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• Genomic Evolution of Breast Cancer Metastasis and Relapse

  Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

  Dataset EGAD00001002696

• Oncogenic Ectodomain deletion of FGFR1 caused by Breakage-Fusion-Bridges in Squamous Cell lung Cancer

  The identification of recurrent 8p11.23 amplifications including FGFR1 raised the hope of a treatable target in squamous cell lung cancer (SQLC). However, only a minority of patients with FGFR1-amplified tumors respond to single agent inhibitor therapy targeting FGFR. To understand the underlying mechanism of FGFR1 dependency, we performed whole genome and transcriptome sequencing of 25 FGFR1-amplified primary tumors with unknown response upon FGFR inhibition. In addition, we performed deep sequencing of 26 FGFR1-amplified samples whereof the response upon FGFR inhibition was known for 25 samples. In both cohorts we identified intra-chromosomal tail-to-tail breaks close to the FGFR1 transcription start site, being responsible for focal amplification of FGFR1. These specific breaks are caused by a Breakage-Fusion-Bridge-like (BFB-like) mechanism. Here, we associate these breaks with FGFR inhibitor sensitivity. Moreover, in some cases these breaks are located within the open reading frame of FGFR1, which leads to the expression of an ΔEC-FGFR1 transcript that lacks the ecto-domain. Overexpression of ΔEC-FGFR1 transforms Baf3 cells and lead to an FGFR1-dependent phenotype. Our results demonstrate that the truncation of the FGFR1 ectodomain is a frequent event in 8p11.23-amplified squamous cell lung cancer caused by tail-to-tail breaks. These breaks might be used as a predictive therapeutic marker to stratify patients for FGFR-inhibitor therapy.

  Study EGAS00001005059

• Neoadjuvant immune checkpoint blockade in mismatch-repair proficient colon cancers

  Immune checkpoint blockade has led to paradigm shifts in the treatment of various tumour types, yet limited efficacy has been observed in patients with metastatic mismatch-repair proficient (pMMR) colorectal cancer. Here we report an in-depth analysis of patients with early-stage pMMR colon cancer from the phase II NICHE study (ClinicalTrials.gov: NCT03026140). A total of 31 patients received neoadjuvant treatment of nivolumab plus ipilimumab followed by surgery. The response rate was 26% and included six patients with a major pathological response (≤10% residual viable tumour). One patient with an ongoing clinical complete response did not undergo surgery. Responses were observed despite a low tumour mutational burden in all tumours, while chromosomal genomic instability scores were significantly higher in responders compared to non-responders. Responding tumours were more likely to be TP53 mutant, KRASG12 wildtype and had significantly higher baseline expression of proliferation signatures and TCF1. Imaging mass cytometry also revealed a higher percentage of Ki-67+ cancer and Ki-67+ CD8+ T cells in responders compared to non-responders. Meanwhile, in non-responders, we observed an enrichment for an inflamed-fibrotic microenvironment associated with TGF-β expression, hinting towards possible resistance mechanisms. These results provide a comprehensive analysis of response to neoadjuvant ICB in early-stage pMMR colon cancers and identify potential biomarkers for patient selection.

  Study EGAS50000000856

• Extracellular transcriptome in seminal plasma for non-invasive prostate cancer diagnosis

  A diagnostic non-invasive biomarker test for prostate cancer at an early stage, with high sensitivity and specificity, would improve diagnostic decision making. Extracellular RNAs present in seminal plasma might contain biomarker potential for the accurate detection of clinically significant prostate cancer. So far, the extracellular messenger RNA (mRNA) profile of seminal plasma has not been interrogated for its biomarker potential in the context of prostate cancer. Here, we investigate the mRNA transcriptome in seminal plasma samples obtained from prostate cancer patients (n=25), patients with benign prostate hyperplasia (n=26) and individuals without prostatic disease (n=6). Seminal plasma harbors a complex mRNA repertoire that reflects prostate as its tissue of origin. The endogenous RNA content is higher in the prostate cancer samples compared to the control samples. Prostate cancer antigen 3 (PCA3), a long non-coding RNA with prostate cancer-specific overexpression, and ATP-binding cassette transporter 1 (ABCA1), known to be involved in the prostate cancer pathogenesis, were more abundant in the prostate cancer group. In addition, twelve high confidence fusion transcripts could be detected in prostate cancer samples, including the bona-fide prostate cancer fusion transcript TMPRSS2-ERG. Our findings provide proof-of-principle that the extracellular transcriptome of seminal plasma can reveal information of an underlying prostate cancer.

  Study EGAS00001005277

• Unraveling the transcriptomic profile of utero-tubal lavage fluid of ovarian cancer patients

  The majority of ovarian cancers are diagnosed at an advanced stage and have a high mortality rate. Current screening strategies fail to improve prognosis because markers of early stage disease are lacking. This medical need justifies the search for biomarkers enabling early detection of ovarian cancer. In this study, we explore the extracellular transcriptome of utero-tubal lavage fluid obtained from 26 ovarian cancer patients and 48 controls using messenger RNA (mRNA) capture and small RNA sequencing. Because of its contact with the fallopian tube and the ovaries, collection of utero-tubal lavage might be the preferred non-invasive method to identify localized lesions compared with analyses based on peripheral blood samples. We observed an enrichment of ovarian and fallopian tube specific messenger RNAs in utero-tubal lavage fluid compared to other human biofluids. Over 300 mRNAs and 41 miRNAs were upregulated in ovarian cancer samples compared with controls. Upregulated genes were enriched for genes involved in cell cycle activation and proliferation, hinting at a tumor derived signal. In conclusion, we provide proof-of-principle that mRNA capture sequencing of utero-tubal lavage fluid is technically feasible, and that the extracellular transcriptome of utero-tubal lavage should be further explored in larger cohorts to assess the diagnostic value of the biomarkers identified in this study.

  Study EGAS00001005498

• Cell-free DNA fragmentation patterns and personalized sequencing reveal circulating tumor DNA in urine and plasma of glioma patients

  Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy as levels in body fluids are low. We determined the glioma-derived DNA fractions in tumor biopsies, in cerebrospinal fluid (CSF), plasma and urine samples, using deep sequencing of personalized capture panels. By sequencing cfDNA across thousands of mutations identified individually in each patient’s matched tumor we detected tumor-derived DNA in plasma (10/12) and urine samples (8/11). The median tumor fraction was 6.4x10-3 in CSF, 3.1x10-5 in plasma and 4.7x10-5 in urine. We identified a shift in the size distribution for mutant cfDNA fragments in these body fluids. Next, we analyzed cfDNA fragment sizes with paired-end shallow whole genome sequencing (WGS) in urine samples from 35 patients with gliomas, 8 individuals with non-malignant brain disorders, and 26 controls (n=69 individuals, 96 samples). cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders (t-test, p=1.7x10-2) and compared to urine of controls (t-test, p=5.2x10-9). The proportion of DNA fragments <60 bp was higher in glioma patients urine and could be used for classification (AUC=0.93). Machine learning models integrating fragment lengths could identify urine samples from glioma patients (AUC=0.97 in cross-validation).

  Study EGAS00001004355

• Population Architecture Using Genomics and Epidemiology (PAGE): Epidemiologic Architecture for Genes Linked to Environment (EAGLE) - BioVU Cancer Project

  As part of Population Architecture using Genomics and Epidemiology PAGE study (Phase I), the Epidemiologic Architecture using Genomics and Epidemiology (EAGLE I) project accessed both epidemiologic- and clinic-based collections. The epidemiologic-based collection of EAGLE I included the National Health and Nutritional Examination Surveys (NHANES), ascertained between 1991-1994 (NHANES III), 1999-2002, and 2007-2008. NHANES is a population-based cross-sectional survey now conducted every year in the United States to assess the health status of Americans at the time of ascertainment and to assess trends over the years of survey. Genetic NHANES consists of 19,613 DNA samples linked to thousands of variables including demographics, health and lifestyle variables, physical examination variables, laboratory variables, and exposures. NHANES is diverse with almost one-half of the samples (46.4%) coming from self-reported Mexican Americans and non-Hispanic blacks. In contrast to NHANES, BioVU is a clinic-based collection of >150,000 DNA samples from Vanderbilt University Medical Center linked to de-identified electronic medical records (EMRs). Approximately 12% of BioVU's overall DNA sample collection is from African American, Hispanic, and Asian patients. The overall goals of PAGE I and EAGLE I were broad and several-fold: Replicate genome-wide association study (GWAS)- identified variants in European Americans; Identify population-specific and trans-population genotype-phenotype associations; Identify genetic and environmental modifiers of these associations. NHANES is an excellent resource for the study of quantitative traits associated with common human diseases. However, given that the age range of NHANES spans childhood to late adulthood and not all diseases are surveyed, NHANES is less useful for the study of adult-onset diseases such as major cancers. Therefore, under American Recovery and Reinvestment Act (ARRA) funding, EAGLE as part of PAGE I defined eight major cancers sites for genetic analysis in BioVU, Vanderbilt's biorepository linked to de-identified EMRs. The eight major cancers defined for this study included melanoma, breast, ovarian, prostate, colorectal, lung, endometrial, and Non-Hodgkin's lymphoma (NHL). Cancer cases were defined using a combination of ICD-9 codes and tumor registry entries. Controls include BioVU participants without cancer and encompassing the age and gender distributions of cancer cases. Targeted genotyping of GWAS-identified variants for these diseases (124 SNPs) and ancestry informative markers (128 AIMs) was performed by the Center for Human Genetics Research Vanderbilt DNA Resources Core. After quality control, a total of 116 cancer-associated SNPs and 122 AIMs were available for downstream analyses.

  Study phs000559

• A Study of the Genetic Causes of Complex Pediatric Disorders

  The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic medical records (EMRs). EMRs are longitudinal, with a mean duration of 6.5 years. CAG has committed to releasing genotype and phenotype data for 4000 individuals diagnosed with asthma, ADHD, atopic dermatitis, GERD (1000 for each), and 1000 individuals on the upper and lower ranges of Low-Density Lipoprotein (LDL) levels to dbGaP. We will also release genotype/phenotype of 3000 controls. Relevant phenotype data includes primary diagnoses (ICD9 codes), secondary diagnoses (ICD9 codes), medical procedures/tests conducted in relation to the phenotype, and a listing of relevant medications. Further details of CAG's research programs and capacity are available at: http://www.caglab.org

  Study phs000490

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• Genomic Data Archive From the Network for Pancreatic Organ Donors With Diabetes

  The Network for Pancreatic Organ Donors with Diabetes (nPOD) is the largest biorepository of human pancreata from organ donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, and islet autoantibody positive (AAb+)/pre-T1D. The mission of the nPOD is to distribute biospecimens and associated de-identified data/metadata to an international researcher network, and to promote the development of new treatments for these diabetes conditions. Here, we describe the release of high-parameter genotyping data for the nPOD cohort. Specifically, 372 subjects were genotyped using a customized precision medicine single nucleotide polymorphism (SNP) microarray (UFDIchip). These data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 subjects were queried for rare known and novel coding region variants via whole exome sequencing (WES). These data are now publicly available, enabling genotype-selected sample requests and the study of novel genotype : phenotype associations, ultimately to explain diabetes heterogeneity and inform precision medicine strategies to interrupt diabetes pathogenesis.

  Study phs002861