Search Results - EGA European Genome-Phenome Archive

Single-cell RNA-sequencing of rhabdomyosarcoma tumour tissue (2025-09-30)

This study investigates high-risk rhabdomyosarcoma (RMS) using multiple single-cell and spatial genomic technologies. We generated and analysed single-cell and single-nucleus RNA-sequencing, chromatin accessibility, and spatial transcriptomics data from primary tumours and validation samples. These datasets characterise cellular diversity within rhabdomyosarcoma and identify cell states associated with aggressive disease. The data support research into tumour biology, risk stratification, and therapeutic target discovery. This repository houses the single-cell RNA sequencing of RMS tumours data. . This dataset contains all the data available for this study on 2025-09-30.

Dataset EGAD00001015713

A next-generation dual guide CRISPR system for genetic interaction library screening

Raw sgRNA sequencing data from a pilot CRISPR screening library to test the dual guide vector system (8,914 guide pairs), and from a large scale genetic interaction screen (~100,136 guide pairs) in HT-29 cells. This data refers to Burgold et al. Nature Communications 2025.

Dataset EGAD00001015754

RNA-Seq dataset of Targeting the dark proteome to expand the lineage-retained antigen landscape in neuroblastoma

This dataset contains bulk RNA-sequencing data generated to enable custom transcriptome assembly and to provide expression context for matched ribosome profiling in the discovery of lineage-retained neuroblastoma tumor antigens. RNA was sequenced from 183 neuroblastoma samples comprising cell lines, patient-derived tumor organoids, and primary patient tumors spanning the adrenergic (ADRN) and mesenchymal (MES) lineage states, with 101 samples prepared as rRNA-depleted (total RNA) libraries and 82 samples prepared as poly(A)-selected libraries. Libraries were sequenced paired-end (2x150 bp) on the Illumina NovaSeq 6000 platform. Raw data are provided as paired-end fastq.gz files.

Dataset EGAD00001016124

ICGC PCAWG Dataset: PACA-CA_PCAWG_WGS_BWA

ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PACA-CA.

Dataset EGAD00001003162

Constit Genome Sequencing

WGS blood data (fastq raw read sequences) for French ICGC leiomyosarcoma cancer sequencing project, 67 samples representing 67 donors. Sequencing was performed on Illumina HiSeq. The libraries were then sequenced with a 2 x 100bp paired-end protocol to a minimum mean coverage of 30x.

Dataset EGAD00001003190

Leiomyosarcoma Cancer Genome Sequencing

WGS cancer data (fastq raw read sequences) for French ICGC leiomyosarcoma cancer sequencing project, 78 samples representing 67 donors. Sequencing was performed on Illumina HiSeq. The libraries were then sequenced with a 2 x 100bp paired-end protocol to a minimum mean coverage of 50x.

Dataset EGAD00001003191

ICGC PCAWG Dataset: OV-AU_PCAWG_WGS_BWA

ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: OV-AU.

Dataset EGAD00001003227

BAM files of total RNA-Seq data of POPS control samples (GRCh37)

Placental biopsies (n = 64 female placentas, n = 67 male placentas) were selected from healthy pregnancies from the POPs cohort. A quality control process was also applied for the RNA-Seq datasets: reads were trimmed with Trim Galore!, which uses cutadapt internally and were mapped to the same version of human genome reference (hg19). TopHat2, a splice-aware mapper built on top of Bowtie2 short-read aligner, was used in the mapping process in which so-called two-pass (or two-scan) alignment protocol was applied to rescue unmapped reads from the initial mapping step. In the second mapping, previously unmapped reads were re-aligned to the exon-intron junctions detected in the first-mapping by TopHat2 and were combined across all 131 placenta samples. The initial and second mapped reads were merged by samtools

Dataset EGAD00001003462

Lung cancer organoids

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term culture conditions of human airway epithelial organoids that contain all major cell populations and allow personalized human disease modelling. We collected macroscopically inconspicuous lung tissue from non-small-cell lung cancer (NSCLC) patients undergoing medically indicated surgery and isolated epithelial cells to engineer 3D organoids. We exploit the potential to derive sub-clones from AOs to demonstrate the feasibility of CRISPR gene editing. Finally, we show that AOs readily allow modelling of viral infections such as RSV and for the first time demonstrate the possibility to study neutrophil-epithelium interaction in an organoid model. Taken together, we anticipate that human AOs will find broad applications in the study of adult human airway epithelium in health and disease.

Dataset EGAD00001004013

Cancer Genomics of the Kidney

The aim of CAGEKID is to carry out comprehensive detection of DNA markers for conventional (clear cell) renal carcinoma. The project includes complete analysis of somatic and constitutional DNA variation, methylation patterns and expression in a large number of constitutional/tumor pairs. CAGEKID is a part of the International Cancer Genome Consortium, ICGC.

Dataset EGAD00001004018

Exome sequencing of 142 gastric cancer and matched normal from Japanese cohorts (UT)

As a contribution to the International Cancer Genome Consortium, exome sequencing of 142 Japanese gastric cancer with various histological subtypes have been conducted. This study aims to identify unique and common driver genes and molecular subtypes in Japanese gastric cancer. Please refer ICGC website for detail: http://icgc.org/icgc/cgp/69/420/1012357

Dataset EGAD00001004041

Exome sequencing of 102 gastric cancer and matched normal from Japanese cohorts (YCU)

As a contribution to the International Cancer Genome Consortium, exome sequencing of 102 Japanese gastric cancer with various histological subtypes have been conducted. This study aims to identify unique and common driver genes and molecular subtypes in Japanese gastric cancer. Please refer ICGC website for detail: http://icgc.org/icgc/cgp/69/420/1012357

Dataset EGAD00001004042

Whole Genome Sequencing of a secondary myelodysplastic syndrome (MDS)

Illumina HiSeq sequence data (with >30x coverage) were aligned to the hg19 human reference genome assembly using BWA (Li and Durbin, 2009); duplicate reads were removed from the final BAM file. No realignment or recalibration was performed. Sample derived from secondary myelodysplastic syndrome (MDS), arising after treatment for medulloblastoma in an 11-year old female Li-Fraumeni syndrome case (LFS-MB1; Rausch et al., 2012; matching WGS data available under EGAS00001000085).

Dataset EGAD00001000665

Next Generation Sequencing in an IBD Pedigree Whole Genome Data

In 2009 we identified a four-generation family with over 700 members and 41 affected with Crohn's disease (CD). At the time we sequenced the exome of 6 affected individuals but did not identify any coding variants which appear to explain the high prevalence of disease. Since then we have collected DNA from a large number of additional family members, genotyped linkage arrays on the entire family to refine genomic regions shared by identity by descent and genotyped affected and unaffected members at known CD risk loci identified by Genome Wide Association Studies (GWAS). These analyses have confirmed that a significant unexplained excess of disease remains after accounting for all known genetic factors, and that several regions of the genome are shared by a large fraction of affected individuals. We therefore perform whole genomes sequencing from 8 individuals which will allow us to impute the complete sequence of nearly all the members of the two largest and most severely affected branches of the family.

Dataset EGAD00001000399

NIHR BioResource Rare Diseases WGS project - Steroid Resistant Nephrotic Syndrome (SRNS) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Steroid Resistant Nephrotic Syndrome (SRNS) Rare Disease domain

Dataset EGAD00001004518

NIHR BioResource Rare Diseases WGS project - Cerebral Small Vessel Disease (CSVD) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Cerebral Small Vessel Disease (CSVD) Rare Disease domain

Dataset EGAD00001004513

NIHR BioResource Rare Diseases WGS project - Hypertrophic Cardiomyopathy (HCM) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Hypertrophic Cardiomyopathy (HCM) Rare Disease domain

Dataset EGAD00001004514

NIHR BioResource Rare Diseases WGS project - Intrahepatic Cholestasis of Pregnancy (ICP) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project.Participants from the Intrahepatic Cholestasis of Pregnancy (ICP) Rare Disease domain

Dataset EGAD00001004515

NIHR BioResource Rare Diseases WGS project - Neuropathic Pain Disorders (NPD) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Neuropathic Pain Disorders (NPD) Rare Disease domain

Dataset EGAD00001004516

NIHR BioResource Rare Diseases WGS project - Primary Membranoproliferative Glomerulonephritis (PMG) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Primary Membranoproliferative Glomerulonephritis (PMG) Rare Disease domain

Dataset EGAD00001004517

NIHR BioResource Rare Diseases WGS project - Bleeding, Thrombotic and Platelet Disorders (BPD) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Bleeding, Thrombotic and Platelet Disorders (BPD) Rare Disease domain

Dataset EGAD00001004519

NIHR BioResource Rare Diseases WGS project - Inherited Retinal Disorders (IRD) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Inherited Retinal Disorders (IRD) Rare Disease domain

Dataset EGAD00001004520

NIHR BioResource Rare Diseases WGS project - Multiple Primary Malignant Tumours (MPMT) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Multiple Primary Malignant Tumours (MPMT) Rare Disease domain

Dataset EGAD00001004521

NIHR BioResource Rare Diseases WGS project - Neurological and Developmental Disorders (NDD) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project – Participants from the Neurological and Developmental Disorders (NDD) Rare Disease domain

Dataset EGAD00001004522

NIHR BioResource Rare Diseases WGS project - Primary Immune Disorders (PID) Rare Disease domain

Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project.Participants from the Primary Immune Disorders (PID) Rare Disease domain

Dataset EGAD00001004523

Whole exome and targeted DNA sequencing data for formalin-fixed paraffin embedded tissue from de novo small cell prostatic carcinoma cases

This dataset consists of 44 compressed paired fastq files, 15 of which are generated from whole exome sequencing, and 29 of which are generated from DNA sequencing using a targeted gene panel capturing the exonic regions of 73 prostate cancer driver genes. Targeted DNA sequencing was performed on an Illumina MiSeq (v3 600 cycle kit), and exome sequencing was done using an Illumina HiSeq 2500 (v4 250 cycle kit) machine. The fastq files are named in accordance with the sample aliases provided, which reflect the pathology of interest to this study (small cell prostatic carcinoma--SCPC), whether it was sequenced using an exome or targeted gene panel, whether the FFPE sample was sourced from tumor or benign tissue (labeled T or B, respectively), and whether there exists multiple samples belonging to a single patient.

Dataset EGAD00001004139

A compendium of mutational signatures due to environmental exposures

Whole-genome-sequencing (WGS) of human tumours has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational-signatures in 324 WGS of human induced pluripotent stem cells (iPSCs) following exposure to known or suspected environmental carcinogens. 79 agents were tested with or without metabolic activation at concentrations that produced measurable cytotoxicity; 41 yielded characteristic substitution mutational signatures. Some exhibit similarity with signatures found in human tumours. Additionally, 6 agents produced double-substitution signatures and 8 produced indel signatures. Investigating mutation asymmetries across genome topography reveals fully functional mismatch and transcription-coupled repair pathways in iPSCs. Primary adducts induced by environmental carcinogens can be resolved by disparate repair/replicative pathways, resulting in an assortment of signature outcomes even for a single mutagen. This compendium of experimentally-induced mutational-signatures permits further exploration of roles of environmental agents in cancer aetiology, and underscores how human stem cell DNA is directly vulnerable to environmental agents.

Dataset EGAD00001004583

Comparison of transcriptional response of induced pluripotent stem (iPS) cell-derived and monocyte-derived macrophages to bacterial lipopolysaccharide stimulation

In the first part of this project, we will differentiate IPS cells from 5 human donors into macrophages, and extract RNA from unstimulated and LPS stimulated macrophages to perform RNA sequencing. We will also extract RNA before and after stimulation in blood- derived macrophages from 5 additional, unrelated healthy samples. In the second part of the project, RNA-seq data will be analysed to compare LPS response of these two macrophage populations. In summary, we will perform 75bp PE RNA-seq on 20 samples (10 pre and post stimulus), on the HiSeq 2500 platform. Samples will be multiplexed at 5 samples / lane, so we will require 4 flow cells in total.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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Dataset EGAD00001001106

High-Risk Breast Cancer GWAS

The GWAS includes High Risk Women from the following epidemiological studies of breast cancer, comprising a total of 3,719 cases and 3,642 controls (cases/controls: MEC, 0/200; ABCFR, 326/418; FCCC, 56/3; BCFR-UT, 66/32; CNIO-BC, 87/92; GESBC, 65/0; LIFE, 164/0; MARIE, 41/105; MAYO, 208/210; MNYR, 293/409; MSKCC, 310/0; NC-BCFR, 234/233; OFBCR, 553/560; POSH, 377/0; HBOC, 47/47; BBCS, 612/1333; UPENN, 280/0 This study was funded by a grant CA165038 to Christopher Haiman (University of Southern California) and John Hopper (University of Melbourne) from the National Cancer Institute, National Institute of Health. The contributing studies: Multiethnic Cohort (MEC). This study was supported by grant UM1 CA164973 from the National Cancer Institute, National Institute of Health. Ontario Familial Breast Cancer Registry, the Ontario site of the Breast Cancer Family Registry Cohort (OFBCR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Utah Breast Cancer Family Registry (BCFR-UT). This study was supported by grant UM1 CA164920 from the National Cancer Institute. New York site of the Breast Cancer Family Registry (MNYR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Northern California site of the Breast Cancer Family Registry (NC-BCFR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Australian Breast Cancer Family Registry (ABCFR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Breast Cancer Study (CNIO-BC). This study has been partially funded by The Spanish Network on Rare Diseases (CIBERER) and the Spanish National Genotyping Center (CEGEN). Genetic Epidemiologic Study of Breast Cancer (GESBC). The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and German Cancer Research Center (DKFZ). Mammary Carcinoma Risk Factor Study (MARIE). This study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Funding for the POSH study was provided by Cancer Research UK (grant refs A7572, A11699, C22524), the Breast Cancer Campaign (grant number: 2013MayPR044) and from 2003-2006 by a grant from The Wessex Cancer Trust. Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Funding for the POSH study was provided by Cancer Research UK (grant refs A7572, A11699, C22524), the Breast Cancer Campaign (grant number: 2013MayPR044) and from 2003-2006 by a grant from The Wessex Cancer Trust. Hereditary Breast and ovarian Cancer: Genetic and Molecular Studies (HBOC). This study was supported by National Cancer Institute grant CA58860 and The Lon V Smith Foundation: LVSF-44528. Mayo Clinic inherited breast and ovarian cancer study (MAYO). This study was supported by the Breast Cancer Research Foundation, NIH grants CA192393, CA176785, and an NIH CA116201 Specialized Program of Research Excellence (SPORE) in Breast Cancer. British Breast Cancer Study (BBCS); Mammographic oestrogens and growth factor study (MOG). The BBCS and the MOG study are funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledge NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). Genotyping of non-BRCA1/2 mutation carriers (UPENN). The study is supported by the Basser Research Center at the University of Pennsylvania, Rooney Family Foundation, NIH grants CA176785 and CA192393, the Breast Cancer Research Foundation, the Susan G. Komen Foundation for the Cure and Macdonald Family Foundation. Clinical Significance of Germline BRCA Mutations (MSKCC). The study is supported by the Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative, The Breast Cancer Research Foundation, and the Cancer Center Support Grant from the National Institute of Health, National Cancer Institute 5P30 CA08748-40. Women's Learning the Influence of Family and Environment (LIFE). This study was supported by grants CA17054 and CA74847 from the National Cancer Institute, National Institutes of Health, No. 4PB-0092 from the California Breast Cancer Research Program of the University of California. Philadelphia site of the Breast Cancer Family Registry at Fox Chase Cancer Center (FCCC). This study is supported by NIH grant CA164920.

Study phs000929

A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children with SCID Disorders

Individuals with a recent or new diagnosis of severe combined immune deficiency (including infants who were identified by newborn screening) may be eligible to be enrolled on the PIDTC research study 6901. Speak to your doctor to determine if you or your child may be eligible. Protocol 6901 follows patients with SCID prospectively, meaning the 6901 study enrolls participants where there is a plan to receive a blood and marrow transplant, enzyme therapy, or gene therapy in the future. Patients are then followed according to a schedule set out by the study protocol after the procedure. The times the study requests follow up will be the same as when your doctor would want to be seeing you or your child as part of their regular ongoing medical care. Patients with "leaky SCID", reticular dysgenesis, and Omenn syndrome may also be eligible to participate in 6901. The 6901 research study does NOT dictate how your or your child's doctors should treat you or your child, as the PIDTC recognizes that there are many complex factors that go into this decision. The decision about how you or your child with SCID will be treated is made by your doctor. The 6901 study simply follows how you or your child do over time. There are no experimental therapies on this study. The 6901 study has been open since August 2010, and continues to be open and enrolling patients to the present day. The study plans to enroll approximately 250 patients with SCID. By studying new patients undergoing treatment for SCID, the goal is to learn more about: (1) outcomes from the treatment of SCID in the modern era of medicine, (2) what factors lead to the best long-term outcomes, such as best donor, conditioning regimen, timing of transplant, etc. and (3) what impact newborn screening and the early diagnosis of SCID has had on the long-term outcomes following BMT or gene therapy. A significant amount of information is also being gathered on how and when the immune system recovers after BMT, quality of life for long-term survivors, and about whether children develop normally after treatment. The 6901 study is the largest coordinated prospective study of patients with SCID ever performed. Information that we will learn, both now and in the future, will help doctors and other health professionals to better treat children with SCID. All hospitals within the PIDTC are enrolling patients with SCID on 6901, ensuring that the outcomes are reflective of what happens in the "real world" as opposed to at just one or two large centers.

Study phs001392

Determination of Cross-Reactive Immunological Material (CRIM) status and longitudinal follow-up of individuals with Pompe disease

Infantile-onset Pompe disease is an inherited disorder that is normally diagnosed within the first months of life. It is caused by lack of or defect in an enzyme (a special protein that carries out normal chemical reactions within the body) called acid alpha-glucosidase (GAA). GAA normally breaks down glycogen (stored sugar) in lysosomes (the part of the cell that digests food and other chemicals). Pompe disease is one of many lysosomal storage diseases (LSDs). LSDs are diseases caused by the malfunction of the lysosome or one of their digestive enzymes. Patients with Pompe disease cannot break down lysosomal glycogen. This causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles. Current treatment for Pompe disease involves enzyme replacement therapy (ERT). In this treatment, the drug alglucosidase alfa (Myozyme) is put into your blood. The drug provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood. This treatment has allowed babies to live longer and achieve developmental milestones. In this study, researchers will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production. A patient's CRIM status (either positive or negative) is an important factor that affects how he or she responds to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM+, while children who do not produce any natural GAA are classified as CRIM-. Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT. Patients who have a poor response to ERT have complications because their body sees Myozyme as "foreign" and triggers an immune response to try to remove it from the body. Treatments are currently being developed to stop this immune response and prevent complications from ERT. We will enroll patients with Infantile Pompe disease in this longitudinal natural history (observational) study. The specific aims of this study are: To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation To investigate the role of immune response to treatment

Study phs001555

Disorders/Differences of Sex Development (DSD) Study Performed at UCLA in Collaboration with the DSD-Translational Research Network (DSD-TRN), with the Support of the Gabriella Miller Kids First Pediatric Research Program

The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Disorders/Differences of Sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. DSD are chronic medical conditions collectively affecting ~1% of the population, frequently requiring life-long care by multiple specialists, and carrying a significant public health burden. Some are associated with life-threatening events, such as adrenal crises in Congenital Adrenal Hyperplasia (CAH). DSD are also associated with increased infertility, cancer, gender dysphoria risks, psychosocial distress and pervasive challenges to health-related quality of life (HRQoL) for patients and families. DSD are broadly classified into three categories: sex chromosome DSD, 46,XY DSD and 46,XX DSD, and further classified according to the type of gonad found in the patient (ovary, testis, ovotestis). We were able to increase significantly the diagnostic success for DSD using Whole Exome Sequencing (WES), with the identification of disease-causing and likely pathogenic variants in a third of a cohort of 46,XY patients. We have therefore proposed a shift in the diagnostic approach to DSD to use next-gen sequencing as a first-line clinical test, which could lead to faster and more accurate diagnosis, and orient further clinical management, limiting unnecessary, costly, and often invasive endocrine testing and imaging. However many remain unexplained (over half of the XY cases, a significant minority of XX cases, including most ovotesticular DSD, and most syndromic cases). In addition, the very large phenotypic variability in cases with known variants in the same gene is unexplained. We here propose to use Whole-Genome Sequencing (WGS), which dramatically improves upon exome sequencing, covering both coding and non-coding parts of the genome more uniformly, as an approach to not only improve diagnostic yield, but also to identify novel genes and regulatory elements involved in DSD.

Study phs001178

New England-Based Case-Control Study of Ovarian Cancer

The case-control data provided to dbGaP were collected under NCI grant number CA54419 which had 3 enrollment phases: I (1992-1997), II (1998-2002) and III (2003-2008). Altogether, CA54419 funded 15 years of data and specimen collection, resulting in one of the longest running population based case-control studies of ovarian cancer. The study goal was to examine reproductive factors, lifestyle exposures, and genetic background in relation to ovarian cancer risk. The project recruited cases from Eastern Massachusetts and New Hampshire, and became known as the New England-based Case-Control study (NECC) of ovarian cancer. 3957 ovarian cancer cases diagnosed at ages 18-80 and residing in Eastern Massachusetts and New Hampshire were identified through tumor boards and registries. Of these, 3083 (78%) were eligible and among those eligible, 2203 (71%) were enrolled. After excluding 127 non-epithelial and 35 mixed mesodermal tumors, 2041 cases with epithelial tumors of ovarian, primary peritoneal, and fallopian tube origin, including borderline malignancies were included. On average, cases were interviewed 10 months after their diagnosis. A pathologist reviewed pathology reports and recorded histologic subtype, grade, and stage. Mixed ovarian cancers described as predominantly one type were classified as that type. Undifferentiated, transitional cell tumors, or mixed serous/transitional cell tumors were counted as serous. Other mixed epithelial, malignant Brenner, and unspecified epithelial tumors were classified as other. 2100 controls were identified through random digit dialing (RDD), driver-license lists, and town-resident lists. During the first funding phase from 1992 to 1997, 420 (72%) controls identified through RDD and 102 (51%) through town-resident lists agreed to participate. From 1998 to 2008, only town-resident lists were used to identify potential controls. 4366 controls were identified, of whom 1426 (33%) were ineligible if they had died, moved, or were seriously ill or if they did not have a working telephone, speak English, or have at least one ovary. Of eligible controls, 1362 (46%) declined to participate by phone or via 'opt-out' postcard and 1578 (54%) were enrolled. Controls were frequency matched to cases by 5-year age groups and region of residence. In all phases, after written informed consent, demographic information, reproductive and medical history, and habits were assessed by in-person or telephone interview (in a few instances). All of the questions were framed with respect to a reference date defined as 1 year before the diagnosis date for women in the case group and the date of interview for those in the control group. This study was approved by institutional review boards at Dana Farber Harvard Cancer Center and Dartmouth Medical Center.

Study phs001034

The Role of CDX2 in Controlling ABCB1 Expression and Chemosensitivity in Human Colon Cancer

This study reports the results of RNA sequencing (RNA-seq) experiments performed on two human colon cancer cell lines (HT-29, DLD-1) that were genetically engineered to achieve either the constitutive expression (in HT-29 cells) or the selective inactivation (in DLD-1 cells) of the transcription factor CDX2, a master regulator of embryonic gut development and a key regulator of multi-lineage differentiation in adult colon epithelial cells. Our previous studies had identified lack of CDX2 expression as a prognostic biomarker of poor prognosis and a predictive biomarker of benefit from adjuvant chemotherapy in Stage-II and Stage-III colon cancer patients (Dalerba et al., NEJM, 374:211-222, 2016; PMID: 26789870). The molecular basis of these associations, however, remained poorly understood. The present study was designed to identify which genes are under the transcriptional control of CDX2, in order to clarify their role in shaping colon cancer resistance to chemotherapy. Of the two lines included in this study, the first (HT-29) is CDX2-negative at baseline, and was infected with a lentivirus vector encoding for the cDNA of the human CDX2 gene under the control of a constitutive promoter (CMV). The second line (DLD-1) is CDX2-positive at baseline, and was infected with a series of lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the CDX2 gene. In both cases, infected cells were purified by fluorescence-activated cell sorting (FACS), based on the differential expression of a green fluorescent reporter (EGFP) that was also encoded by the lentivirus vectors, and transcribed in tandem with either the CDX2 cDNA (HT-29) or CRISPR/Cas9 gRNAs targeting CDX2 (DLD-1). The experiments were designed to include 3 experimental replicates per condition, and to compare the transcriptional profile of genetically engineered cells with that of autologous controls (i.e., HT-29 cells infected with an "empty" version of the same lentivirus vector used to over-express CDX2, DLD-1 cells engineered with a "non-targeting" CRISPR/Cas9 gRNA). In the specific case of DLD-1 cells engineered with CRIPSR-Cas9 constructs targeting CDX2, infected cells were sorted based on the differential expression of EGFP and then plated as single-cells, in order to sub-culture three isogenic clones, all of which were genetically sequenced to confirm bi-allelic knock-out of the CDX2 gene, and confirmed to lack CDX2 protein expression by Western blot. The results of our experiments demonstrate that, in human colon epithelial cells, CDX2 controls the expression of the ABCB1 efflux pump, by positively regulating the transcription of the corresponding gene.

Study phs002903

A Clone's Genomic Stability as a Biomarker of Its DNA-Damage Resilience

A main problem in the treatment of advanced cancers, including gastric cancers and glioblastoma, is the incertitude at which we predict how individual patients will respond to DNA-damaging agents, especially on the long run. Knowing the mechanism behind a patient's response, or the lack thereof, will help us depart from the oversimplified “more-is-better” and “one-size-fits-all” principles according to which DNA-damaging agents are administered. This will improve clinical outcome by allowing us to pinpoint those who would respond better and longer to lower doses than to higher doses of DNA-damaging agents. Under the assumption that the success of DNA-damaging therapy increases with the proliferation rate of a relatively homogeneous tumor population, there was little reason to assume anything other than monotonic dose-response relations. With the recent paradigm shift that most cancers are in fact DNA mosaic products of ongoing evolution, comes the urgency to reconsider these fundamental principles behind DNA-damaging therapy administration. As the developers of one of the first DNA deconvolution methods and with access to technologies to profile the transcriptomes of up to 10,000 cells simultaneously, we are equipped to embark on first personalized dose-finding strategies for DNA-damaging therapies. We will test the potential of the very long-term legacy that DNA-damage entails on a cell “genomic instability” as new biomarker of DNA-damage response. Our preliminary studies showed that, for most cancer types, DNA-damaging agents change a clone's genomic instability and that clones succumb to a limit in the amount of genomic instability they can tolerate. In particular, our results showed that patients with intermediate genomic instability have a very poor outcome and that this relation is only evident among treatment-naive patients, but not among patients treated with DNA-damaging agents. Further they show that we can measure genomic instability per clone and that clones with extreme genomic instability typically don't grow large. Our hypothesis that genomic instability, rather than proliferation rate, determines how sensitive a tumor is to DNA-damaging agents on the long-term, is founded on two unexpected findings. Patients with extremely high genomic instability per tumor clone have an exceptionally good outcome. Aim 1 will integrate exome- and single cell RNA-Seq (scRNA-Seq) data to characterize clones and to measure how much genomic instability they can tolerate. Low genomic instability is associated with reduced benefit from DNA-damaging agents. Aim 2 will use comet assays and treatment history to quantify DNA damage per clone, relating it to the clones' ability to tolerate DNA damage and to changes in the genomic instability of therapy-surviving clones.

Study phs003762

Sanger sequencing of catalytic-domain encoding exons of tyrosine kinase genes from human endometrial tumor DNAs

The purpose of the original study was to search for somatic mutations in the tyrosine kinome of serous and clear cell endometrial carcinomas (human). The study was conducted in two phases. Phase 1: A mutation discovery screen, in which ~577 exons encoding the catalytic domains of 86 tyrosine kinases were PCR-amplified and bidirectionally Sanger sequenced from 24 serous, 11 clear cell, and 5 mixed histology endometrial tumors. This was followed by alignment of sequence reads to the human reference sequence and subsequent nucleotide variant calling to identify potential somatic (tumor-specific) mutations. Potential somatic mutations were confirmed by re-amplification and sequencing of the relevant tumor DNA as well as matched non-tumor ("normal") DNA from the same case. Phase 2: A mutation prevalence screen, in which the non-catalytic regions two tyrosine kinase genes, TNK2 and DDR1, were PCR-amplified and sequenced from the 40 discovery screen tumors, and all coding exons of TNK2 and DDR1 were PCR-amplified and sequenced from another 10 clear cell, 21 serous, and 41 endometrioid endometrial tumors, in an effort to identify additional somatic mutations in each gene. Exons encoding the exonuclease domain of POLE were also sequenced to document somatic mutations.

Study phs000841

Analysis of the Whole Transcriptomes of Human Testis with Complete Spermatogenesis and of Human Testes with Sertoli Cell-Only Syndrome

Sertoli cell-only syndrome is severe form of human male infertility in which most seminiferous tubules appear to lack all spermatogenic cells, including spermatogonial stem cells (SSCs). However, a few small tubule segments of some patients have active spermatogenesis and, thus, functional stem cell niches and SSCs. Normally SSCs replicate, migrate and refill adjacent empty niches, but this does not appear to occur in SCO syndrome. We hypothesized that this failure occurs because most niches are dysfunctional. As Sertoli cells are essential to formation of these niches, we used RNAseq to compare the transcriptomes of human testes with qualitatively normal (complete) spermatogenesis (n=4) with the transcriptomes of human testes with SCO syndrome (n=7). We then focused our analysis on the expression of transcripts that bioinformatic analyses identified as Sertoli cell signature transcripts. Results show that Sertoli cells in SCO testes express abnormally low levels of GDNF, FGF8 and BMP4, all of which are important regulators of mouse SSCs and/or progenitor spermatogonia. Sertoli cells in SCO testes express significantly reduced levels of transcripts for proteins that polarize the Sertoli cell plasma membrane and regulate the trafficking of cell adhesion and gap junction proteins in and out of that plasma membrane.

Study phs001777

Relationship between low LDL cholesterol concentrations not due to statin therapy and risk of type 2 diabetes: a US-based cross-sectional observational study using electronic medical records

Lipid lowering therapy using HMG-CoA reductase inhibitors (statins) is associated with an approximately 9-12% increase in the risk of new-onset type 2 diabetes (T2DM). The risk of diabetes could be increased by statins directly; however, genetic approaches have also implicated low LDL cholesterol (LDL-C) concentrations as a risk factor for T2DM. Mendelian randomization studies using functional variants in both HMGCR (GeneID:3156) and PCSK9 (GeneID:255738) genes found a higher risk of T2DM in individuals with variants associated with lower LDL-C concentrations. Since PCSK9 and HMGCR are involved in lipid metabolism through distinct molecular pathways, the altered glycemic effect associated with variants in both genes is likely to be the result of their common effect on LDL-C concentrations. Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations with increased risk of T2DM. Individuals who have very low LDL-C concentrations not due to lipid lowering therapy can provide insights into the relationship between low LDL-C concentrations and T2DM. Here, we used de-identified electronic health records (EHRs) to test the hypothesis that low LDL-C concentrations are associated with T2DM.

Study phs001588

Predicting the Prevalence of Complex Genetic Diseases from Individual Genotype Profiles Using Capsule Networks

Diseases with a complex genetic architecture, such as amyotrophic lateral sclerosis (ALS) as a most prominent example, are hard to disentangle. "Human mind-friendly" methods, such as linear approaches used in genome wide association studies (GWAS), remain blind to many genetic variants that matter. On the other hand, methods that are sufficiently sophisticated to entirely capture the characteristic interplay of genetic variants remain black boxes for the human mind. Here, we give this a decided, and as we argue, a very promising try. We present DiseaseCapsule, a capsule network-based approach that enables us to predict prevalence/occurrence of a genetically complex disease from individual genotype profiles. Importantly, capsule networks are considerably easier to decompose into their components than ordinary deep neural networks, which promotes the interpretability of their results. The data we used are from Project MinE, a large-scale study that aims to reveal the genetic and epigenetic mechanisms that underlie ALS in the framework of a globally concerted collaboration. Specifically, we used data from the Dutch cohort of the project, which contains 7213 healthy ('control') individuals and 3192 individuals affected with ALS. The cohort includes 5208 females and 5197 males. All participants of the study were genotyped using an Illumina 2.5M SNP array.

Study phs003146

Genome-Wide Assessment of DNA Methylation in Systemic Lupus Erythematosus-Related Autoantibodies

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can have debilitating effects on multiple organ systems. In SLE, the pivotal immunologic disturbance is the formation of autoantibodies directed against nuclear and cellular antigens. These autoantibodies are associated with specific organ manifestations. Our previous work has shown that certain single nucleotide polymorphisms (SNPs) are associated with the production of SLE-related autoantibodies. However, these genetic associations do not completely explain autoantibody development in SLE. Therefore, we examined whether epigenetic factors such as DNA methylation may be associated with the development of SLE-related autoantibodies. In this study, we examined whether differential DNA methylation is associated with anti-dsDNA, anti-SSA/Ro, anti-Smith, and anti-RNP autoantibodies. Using the Illumina HumanMethylation450 Beadchip, over 450,000 DNA methylation sites were characterized in 325 female SLE cases of European descent. Using a multivariable regression analyses, the methylation status of 16 CpG sites in 11 genes was found to be associated with the SLE-related autoantibodies under study. This study shows that epigenetic factors are associated with autoimmune disease phenotypes, and epigenetic studies are a complementary method to genetic association studies for understanding the biologic mechanisms contributing to autoimmune disease.

Study phs000947

Identification and Targeting of Inflammatory Macrophage-Fibroblast Crosstalk in Rheumatoid Arthritis

Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, redirecting them into a state is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions. Reprinted from Kuo, Ding et al., Science Translational Medicine 2019, PMID: 31068444, with permission from American Association for the Advancement of Science.

Study phs001340

Genomic Sequencing of Cervical Cancers

Cervical cancer is responsible for 10-15% of cancer related deaths in women worldwide. The etiological role of infection with high-risk human papilloma viruses (HPV) in carcinomas of the cervix is well established. In general, the development of cervical carcinomas follows a progression from persistent HPV infection through precancerous lesions to invasive cancer. Previous studies have implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as chromosome-arm level copy number alterations in the pathogenesis of cervical carcinomas. Here, we report whole exome sequencing analysis of 118 cervical carcinoma-normal paired samples from patients in Norway and Mexico, as well as transcriptome sequencing of 80 cases and whole genome sequencing of 13 tumor-normal pairs. Novel somatic mutations include recurrent E322K substitutions in the MAPK1 gene encoding the ERK2 kinase and inactivating mutations in the HLA-B gene. In addition, recurrent somatic mutations in FBXW7, EP300, and NFE2L2 are novel in the context of primary cervical carcinomas. Analysis of HPV integration sites revealed recurrent integration into the RAD51B locus as well as co-occurrence of HPV genome integration and copy number gains within several genomic loci. These findings shed new light on the pathogenesis of cervical carcinomas and suggest potential novel therapeutic targets.

Study phs000600

Identification of Targetable FGFR Gene Fusions in Diverse Cancers

In this study, patients with advanced cancer across all histologies were enrolled in our IRB approved clinical sequencing program, called MI-ONCOSEQ, to go through an integrative sequencing which includes whole exome sequencing of the tumor and matched normal, and transcriptome sequencing. Four index cases were identified which harbor gene rearrangements of FGFR2 including two cholangiocarcinoma cases, a metastatic breast cancer case, and a metastatic prostate cancer case. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, including TCGA, we identified FGFR gene fusions with intact kinase domains of FGFR1, FGFR2, or FGFR3 in cholangiocarcinoma, breast cancer, prostate cancer, lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins in vitro induced cell proliferation, and bladder cancer cell lines that harbors FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.

Study phs000602

International Multi-Center ADHD Genetics Project

The goal of the project is to complete a 600,000 tag SNP genome-wide association scan of 958 parent-child trios from the International Multisite ADHD Genetics (IMAGE) project, in order to assess the association of SNP markers with ADHD, analyze quantitative ADHD phenotypes, complete copy number analyses, assess parent of origin effects and season of birth effects, and test for epistasis among apparently uncorrelated genes. Acquiring DNA Samples All consent forms stipulate that the samples can only be used by researchers who have been approved by the National Institute of Mental Health (NIMH), National Institutes of Health. All consent forms, except those used at the Zürich site (N=141 subjects), explicitly indicate that the samples may be used by researchers from commercial enterprises seeking to benefit financially from the analysis of the samples. The Zürich consent does not prohibit such use. The Zürich consent form also included an "opt out" that allowed the subjects to indicate that they did not want their samples stored at the NIMH repository or used by researchers external to the project. No subjects enrolled in the project opted out. Consent groups and participant set ADHD (ADHD): 2758 (924 trios)

Study phs000016

Autism Post-Mortem Brain RNA-Sequencing: SRRM4 Splicing Study

Purpose: The goal of this study was to assess the status of splicing changes in microexons in the cortex of individuals with autism. Methods: We performed RiboZero Gold (rRNA depleted) 50bp PE RNA-seq in a larger set of case and control samples to define 12 autism and 12 control samples showing the greatest global differential gene expression change. These samples, which show differential expression of the splicing regulator SRRM4, were used to evaluate global splicing changes. Results: Within these samples, 126 of 504 (30%) detected alternative microexons display, a mean ΔPSI > 10 between ASD and control subjects of which 113 (90%) also display neural-differential regulation. By contrast, only 825 of 15,405 (5.4%) longer (i.e. > 27 nt) exons show such misregulation, of which 285 (35%) correspond to neural-regulated exons. Notably, we also observe significantly higher correlations between microexon inclusion and nSR100 mRNA expression levels across the stratified ASD samples and controls, for those microexons regulated by nSR100 relative to those microexons that are not regulated by this factor (p=1.4x10-7, Wilcoxon Sum Rank test). Conclusions: These data suggest microexon regulation is a potentially important mechanism underlying ASD and likely other neurodevelopmental disorders.

Study phs000872

Sporadic Amyotrophic Lateral Sclerosis (ALS): Parent-Offspring and Twin Sequencing Study

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that affects the nerves in the brain and spinal cord, leading to muscle weakening and eventual paralysis and death. Ten percent of ALS cases are thought to be familial while the majority of cases are sporadic and the causative factors unknown. Dr. Roger Pamphlett of the University of Sydney has collected a unique cohort of consented trios where the child has ALS but the parents are unaffected. Since the age of onset is so late, it is very difficult to obtain this kind of trio. We have performed whole exome sequencing on these trios to identify de novo and recessive germline variants associated with sporadic ALS. In addition, Dr. Pamphlett has assembled a collection of consented discordant monozygotic twins, where one twin has ALS and the other is unaffected. We performed whole genome sequencing on these twin pairs to identify postzygotic variants that may contribute to sporadic ALS susceptibility. Finally, we have the opportunity to compare the sequence and gene expression in affected and unaffected tissues from blood, brain and/or spinal cord samples from consented ALS patients to look for somatic mutations or gene expression changes that may further our understanding of the disease.

Study phs000831

NextGen Consortium: GENESiPS Study: Identifying the Gene Networks of Insulin Resistance

Variability in induced pluripotent stem cell (iPSC) lines remains a roadblock for disease modeling and regenerative medicine. Through linear mixed models we have described different sources of gene expression variability from RNA sequencing data in 317 human iPSC lines from 101 individuals. We found that ~50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele specific expression show that iPSCs retain a subject-specific gene expression pattern. Pathway enrichment and key driver analyses, based on predictive causal gene networks, found that Polycomb targets explain a significant part of the non-genetic variability present in iPSCs within and across individuals. These publically available iPSC lines and genetic datasets will be a resource to the scientific community and will open new avenues to reduce variability in iPSCs and improve their utility in disease modeling. SNP array data from individuals included in RNA-seq transcriptome profiling study of human induced pluripotent stem cells to characterize gene expression variation across individuals and within multiple iPSC lines from the same individual. Genotyping was performed on patient blood. Data availability: SNP-genotyping: dbGaP - current study RNA-seq counts: GEO - GSE79636 FASTQ files: SRA - SRP072417

Study phs001139

Host Genetic Determinants of the Outcome of Staphylococcus Aureus Bacteremia by Whole Exome Sequencing

In this case-control study, Complicated Staphylococcus aureus (case) is defined as bacteremia plus endocarditis or bone/joint infection, and Uncomplicated Staphylococcus aureus (control) has no such complications and was cured at follow-up. We used whole exome sequencing to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 Complicated SAB and 84 Uncomplicated SAB, frequency matched by age, sex and bacterial clonal complex). Then we evaluated the 334 most significantly associated genes and 8 biological candidate genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched by age, sex and bacterial clonal complex). All participants were white, non-Hispanic of European descent. In the discovery sample, gene-based analysis using SKAT-O identified 334 genes associated with complicated SAB at p<3.5 x 10-3;. Gene-based analysis of the 342 genes in the replication sample using SKATO identified one gene, GLS2 (GeneID: 27165), significantly associated with complicated SAB (p=1.2 x10-4;) after Bonferroni correction. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in white blood cell proliferation and activation.

Study phs001505

Discovery of Non-ETS Gene Fusions in Human Prostate Cancer using Next Generation RNA Sequencing

Half of prostate cancers harbor gene fusions between TMPRSS2 and members of the ETS transcription factor family. To date little is known about the presence of non-ETS fusion events in prostate cancer. We employed next-generation transcriptome sequencing (RNA-Seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes ETV1 and ERG, and five involving non-ETS genes such as CDKN1A (p21), CD9 and IKBKB (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene RSRC2. The novel gene fusions are found to be of low frequency but interestingly, the non-ETS fusions were all present in prostate cancer harboring the TMPRSS2-ERG gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement prone phenotype.

Study phs000310

Somatic Mutation Profile by Next Generation Sequencing in HER2+ Breast Cancer

The HER pathway is the driving force behind 30% of human breast cancers. It is important to understand how targeted therapies block different cellular pathways, and mechanisms of escape from this blockage. Therapies directed at HER2 establish a successful treatment paradigm, but de novo and acquired resistance exist. The HER signaling system is a complex network with four receptors and eleven ligands, a phosphorylation signaling cascade, and many transcription factors, all complicated by both positive and negative feedback circuits. Analysis of genomes, exomes and transcriptomes by next generation sequencing is aimed at uncovering the genetic factors responsible for patient responses to HER2-directed therapies. We are sequencing HER2-overexpressing cancers, in order to identify potential somatic changes that may better select patients who will benefit from therapy, to determine new targets that may overcome resistance, and to improve outcomes with known current HER2-targeted therapies. Whole exome capture sequencing will determine somatic mutation profiles in HER2-overexpressing tumors, to comprehensively characterize the somatic alterations, with the goal of identifying those patients most likely to respond, as well as discovering new targets that may overcome resistance to HER2-directed therapy. We augment the whole exome data with RNA-seq data to determine expression levels of somatic mutations we discover.

Study phs000770

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