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• Genetics of Chemotherapy Induced Peripheral Neuropathy in N08C1 and N08CB

  Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting toxicity of chemotherapy treatment. CIPN severity varies widely between cancer patients, and previous studies had found evidence of genes and single nucleotide variants (SNV) being associated with CIPN. The goal of this study was to further identify genetic markers and pathways associated with CIPN severity using whole exome sequencing (WES) and whole genome sequencing (WGS) of participants in two clinical studies which collected longitudinal patient-reported outcome (PRO) measures of CIPN. NCCTG/Alliance study N08C1 was a prospective cohort study of the natural history of paclitaxel-associated acute pain syndrome (P-APS) and CIPN. NCCTG/Alliance trial N08CB was a randomized, placebo-controlled trial of calcium and magnesium for prevention of oxaliplatin-induced sensory neuropathy in which the treatment had no significant effect on either acute pain or sensory neuropathy. Both N08C1 and N08CB collected patient assessments of CIPN symptoms before each cycle of chemotherapy using the EORTC QLQ-CIPN20 instrument. For this study, CIPN cases were selected from each of N08C1 and N08CB as those patients with the most severe CIPN symptoms (assessed longitudinally). CIPN controls were selected as those with the least severe symptoms. WGS was obtained for N08C1 samples (WES had been obtained and analyzed previously), and WES was obtained for N08CB samples.

  Study phs001480

• Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

  In this study, we performed metabolite profiling and RNA-sequencing on human breast cancer tumors and normal breast tissue samples, including triple negative breast cancer (TNBC), estrogen receptor positive breast cancer (ER+) and paired normal samples, and patient-derived xenografts (PDX) samples. Here, we report two distinctive groups defined by metabolites; a TNBC-HIGH group that shows high levels of pyrimidine pathway metabolites and biosynthetic enzymes, and an ER-HIGH group that shows high levels of fatty acid and arginine biosynthesis intermediates. We identify different metabolic enrichment profiles between cell lines grown in vitro vs. in vivo; cell lines grown in vivo recapitulate patient tumors metabolic profiles. Further, we identify a subset of genes that strongly correlates with the TNBC-HIGH metabolic profile using integrated metabolic and gene expression profiling, which strongly predicts patient prognosis when tested on larger human datasets. As a proof-of-principle, when we target TNBC-HIGH metabolic dysregulation with a pyrimidine biosynthesis inhibitor (Brequinar), and/or a glutaminase inhibitor (CB-839), we observe therapeutic efficacy and decreased tumor growth in representative TNBC cell lines, murine p53-null mammary tumors, and in vivo patient-derived xenografts (PDXs) upon multi-agent drug treatment. This study highlights potential new therapeutic opportunities in breast cancers guided by a genomic biomarker, which could prove impactful for breast cancers that rapidly proliferate.

  Study phs002396

• Genomic Characterization CS-MATCH-0007 Arm Z1D

  The CS-MATCH-0007 protocol is a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing, RNA sequencing and if possible, whole-genome, methylation and miRNA sequencing using pre-and posttreatment tumor biopsy specimens from all patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to their corresponding genomic alterations. Arm Z1D is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with MMR deficiency are treated with nivolumab. This subprotocol is one of the treatment arms in the EAY-131 trial included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood and RNA from tumor tissue. A fuller genomic landscape of tumors from these patients will enable discovery of potential molecular features correlated to clinical outcomes or lay the foundation for future studies leading to new and more effective treatments.

  Study phs001859

• E5103 Correlative Studies

  ECOG-ACRIN E5103 (E5103) was a phase III adjuvant breast cancer trial that randomized 4994 patients with node-positive or high-risk node-negative breast cancer to intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks (at the discretion of treating physician), for four cycles of adriamycin and cyclophosphamide (AC) followed by 12 weeks of weekly paclitaxel (80 mg/m2) alone (Arm A), or to the same chemotherapy with either concurrent bevacizumab (Arm B), or concurrent plus sequential bevacizumab (Arm C). To develop predictive genetic biomarkers for chemotherapy efficacy and toxicities, we have successfully performed genome-wide genotyping and whole exome sequencing in the germline (blood) DNA of 3215 and 672 patients, respectively, from the E5103 trial to investigate the association of genetic variants with chemotherapy efficacy and toxicities. Case and control studies were performed with genome-wide analyses (GWAS) and whole exome analyses (WES) across all arms of E5103 to identify genotypes at single-nucleotide polymorphisms (SNPs) and deleterious gene mutations that were associated with paclitaxel-induced peripheral neuropathy (TIPN). Through GWAS, we have identified a SNP, rs3125923, and through WES, Cytochrome P450 oxidoreductase (POR), that was significantly associated with grade 3-4 TIPN.

  Study phs003201

• Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

  ​​Multiple Myeloma (MM) develops from well-defined precursor stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering MM (SMM); however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. In this study, we enumerated circulating tumor cells (CTCs) from patients with precursor and overt diseases, and developed a novel approach, MinimuMM-seq, which enables detection of translocations and copy number abnormalities through whole-genome sequencing of highly pure CTCs. In a cohort of 51 patients, 24 with paired BM, we applied our method MinimuMM-seq and detected 100% of clinically reported BM biopsy events. The next-generation sequencing (NGS) assay could replace molecular cytogenetics by Fluorescence In Situ Hybridization (FISH) for diagnostic yield and risk classification. In 8 patients we could apply MinimuMM-seq on serially collected samples to track and monitor major clones in peripheral blood. We describe clonal evolution and shifting dynamics of subclones over time, as well as in between blood and marrow compartments. All whole-genome sequencing (WGS) data generated in this study will be made accessible through dbGaP.

  Study phs003084

• Genomic Characterization CS-MATCH-0007 Arm Y

  The CS-MATCH-0007 protocol is a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing, RNA sequencing and if possible, whole-genome, methylation and miRNA sequencing using pre-and post-treatment tumor biopsy specimens from all patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to their corresponding genomic alterations. Arm Y is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with AKT mutations are treated with AZD5363. This subprotocol is one of the treatment arms in the EAY-131 trial included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood and RNA from tumor tissue. A fuller genomic landscape of tumors from these patients will enable discovery of potential molecular features correlated to clinical outcomes or lay the foundation for future studies leading to new and more effective treatments.

  Study phs001904

• Genomic Characterization CS-MATCH-0007 Arm H

  The CS-MATCH-0007 protocol is a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from all patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to their corresponding genomic alterations. Arm H is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with BRAF V600K/V600E mutations are treated with Dabrafenib and Trametinib. This subprotocol is one of the treatment arms in the EAY-131 trial included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood and RNA from tumor tissue. A fuller genomic landscape of tumors from these patients will enable discovery of potential molecular features correlated to clinical outcomes or lay the foundation for future studies leading to new and more effective treatments.

  Study phs001888

• Transcription Factor Analysis of SLE

  Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations. This study identifies two histone marks of activation and the binding of p300 genome-wide in three cell types and three clinical subsets to better understand cell-specific effects and differences across clinical subsets. Results: We examined 20 patients with SLE and 8 controls and found the TNF, IL-2/STAT5, and KRAS pathways were identified across multiple cell types and ChIP data sets. Patients with cutaneous lupus and lupus nephritis generally had less dramatically altered chromatin than the general SLE group. Conclusions: NFkB and classical inflammatory pathways were strongly associated with increased peak heights across all cell types but were the highest-ranking pathway for all three antibodies in monocytes according to fgsea analysis. IL-6 Jak/STAT3 signaling was the most significant pathway association in T cells marked by H3K27ac change. Therefore, each cell type experiences the disease process distinctly although in all cases there was a strong theme of classical inflammatory pathways. These studies define important cell type differences and emphasize the breadth of the inflammatory effects in SLE.

  Study phs003713

• The genomic basis of childhood T-lineage acute lymphoblastic leukemia

  T-lineage acute lymphoblastic leukemia (T-ALL) is a high-risk tumor that has eluded comprehensive genomic characterization, in part due to the high frequency of non-coding genomic alterations resulting in oncogenic dysregulation. Here we report integrated genome and transcriptome sequencing of T-ALL tumor and remission samples obtained from over 1300 uniformly treated children with T-ALL, coupled with epigenomic and single cell analysis of malignant and normal T cell precursors. Integrated analysis identified 15 subtypes with distinct genomic drivers, gene expression, developmental state and outcome. Integration with chromatin topology analyses enabled elucidation of multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific fashion. We show that the immunophenotypically-described, high-risk entity of early T-cell precursor ALL is superseded by a broader category of leukemias of variable immunophenotype with diverse genomic alterations of a core set of genes encoding regulators of hematopoietic stem cell development. Numerous genetic alterations and disease subtypes emerged as independent predictors of survival and treatment failure in univariable and multivariable outcome models. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

  Study EGAS50000000016

• SHANK2 mutations associated with Autism Spectrum Disorder cause hyperconnectivity of human neurons

  Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in dendrite length, dendrite complexity, total synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 muation, supporting a role for SHANK2 as a regulator of connectivity in developing human neurons. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.

  Study EGAS00001003436