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• Integration of Clinical and Molecular Biomarkers for Melanoma Survival (Berwick)

  The long-term goal of the InterMEL Program Project: Integration of Clinical and Molecular Biomarkers for Melanoma Survival is to identify molecular and clinical factors that predict survival of melanoma patients. Our overarching hypothesis is that we can identify factors in the primary melanoma tumor that will lead to more aggressive disease. Melanoma patients diagnosed at American Joint Committee on Cancer (AJCC) tumor, lymph nodes, and metastases (TNM) stages IIA/IIB/IIC/IIIA/IIIB/IIIC/IIID display highly variable clinical outcomes and responses to therapy. We wish to identify robust and reproducible biomarkers or sets of classifiers that distinguish patients likely to have poor prognosis. These biomarkers will help establish targets for adjuvant therapies for this set of patients before the tumors metastasize. Aim 1. Classify actionable somatic mutations, and copy number variations (CNVs) in relationship to melanoma survival. In Project 1, Targeted Sequencing and Clinicopathology to Evaluate Primary Melanoma Molecular Subtypes and Outcomes, we will profile 468 genes using the MSKIMPACT ™ assay and identify somatic mutations and CNVs associated with melanoma-specific survival, as well as their co-occurrence with other mutations, in 1,000 tumors from patients at AJCC TNM stages IIA-IIID: approximately 500 from patients who died with melanoma within five years and approximately 500 from individuals who have lived at least five years. We will also evaluate the joint effects of somatic mutations, CNVs and pathologic characteristics associated with good and poor outcomes. Aim 2. Identify primary melanoma DNA methylation profiles to evaluate subtypes and survival. Although it has been established that melanomas frequently have aberrant DNA methylation, it is unknown if DNA methylation in primary melanomas predicts outcome. In Project 2, Primary Melanoma DNA Methylation Profiling for Evaluating Subtypes and Survival, we will profile the same primary melanomas as in Project 1 with Illumina Infinium 850K methylation arrays. We expect to: identify and characterize DNA methylation-based melanoma subclasses; train, test and validate a CpG signature prognostic for survival from melanoma; determine whether this profile adds information to outcome prediction beyond AJCC TNM staging. This project is based on the hypothesis that DNA methylation in primary melanoma will define subgroups (including a poor-prognosis CIMP – ‘CpG island methylator phenotype' subtype) and that a CpG signature will be prognostic for melanoma survival. Aim 3. Define microRNA expression changes in relation to melanoma survival. MicroRNAs have been associated with poor prognosis in melanoma, as well as in other cancers. In Project 3, Prognostic and Functional Role of a Gene Expression Signature in Melanoma Patients, we hypothesize that altered miRNA expression, captured at the time of diagnosis, may contribute to the aggressive behavior of a subset of early stage primary melanomas. We will profile the same primary melanomas as in Projects 1 and 2 with a Nanostring assay. This project will define and validate a tissue-based microRNA signature in conducted to determine whether the prognostic miRNA signature, as well as other candidate genes emerging from other projects, contribute to melanoma survival. Aim 4. Integrate data from multiple platforms to identify melanoma subtypes and survival. Despite substantial literature on gene tumor mutation-, methylation- and gene expression-based prognostic and predictive signatures for melanoma, few such signatures are used in clinical practice. Project 4, Multiplatform Analysis of Melanoma Molecular Subtypes and Patient Survival Outcome, will use novel integrative clustering methods to identify molecular subtypes of melanoma jointly defined across these platforms.

  Study phs003099

• Single Cell RNA-Sequencing in Adenoid Cystic Carcinoma

  This study of salivary adenoid cystic carcinoma aimed to profile individual malignant and stromal cells in treatment-naive head and neck adenoid cystic carcinoma, with or without metastatic cervical lymph nodes. Clinical and pathologic information was collected on all patients, in addition to a fresh biopsy sample from the primary tumor and/or metastatic lymph node at the time of initial surgery. A fresh biopsy sample from a matched local recurrence was also collected for a single unique patient. Biopsy specimens were processed for single cell RNA-seq. A total of ~1,700 single cells from seven participants were included in the final dataset.

  Study phs003070

• Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform

  Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell Carcinoma (ccRCC) with percutaneous biopsies and is a confounding factor in selection of molecular-targeted versus immune-based therapy. Magnetic Resonance (MR) Imaging can noninvasively assess the spatial landscape of the entire tumor. To validate MRI for ITH assessment, we implemented a radiogenomic platform through a systematic imaging based co-localization approach for multi region tissue acquisition from single tumors. We investigated if the spatial changes in imaging can predict the molecular changes using transcriptome and histopathological correlatives. Our study confirmed imaging heterogeneity as a predictor of molecular heterogeneity in ccRCC.

  Study EGAS00001003846

• NHLBI TOPMed: Whole Genome Sequencing of Venous Thromboembolism (WGS of VTE)

  This study consists of 338 VTE cases from an inception cohort of Olmsted County, MN residents (OC) with a first lifetime objectively-diagnosed idiopathic VTE during the 40-year study period, 1966-2005. All living study subjects were invited to provide a whole blood sample at the Mayo Clinical Research Unit for leukocyte genomic DNA and plasma collection. For living study subjects who did not provide a blood sample, we retrieved any leftover blood ("waste" blood) from samples collected as part of routine clinical diagnostic testing and used this to extract DNA after obtaining patient consent. For deceased cases, with IRB approval, we extracted DNA from any available stored tissue within the Mayo Tissue Archive. This "tissue" DNA has been successfully genotyped in prior studies. Three trained and experienced study nurse abstractors reviewed the complete medical records in the community of all potential cases. Note: WGS sample IDs for the previous GENEVA study cases (phs000289) are included in this dataset. The phenotypes for the GENEVA study are located under the above phs number.

  Study phs001402

• Detection and Targeting of Splicing Deregulation in Pediatric Acute Myeloid Leukemia Stem Cells

  This study evaluates the gene expression and splicing changes between pediatric patients with and without Acute Myeloid Leukemia (AML) and pediatric and adult patients with AML. We obtained bone marrow or peripheral blood from patients and isolated CD34+ stem and/or progenitor cells from pediatric patients with AML (10) or without AML (6) and adult patients with AML (5). In parallel, a targeted analysis for known, deleterious, genetic mutations in the KRAS, NRAS, and KMT2C genes identified 2, 5, and 6 AML patients with alterations, respectively. Additionally, Tapestri analysis further identified a mutation in the intronic region of the SF3B1 gene in multiple pediatric AML patients. RNA-Seq was performed on the purified cell populations at The Scripps Research Institute Next Generation Core on an Illumina NextSeq 500 sequencer with 150bp paired-end reads.These datasets revealed that, similar to adult AML, pediatric AML samples were enriched for Leukemia Stem Cells (LSC) markers. A deeper analysis showed widespread dysregulation of splicing in pediatric AML samples compared to age-matched non-leukemic samples. In addition, the splicing regulator RBFOX2 was downregulated with an accompanying increase in specific CD47 splice isoforms in the pediatric AML samples. Thus, the increased presence of LSCs in pediatric AML is possibly driven by global splicing deregulation, and the treatment with splicing modulators like Rebecsinib has a potential therapeutic value for eradicating LSCs in these patients.

  Study phs003196

• Characterization of genetic intratumor heterogeneity in colorectal cancer and matching patient-derived spheroid cultures.

  Patient-derived in vitro cultures of colorectal cancer (CRC) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from CRCs and see how well intratumor heterogeneity (ITH) was recapitulated in matching patient-derived spheroids. Three to five biopsies were collected from six CRC tumors. Each biopsy was split in two; one half was used for spheroid culturing, the other half was used for direct DNA and RNA purification. For two of the patients, lymph node metastases were analyzed. Somatic mutations were called from whole exome sequencing data. Each tumor contained multiple mutations shared across all biopsies and spheroids, including major CRC drivers such as APC, KRAS, and TP53. At the same time, all tumors exhibited ITH on both mutation and copy number level. The concordance between biopsies and spheroids ranged between 40-70% for coding mutations. For three of the patients the biopsy and spheroid from matching areas clustered together, meaning that the spheroid resembled the area of origin more than the other areas. However, all biopsies and spheroids contained private mutations. Thereby, multiple cultures from spatially distinct sites of the tumor increase the insight into the genetic profile of the entire tumor. RNA sequencing based molecular subtyping was stable and seemed independent of genetic ITH. In conclusion, all examined CRC tumors contained genetic ITH on mutation and copy number level. Spheroid cultures partly reflected this ITH, meaning that multiple cultures from distinct sites of the tumor improved the representation of the different genetic subclones in the primary tumor. This should be taken in to account when establishing patient-derived models for drug screening.

  Study EGAS00001002684

• Comprehensive molecular and clinicopathological profiling of desmoid tumors

  Previous studies have not clearly identified a prognostic factor for desmoid tumors (DT). Whole-exome sequencing and/or RNA sequencing were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics.

  Study JGAS000270

• Whole exome sequencing of virus-associated HCC

  To understand comprehensive combinations of molecular alterations and seek for potential therapeutic targets/pathways in virus-associated HCC, we have conducted a whole exome sequencing (in-solution capturing all human coding exons) of 150 pairs of HCC cases.

  Study EGAS00001000389

• Whole genome sequencing of Xeroderma Pigmentosum leukemias samples

  In the current study we report for the first time the unique collection of 6 leukemias and two sarcomas from XP-C. Comprehensive WGS-based mutational analysis provides genetic explanation for the increased incidence of leukemia in XP-C and describes an unique mutational process in internal tumors associated with NER deficiency. Raw data are provided in FASTQ format and variant analysis as VCF files.

  Dataset EGAD00001006322

• GeneSTAR (Genetic Study of Atherosclerosis Risk) NextGen Consortium: Functional Genomics of Platelet Aggregation Using iPS and Derived Megakaryocytes

  The causal mechanisms of common diseases and their therapies have been only marginally illuminated by genetic variants identified in genome wide association studies (GWAS) utilizing single nucleotide polymorphism (SNPs). Platelet activation pathways reflecting hemostasis and thrombosis are the underlying substrate for many cardiovascular diseases and related acute events. To overcome GWAS limitations, genomic studies are needed that integrate molecular surrogates for platelet-related phenotypes assayed in cell-based models derived from individuals of known genotypes and phenotypes. In our GWAS study of native platelet aggregation phenotypes and aggregation in response to low dose aspirin in 2200 subjects (GeneSTAR, Genetic Study of Aspirin Responsiveness), important genome wide "signals" (p<5x10-8) associated with native platelet aggregation and important "signals" associated with platelet responsiveness to aspirin were identified and replicated. Although we are currently performing functional genomics studies to elucidate our most promising findings in known genes (PEAR1, MET, PIKC3G), most "signals" occurred in intergenic regions or in introns. Mechanistic interpretation is limited by uncertainty as to which gene(s) are up- or down-regulated in the presence of most SNP modifications. In this 3 phase proposal, we will (1) create pluripotent stem cells (iPS) from peripheral blood mononuclear cells, and then differentiate these stem cells into megakaryocytes (2) develop an efficient strategy to produce iPS and megakaryocytes using a novel pooling method, and (3) produce iPS and megakaryocytes from 250 subjects in GeneSTAR (European Americans and African Americans), selected based on specific hypotheses derived from GWAS signals in native and post aspirin platelet function; characterize genetic mRNA transcripts using a comprehensive Affymetrix array; measure protein expression for transcripts of interest using mass spectrometry; examine mRNA and protein expression patterns for each GWAS signal to determine the functional pathway(s) involved in native platelet phenotypes; and examine the functional genomics of variations in responsiveness to aspirin using our prior genotyped and phenotyped population. Precise information about the exact functional processes in megakaryocytes and platelets may lead to innovative and tailored approaches to risk assessment and novel therapeutic targets to prevent first and recurrent cardiovascular and related thrombotic events.

  Study phs001074