (Fecal WGS).

Study EGAS00001002698

Whole exome sequencing of cell-free DNA reveals temporo-spatial heterogeneity and identifies treatment-resistant clones in neuroblastoma

Background: Neuroblastoma (NB) displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression. Patients and Methods: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 NB patients. Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of Single Nucleotide Variants (SNVs) and Copy Number Alterations (CNAs), with 41% and 93% of all detected alterations common to the primary NB and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate timepoints during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2. Conclusion: Modelisation of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating towards tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies.cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target.

Study EGAS00001002705

Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.

Study EGAS00001002707

Targeted_sequencing_of_cylindroma_patients

Patients with cylindroma show multiple large tumours on the scalp and forehead. These large tumours will allow us to look at clonality within a tumour. We wish to asses the mutational load and diversity within and across tumours as well as compare with perilesional skin.

Study EGAS00001002708

Comprehensive genomic profiling of matched glioblastoma tumours, cell-lines, and xenografts reveals genomic stability and adaptation to disparate growth environments

The mandate of this project was to use drug screening to deliver new drugs for glioblastoma (GBM) to clinical trials, and perform genomic assessment of GBM to discover new therapeutic targets and predictors of response. The sequencing data in this set was derived from GBM patient tumor samples, matched brain tumor initiating cells lines (BTICs), and tumor tissue derived from orthotopic implants.

Study EGAS00001002709

Defective Homologous Recombination DNA Repair as Therapeutic Target in Advanced-Stage Chordoma (HIPO_021)

HIPO project: HIPO_021 Importance: Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown.Objective: To identify therapeutically tractable genetic lesions in a cohort of chordoma patients within a genomics-guided precision oncology program and to document the outcome of individualized, molecularly targeted chordoma therapy.Design, Setting, and Participants: We performed whole-exome sequencing of tumor and matched germline control samples from seven patients with locally advanced or metastatic chordoma who were enrolled in a cross-institutional molecular stratification registry trial for younger adults with advanced-stage cancer across all histologies and patients with rare tumors. All patients were heavily pretreated and had progressive disease prior to molecular analysis.Interventions: Individualized medical therapy was administered according to the patients’ molecular profiles.Main Outcomes and Measures: Candidate therapeutic targets identified by whole-exome sequencing and response to genotype-directed therapy.Results: All patients harbored alterations of two or more genes known to be involved in DNA repair via homologous recombination (HR), including heterozygous deletions of ERCC6, FANC family members, RAD51L (n = 6), BRCA2 (n = 5), ATR, CHEK2, RAD18, RAD51B, and XRCC3 (n = 4); inactivating PTEN mutations coupled with loss of heterozygosity (n = 2); and pathogenic germline variants in BRCA2 (n = 1), NBN (n = 1), and CHEK2 (n = 1) that were accompanied by somatic deletion of the corresponding wild-type alleles. Consistently, a mutational signature associated with defective HR was enriched in all samples and co-occurred with extensive genomic instability, as evidenced by HR deficiency scores and high numbers of large-scale state transitions. These results prompted off-label treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib in a patient whose tumor was refractory to irradiation and systemic treatment with imatinib, which led to a prolonged response and substantial clinical improvement.Conclusions and Relevance: Advanced-stage chordomas are frequently characterized by genomic imprints of defective HR DNA repair. HR deficiency represents a new therapeutic opportunity in this intractable disease through repositioning of PARP inhibitors that warrants further exploration in clinical trials.

Study EGAS00001002720

MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Oesophageal_squamous_cell_carcinoma

The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute (Illumina HiSeqX, 40X and 20X depth respectively). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

Study EGAS00001002725

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