10173 results for "cancer rna-seq"

in 54.04 milliseconds.

• The Genomic Landscape of Endocrine Resistant Advanced Breast Cancers: Paired Pre- and Post-endocrine Therapy Samples.

  The genomic evolution of breast cancers exposed to systemic therapy and its effects on clinical outcome have not been broadly characterized. We integrated the genomic sequencing of 1918 breast cancers, including 1501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. Functional mutations in ERBB2 and loss-of-function mutations in NF1 were more than twice as common in post-endocrine therapy tumors compared to treatment-naive tumors. Additional alterations in the MAPK pathway (EGFR, KRAS among others) and in estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1 and TBX3) were also more common compared to hormonal therapy-naive tumors. To determine whether candidate genomic lesions in the MAPK pathway and estrogen receptor transcriptional regulators were present prior to therapy or whether such lesions arose under the selective pressure of therapy, we performed whole-exome sequencing in select patients who had adequate samples acquired prior to and after progression on endocrine therapy. In total, 95 specimens corresponding to 30 treatment-naive primary tumors, 35 post-treatment tumors, and 30 normal samples were sequenced from 30 patients with endocrine-resistant metastatic breast cancer.

  Study phs001674

• Characterizing TP53 and PPM1D Mutations as Resistance Drivers to Radiation Therapy in Diffuse Intrinsic Pontine Gliomas

  Pediatric high-grade gliomas (pHGGs), encompassing diffuse midline gliomas (DMGs) and hemispheric tumors, represent the most common cause of cancer-related deaths in children age 0-14 years. Over the last decade, several landmark papers have revealed recurrent single nucleotide variants (SNVs) in the core histones H3.3 and H3.1, co-occurring with alterations in the TP53 signaling pathway and receptor tyrosine kinases (RTKs). However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored. We performed a comprehensive analysis of whole genome sequencing (WGS) data on pediatric high-grade gliomas (pHGGs) from 179 children, including 61 hemispheric tumors and 118 diffuse midline gliomas, or DMGs, of which 61 are novel to this study. Among the DMGs, 84 (71%) were from pre-treatment biopsies including 33 obtained from the first multi-institutional North American clinical trial to incorporate diagnostic biopsies. This represents the largest cohort of pretreatment DMGs with whole genome sequencing to date. This large cohort of whole genome sequences provides an unparalleled opportunity to assess significantly recurrent structural variants in pHGG and their associations with driver SNVs and SCNAs. 

  Study phs002380

• High response rate to anti PD-1 therapy in desmoplastic melanoma

  Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

  Study phs001469

• Cohort-Based Genome-Wide Association Study of Glioma (GliomaScan)

  We conducted a new independent GWAS of adult glioma using 1,856 cases and 4,955 controls from 14 cohort studies belonging to the Cohort Consortium, 3 case-control studies, and 1 population-based case only study. Cases were newly diagnosed glioma [ICDO-3 codes 9380-9480 or equivalent], and controls were cancer-free at the time of glioma diagnosis. We found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to higher grade tumors being captured in the cohort studies. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.

  Study phs000652

• Altered chromosomal topology drives oncogenic programs in gastrointestinal stromal tumors

  Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.

  Study phs001906

• Whole Genome Association Study of Systemic Lupus Erythematosus

  The goal of this collaborative study was to identify new genetic risk factors for Systemic Lupus Erythematosus (SLE). To do this we conducted a genome-wide scan by combining the resources and expertise from a number of SLE researchers to establish a large sample set comprising 1311 SLE cases and 3340 controls. The SLE case samples were genotyped from the following collections: 338 subjects from the Autoimmune Biomarkers Collaborative Network (ABCoN), an NIH/NIAMS funded repository, 141 subjects from the Multiple Autoimmune Disease Genetics Consortium (MADGC), 613 subjects from the University of California San Francisco (UCSF) Lupus Genetics, and 335 subjects from the University of Pittsburgh Medical Center (UPMC), plus 8 samples collected at The Feinstein Institute for Medical Research. A total of 3583 control samples were examined in the association analyses. As part of this project, 1861 control samples were selected and then genotyped from the New York Cancer Project (NYCP), based on self-described ethnicity, gender and age. In addition, genotype data from 1722 control samples (all self-described North Americans of European descent) were obtained from the publicly available iControlDB database (http://www.illumina.com/pages.ilmn?ID=231).

  Study phs000122

• Germline Genetics of Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

  Myelodysplastic syndromes (MDS) are part of a heterogeneous and overlapping group of clonal diseases including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and the hybrid MDS/MPN entities that arise in hematopoietic stem or progenitor cells. Individuals with MDS have a high risk of progressing to leukemia, with approximately 30% expected to develop AML. Epidemiologic studies have identified common risk factors for MDS and AML, including smoking, chemical exposures, and previous treatment with chemotherapy and radiation. Analyses of the role of common germline genetic variation in MDS and AML have been limited to date. Our study used data from population-based case-control studies of MDS and AML in Minnesota to evaluate genetic contributions to disease. Cases were enrolled through rapid case ascertainment from the Minnesota Cancer Reporting System, a registry that collects information on all cancers diagnosed in Minnesota. Minnesota State driver's license/identification lists were used to identify controls. Medical record review was completed for cases and centralized review was conducted for diagnosis confirmation and MDS subtype verification. Additionally, saliva was collected from cases and controls and genotyped for genetic studies. Genotyping was conducted using the Illumina Human Global Diversity Array.

  Study phs002962

• Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

  Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

  Study EGAS00001004684

• Prediction of homologous recombination deficiency identifies colorectal tumors sensitive to PARP inhibition

  BRCAness is a well-established feature in breast, ovarian, prostate and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HRD from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology (TSO) _500 HRD panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

  Study EGAS50000000426

• Functional Significance of Prostate Cancer Risk-SNPs

  Prostate Cancer (PrCa), the most frequently diagnosed solid tumor in men in the U.S., results in ~192,000 new cases and ~27,000 deaths per year. Although the variation of PrCa incidence is likely to be the result of several factors, there is a large body of literature that strongly implicates a genetic etiology. Genome-wide association studies (GWAS) have emerged as the most widely used contemporary approach to identify genetic variants (in particular SNPs) that are associated with increased risk of human disease. For PrCa, at least five GWAS have now been performed yielding a substantial number of well-validated SNPs that are associated with an increased risk of PrCa, and that number continues to grow. A significant problem for many of the PrCa risk-SNPs identified so far, however, is that they do not lie within or near a known gene and they have no obvious functional properties. These findings suggest that many (if not most) of these risk-SNPs will be located in regulatory regions that control gene expression rather than in coding regions that may directly affect protein function. Therefore, in order to define the functional role of currently known risk-SNPs, the target genes must first be identified. A promising strategy to address this problem involves the use of expression quantitative trait loci (eQTL) analysis. Unfortunately, most of the publically available SNP-Transcript eQTL datasets utilize lymphoblastoid cells with only a handful using tissue from target organs. Although useful, these datasets alone are unlikely to be sufficient. Recent studies have demonstrated that gene expression and gene regulation occur in both a tissue-specific and tissue independent fashion and suggest that a complete repertoire of regulatory SNPs can only be uncovered in the context of cell type specificity. To date, such a tissue-specific dataset for normal prostate tissue does not exist. In this study, we have constructed a normal prostate tissue specific eQTL data set.

  Study phs000985