12298 results for "cancer rna-seq"

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• Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

  Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that promotes the aggressive biology of this disease. While the varied mechanisms by which fibrillar collagens contribute to PDAC have been defined, little is known about the contribution of transmembrane collagens. Among this class of collagens, Collagen XVII uniquely contains an extensive intracellular domain that connects intracellular cytoplasmic components with the extracellular matrix. Collagen XVII is best characterized as the defining component of the type I hemidesmosome, an anchoring complex that attaches epithelial cells to the underlying basement membrane. In this study, we characterize the expression of collagen XVII in PDAC and the mechanisms by which it contributes to PDAC biology. We demonstrate that crosstalk between PDAC cells and cancer associated fibroblasts drive collagen XVII expression in vitro and xenograft tumor models in vivo. Genetic depletion of collagen XVII in low-passage patient derived cell lines diminishes their metastatic potential and ability to form tumors in mice. Whole transcriptome sequencing of tumors formed by cells with diminished collagen XVII levels revealed dramatically lower levels of PIK3R5, a regulatory subunit of class IB phosphatidylinositol-3-kinase (PI3K) that interacts with G protein-coupled receptors. Consistent with this, collagen XVII-deficient tumors exhibited lower levels of phosphorylated AKT, a downstream effector of PI3K. The studies highlight the importance of collagen XVII signaling in PDAC and define a novel mechanism by which collagen XVII mediates activation of PI3K.

  Study phs003641

• Genomic landscapes of endometrioid and mucinous ovarian cancers and morphologically similar tumor types

  While endometrioid and mucinous ovarian cancers represent nearly a quarter of ovarian cancers, their molecular characteristics and pathologic origins are poorly understood. To characterize the genomic and epigenomic alterations of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed sequence, copy number, mutation signature, rearrangement, and methylation analyses from tumor samples and matched normal tissues of 133 patients. These analyses included patients with ovarian endometrioid (n=44), ovarian mucinous (n=43), uterine endometrial (n=15), and gastrointestinal mucinous cancers (n=31). In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4 and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous cancers. Whole genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid tumors, and NF1 and MED1 in ovarian mucinous cancers. The number of alterations and affected genes in ovarian and uterine endometrioid cancers were similar as were genome-wide methylation profiles, suggesting that these tumors may have a similar tissue of origin. By contrast, methylation patterns in ovarian mucinous cancers were more similar to other gastrointestinal mucinous cancers, including mucinous cancers of the stomach, colon, and pancreas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.

  Study EGAS50000000523

• Ultra-sensitive tumor-informed ctDNA monitoring of treatment response in advanced esophagogastric cancer patients

  To explore whether ultra-sensitive circulating tumor DNA (ctDNA) profiling enables earlier prediction of treatment response and detection of disease progression, we applied NeXT Personal, an ultra-sensitive bespoke tumor-informed liquid biopsy platform, to profile tumor samples from the KeyLargo study, a phase II trial in which metastatic esophagogastric cancer (mEGC) patients received capecitabine, oxaliplatin, and pembrolizumab. A total of 24 patients were evaluated, and all were ctDNA-positive at baseline. ctDNA levels varied from 406,067 down to 1.5 parts per million (PPM) with a median limit of detection of 2.03 PPM. ctDNA dynamics were highly correlated with changes in tumor size (ρ = 0.59, p = 7.3×10-9). Lack of early molecular response (50% or greater decrease in ctDNA levels at first available time point after 30 days, C2D1 or C4D1) was associated with worse overall survival (OS) (HR 6.6, 95% CI 1.8-24.1, p = 0.005) and progression-free survival (PFS) (HR 15.4, 95% CI 2.7-87.0, p = 0.002). Lack of molecular clearance of ctDNA was associated with worse OS (HR 6.9, 95% CI 1.5-30.8, p = 0.012) and PFS (HR 19.2, 95% CI 2.4-152.8, p = 0.005). Molecular progression (ctDNA increase) preceded imaging-derived progression by a median lead time of 65 days. These results suggest that ultra-sensitive liquid biopsy approaches could improve treatment decision-making for mEGC patients receiving chemotherapy and immunotherapy.

  Study EGAS50000001224

• Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guérin

  The recommended treatment for patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. In case of progression to advanced disease, patients must undergo a radical cystectomy with significant morbidity and have a poor clinical outcome. Identifying tumors least likely to respond to BCG can translate into alternative treatments, such as early radical cystectomy or novel targeted or immunotherapies. Here we present molecular profiling of 132 BCG-naive, HR-NMIBC patients, and 44 post-BCG recurrences (34 matched), which uncovered three distinct BCG Response Subtypes (BRS1-3). Patients with BRS3 tumors have reduced recurrence and progression-free survival compared to BRS1-2. BRS3 tumors expressed high EMT-basal markers and had an immunosuppresive profile, which was confirmed with spatial proteomics. Tumors which recurred post-BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive HR-NMIBC patients and the molecular subtypes outperformed guideline recommended risk stratification based on clinicopathological variables. For clinical application, we validated that a commercially approved assay was able to accurately predict BRS3 tumors (AUROC 0.86). Our findings provide a potential clinical tool for improved identification of HR-NMIBC patients at the highest risk of progression, which can be used to select patients for early radical cystectomy or novel subtype-directed therapies.

  Study EGAS00001006879

• DFCI Gynecological Oncology Data Access Committee

  This Data Access Committee is responsible for reviewing requests to access controlled human genomic data generated as part of the RESOLVE clinical trial at DFCI. The committee ensures that access complies with participant consent, institutional policies, and applicable data protection regulations (e.g., GDPR). Data access decisions are made by a multidisciplinary panel including clinical researchers, bioinformaticians, and data governance officers from Dana-Farber Cancer Institute. The committee reviews each access request to determine whether the proposed research aligns with the study’s consent terms and the data access policy. If approved, access is granted via the European Genome-phenome Archive (EGA) in accordance with EGA’s data use and security guidelines.

  Dac EGAC50000000712

• Immunoreactive_p53_areas_in_human_skin_2

  Previous work has suggested that in mice there may be a difference in mutational burden between areas expressing stabilised p53 protein and others. We wish to see if this observation holds true in human sun-exposed epidermis. We will take 0.25mm punch biopsies from peeled human skin epidermis which will be submitted to the low input pipeline prior to sequencing.

  Study EGAS00001004463

• Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders

  PPM1D, a central regulator of the DNA damage response, is commonly mutated in therapy-related clonal hematopoiesis (CH), acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under selective pressure of DNA-damaging chemotherapy. However, whether PPM1D mutations promote the development of hematologic malignancies remains unclear.

  Study EGAS50000000840

• Amplicon based re-sequencing of multi-region PDAC samples

  Multi-region tumor samples were cut from frozen sections or FFPEs and reviewed from microdissection and H&E staining in order to select ones with high cellularity. DNA extraction was done using DNeasy Blood & Tissue Kits for frozen samples following the manufacturer’s guideline. Extracted DNAs were processed on an Illumina HiSeq 2500 in a paired end mode (100x100) using a custom targeted panel based on the list of all unique somatic mutations from the original WES data by the Integrated Genomics Operation (IGO) at Memorial Sloan Kettering Cancer Center (New York, NY).

  Dataset EGAD50000000354

• WES of pleomorphic lung cancer

  Pulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous non-small-cell lung carcinoma whose underlying biology is still poorly understood. Forty-two tumor areas including 39 primary tumors and 3 metastases from 20 PPC patients were microdissected and the histologically distinct components were subjected to whole exome sequencing (WES) separately. Twist Human Core Exome + RefSeq + Mito-Panel kit (Twist Bioscience) was used for the whole exome capturing according to manufacturer’s guidelines. Paired-end 100-bp reads were generated on the Illumina NovaSeq 6000. After the sequencing, reads were aligned against the reference human genome GRCh38 using Burrows-Wheeler Aligner (BWA, v0.7.12)

  Dataset EGAD50000000453

• Chordoma_Targeted_Sequencing_Study

  This Study uses a focused bespoke bait pull down library method to target findings of Chordoma whole genome and whole exome sequencing studies in order to validate findings. This method will also be used on a larger set of tumour only samples in order to find precedence of these findings in a larger set of patient samples.

  Study EGAS00001000280