6137 results for "canc*"

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• Pancreatic Cancer Case Control Association Study

  Pancreatic cancer is the fourth leading cause of cancer death in the United States. This is in large part due to the rapidly fatal course of this disease, as the vast majority of patients die within months of diagnosis and the five-year survival rate is less than 5. We have brought together over 8000 participants from 9 studies of pancreatic cancer, to conduct a GWAS of pancreatic cancer. The studies were drawn from the Pancreatic Cancer Case-Control consortium and include case-control studies from the United States, Europe and Australia. Sites include: Johns Hopkins National Familial Pancreas Tumor Registry, Mayo Clinic Biospecimen Resource for Pancreas Research, Ontario Pancreas Cancer Study (OPCS), Yale University, MD Anderson Case Control Study, Queensland Pancreatic Cancer Study, University of California San Francisco Molecular Epidemiology of Pancreatic Cancer Study, International Agency of Cancer Research and Memorial Sloan Kettering Cancer Center.

  Study phs000648

• Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care (BASIC3) Clinical Exome Sequencing Study - Clinical Sequencing Exploratory Research Consortium

  The BASIC3 (Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care) study is a National Genome Human Research Institute (NHGRI) and National Cancer Institute-funded Clinical Sequencing Exploratory Research (CSER) consortium project that focuses on prospective implementation of clinical whole exome sequencing in the pediatric oncology clinic. The primary study objective are to integrate information from CLIA-certified germline and tumor exome sequencing into the care of newly diagnosed solid tumor patients at Texas Children's Cancer Center, and to perform parallel evaluation of the impact of tumor and germline exomes on families and physicians. Blood and frozen tumor (if available) samples are collected from children undergoing surgery or biopsy of newly diagnosed solid tumors and subjected to exome sequencing in a CLIA-certified laboratory. Germline and tumor (if applicable) exome sequencing reports are generated and submitted into the electronic health record and returned to each patient/family by their primary oncologist. If specific (optional) consent is obtained, research sequencing studies (including transcriptome sequencing) are performed in addition to the clinical exome sequencing.

  Study phs001026

• Aurora US Metastatic Breast Cancer Retrospective Project

  The AURORA US Metastatic Breast Cancer project is funded by the Breast Cancer Research Foundation (BCRF) Evelyn H. Lauder Founder's Fund for Metastatic Breast Cancer Research. This multi-center effort conducted within the Translational Breast Cancer Research Consortium (TBCRC) and cancer researchers to better understand the metastatic process through the study of both the primary and metastatic tissue. In the retrospective phase, TBCRC sites submitted matched primary and metastatic tissues and blood from previous collections for piloting the process. Samples were profiled using whole genome DNA sequencing, whole exome DNA sequencing, DNA methylation arrays, and RNA sequencing. The final freeze set for samples with successful nucleic acid extraction and molecular assays included 55 patients with 31 primary tissues and 102 metastases. Twenty patients had tissue collected at autopsy and included 19 with more than one metastasis. Metastases were from 20 different tissue locations with the most common sites being liver, lung, lymph node, and brain. The median age at primary diagnosis was 49 years. The clinical subtypes of the primary tumors were 34% Triple Negative, 30% ER+HER2-, 11% ER+HER2+, and 7% ER-HER2+. Patients received an average of 3 lines of therapy in the metastatic setting. The median overall survival from primary diagnosis was 4.5 years and overall survival from metastatic diagnosis was 2 years.

  Study phs002622

• Division of Cancer Epidemiology and Genetics (DCEG) Imputation Reference Dataset

  We have built a new resource for imputation of SNPs for existing and future genome-wide association studies (GWAS), known as the Division of Cancer Epidemiology and Genetics (DCEG) Reference Set. The first build of the data set includes 728 cancer-free individuals of European descent from three large prospectively sampled studies, 98 African-American individuals from the Prostate, Lung, Colon, and Ovary Cancer Screening Trial (PLCO), 74 Chinese individuals from a Chinese clinical trial in Shanxi, China (SHNX), and 349 unrelated individuals from the HapMap Project (see Molecular Data Section for details on arrays used). The final harmonized dataset includes 2.8 million autosomal polymorphic SNPs on 1,249 subjects after rigorous quality control metrics were applied.

  Study phs000396

• Kids First: Genetics of Pediatric Germ Cell Tumors

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the genomic and phenotypic data from this study are accessible through dbGaP. The data is also available at the Kids First Portal, where other Kids First datasets can also be accessed in the cloud for data analysis, data visualization, collaboration and interoperability, open to all researchers and developers. Pediatric malignant germ cell tumors (GCTs) represent approximately 6% of childhood cancers, including 3% of tumors in children aged 0-14 years and 15% of tumors in adolescents. GCTs are heterogeneous and grouped together due to the presumed common cell of origin, the primordial germ cell (PGC). GCTs typically occur in the testes or ovaries; however, extragonadal GCTs can occur and are likely a result of abnormal germ cell migration during development. Evidence suggests that GCTs, including those diagnosed in adults, are initiated in utero. Thus, alterations in normal embryonic development are likely to be especially relevant to GCT etiology. Germline susceptibility has not been evaluated in an agnostic fashion in pediatric GCT, mainly due to a lack of an adequate number of samples; however, emerging evidence supports a genetic etiology. In the two Kids First GCT projects, we will evaluate genetic susceptibility to intracranial and extracranial GCT by sequencing probands and their unaffected parents. The goals of the project are to: 1) Evaluate the contribution of rare genetic variants in GCT through the use of aggregate burden tests, focusing on genes and established regulatory regions; 2) Identify de novo SNVs and CNVs in pediatric GCT using a case-parent triad design; and 3) Identify molecular signatures in GCT tumor specimens, overall and by age group and tumor characteristics. Whole Genome Sequencing data generated through the Gabriella Miller Kids First Pediatric Research Program will provide an opportunity to investigate the genetic origins of GCT in a diverse set of samples. Given the limited knowledge of GCT etiology and biology, the results of the proposed analyses are likely to have a big impact on the field.

  Study phs002322

• The Spatio-Temporal Evolution of Multiple Myeloma from Baseline to Relapse-Refractory States

  In multiple myeloma, the spatio-temporal evolution patterns of cancer cells in the bone marrow remain largely unknown. Here, we applied spatial-longitudinal sequencing, including a total of 179 samples collected from 25 patients during a follow-up of up to 14 years. Our study highlights focal bone lesions (FL) as hotspots of tumor evolution and provides possible explanations for their negative prognostic impact. We show a close phylogenetic relationship between baseline FL and relapse clones. In patients with ≥3 FDG-PET-positive FL at diagnosis, relapse was driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion was typically seen (p<0.01). Applying imaging-guided sampling, we identified a novel evolutionary pattern with unique treatment-resistant sub-clones at distinct locations. We observed multiple selective clonal sweeps, resistant clones that can be hidden over years, and epigenetic modifier mutations as a new class of relapse aberrations. Here we show that imaging can enhance tumor evolution studies and response assessment. The sophisticated evolution mechanisms in myeloma and presence of single cells that can drive relapse even after 10 years of remission suggest that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.

  Study phs002625

• Breakpoint detection using long insert whole genome sequencing

  In this study, we hypothesize that shallow long insert whole genome sequencing (LI-WGS) increases our power for detecting breakpoints compared to shallow short insert WGS. We performed a priori analyses to demonstrate the benefits of LI-WGS, developed a long insert library preparation protocol based off Illumina's protocol, and compared LI-WGS against short insert WGS on test samples. We then used long insert WGS to identify translocations and copy number changes in tumor and germline samples collected from cancer patients with different malignancies.

  Study phs000646

• MP2PRT: Comprehensive Genomic Profiling to Identify Alterations Associated with Relapse for NCI Standard Risk (SR) B-Lineage ALL and NCI High Risk (HR) B-Lineage ALL with Favorable Genetic Features

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Comprehensive Genomic Profiling to Identify Alterations Associated with Relapse for NCI Standard Risk (SR) B-Lineage ALL and NCI High Risk (HR) B-Lineage ALL with Favorable Genetic Features," is one of the selected studies under this program. For this study, genomic characterization (WGS 30X, WXS, Total RNAseq) was performed on NCI Standard Risk B-lineage ALL patients who relapse and subsets of NCI High Risk B-lineage ALL patients who relapse as well as two non-relapse control cases for each relapse case. It was hypothesized that the comprehensive characterization of these sample sets will allow the identification of somatic genetic features that will facilitate early intervention to improve cure rates for those enrolled on future trials. Data were generated and genetic subtype was integrated with clinical variables, including age, presenting white blood cell count, sex, race, and levels of minimal residual disease at the end of induction. Additional secondary alterations were identified and included if they occurred in more than 10 patients. The study has been completed and a manuscript has been prepared.

  Study phs002005

• De Novo Characterization of Cell-Free DNA Fragmentation Hotspots in Plasma Whole-Genome Sequencing

  The raw sequencing data deposited here are low-coverage (~1X) whole-genome sequencing (WGS) of plasma cell-free DNA (cfDNA). The purpose is to validate the performance of early-stage cancer diagnosis in the Zhou et al. 2020 BioRxiv paper, mainly for two types of cancer: early-stage liver cancer and breast cancer. The cases and controls are matched with age, gender, smoking history, and alcohol usage. We developed a computational method to identify the cfDNA fragmentation hotspots from pooled low-coverage cfDNA WGS data. We found the cfDNA fragmentation hotspots are highly enriched in regulatory regions, such as open chromatin regions. The signals from these regions can help the diagnosis of early-stage cancers and their tissues-of-origin.

  Study phs003062

• Lobular Carcinomas In Situ Display Intra-Lesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Disease

  This study comprises prospectively accrued, microdissected fresh frozen samples of multifocal lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive lobular carcinoma and invasive ductal carcinoma from patients undergoing prophylactic or therapeutic mastectomies after a diagnosis on LCIS diagnosed and managed at Memorial Sloan Kettering Cancer Center (MSKCC). Microdissected samples were subjected to paired-end whole exome sequencing on an Illumina HiSeq 2000. The data generated were used to define the landscape of somatic genetic alterations of LCIS, DCIS, invasive lobular carcinoma and invasive ductal carcinoma, to define clonal relatedness of these lesions and to investigate the clonal shifts in the progression from in situ to invasive breast cancer.

  Study phs001006

• Mutational Landscape of MCPyV-Positive and MCPyV-Negative Merkel Cell Carcinomas

  Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin most commonly found on the sun-exposed skin of older Caucasian adults. Roughly one-third of patients with MCCs die of the disease; therefore, MCC is the most lethal skin cancer on a case-by-case basis. 49 cases were studied, and putative cancer driver gene mutations and tumor antigens in both MCPyV-negative and MCPyV-positive MCCs were identified.

  Study phs002515

• Bone Microarchitecture

  Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are currently nearly 13 billion dollars per annum and are predicted to increase markedly in the next decades due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to study the genetics of more highly refined peripheral skeletal microarchitecture phenotypes. Because these refined phenotypes have not been measured in many cohort studies, this project was a collaborative effort to include almost all the existing data on HR-pQCT of the radius and tibia, and genetics from around the world. Cohorts involved in the discovery included: 1) Framingham Osteoporosis Study, 2) Mayo Clinic cohort; 3) Geneva Retirees cohort; 4) OFELY cohort from Lyon France; 5) STRAMBO cohort from Lyon France; 6) Swedish Male cohorts. Replication cohorts undergoing de novo genotyping include: 1) QUALYOR cohort from Lyon France; 2) CaMOS cohort from Canada. Other than the Framingham cohort and the Swedish male cohorts, all discovery cohorts underwent genome wide genotyping with the Affymetrix Axiom Biobank array that had common variants along with exome content based on the early findings from the Exome Sequencing Project. All genotype data from the discovery cohorts were then imputed using the Haplotype Reference Consortium reference panel. Variants for replication genotyping using the Kasp technology were selected based on novelty compared with previously identified loci using DXA phenotypes, minor allele frequency, underlying LD structure within a locus, and likelihood of a variant being functional as assessed using various algorithms for coding and non-coding variants.    

  Study phs002102

• 99 Cases of Small Cell Lung Cancer Study

  Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC. The manuscript has been accepted by Plos Genetics.

  Study phs001083

• Genomic Analyses in Neoadjuvant Immunotherapy-Treated Head and Neck Cancers

  This is a phase 2 multicenter interventional trial involving the preoperative (neoadjuvant) administration of pembrolizumab, an anti-programmed cell death protein-1 (anti-PD-1) agent, to patients with pathologically confirmed, surgically resectable advanced head and neck squamous cell carcinoma (HNSCC). Participating centers were Dana-Farber/Harvard Cancer Center, Alvin J. Siteman Cancer Center, Washington University and Memorial Sloan Kettering Cancer Center. The trial (NCT02296684) consisted of two cohorts: Cohort 1 enrolled and treated patients received one dose of pembrolizumab prior to surgical resection with curative intent, and adjuvant pembrolizumab was planned for patients with high risk pathological features (positive margins and/or extranodal extension) in the surgical specimen. Cohort 2 enrolled and treated patients received 2 doses of pembrolizumab prior to surgical resection with curative intent. Adjuvant treatment was not dictated by the trial protocol for Cohort 2. The primary endpoint was rate of at least 50% pathological tumor response (pTR), defined as the presence of tumor necrosis/keratinous debris in the tumor bed following neoadjuvant pembrolizumab. pTR was graded as follows: pTR0 (<10%), pTR1 (10-49%) and pTR2 (≥50%). Baseline, pre-treatment tumor biopsy and post-neoadjuvant pembrolizumab surgically resected tumor specimens were dissociated, and CD3+CD45+ cells were analyzed for T cell receptor (TCR) expression and 5' gene expression analysis using single cell sequencing technologies for a subset of patients.

  Study phs002864

• Inherited Genetic Variation and Predisposition to Testicular Germ Cell Tumor: UPenn Local TGCT Study

  Testicular germ cell tumors (TGCT) are the most common cancer in men ages 20-40. The incidence of TGCT has more than doubled over the past forty years, without clear etiology. Both genetic effects and environmental exposures, specifically during the pre-natal period, are likely to play an important role in determining TGCT susceptibility. TGCT is known to develop from primordial germ cells (PGCs). We hypothesize that variation in genes that impact upon the differentiation and maturation of PGCs will be important determinants of TGCT susceptibility and based on this hypothesis have selected three important pathways for study, i) male germ cell development, ii) androgen and estrogen biosynthesis and metabolism, and iii) IGF signaling. The proteins involved in early male germ cell development, normally only expressed in PGCs, are markers of and are overexpressed in TGCT. Markers of increased exposure to estrogen (or relatively decreased exposure to androgen) in utero and exogenous estrogen exposures, such as endocrine disruptors, have been associated with TGCT case status in multiple studies. IGF signaling is necessary for testis differentiation and maturation in mice and interacts synergistically with the estrogen signaling pathway. Additionally, we are interested in examining genetic factors predisposing to TGCT in an unbiased fashion, and thus will conduct a Genome Wide Association Study. As well disease susceptiblity, genetics are likely to play a role in disease progression, disease outcomes and response to treatement. We will also assess association of inherited genetics with these outcomes. We will analyze the contribution of genetic variants in these pathways to TGCT risk using a population-based case-control study in the Philadelphia metropolitian area. Our goal is the collection of 550 TGCT cases and 1100 age, race and cell phone use matched controls without a history of TGCT, which will yield 500 and 1000 white cases and controls, respectively, available for final analyses. All cases will be enumerated through the New Jersey and Pennsylvania state cancer registries. We will use a two-tiered approach for case recruitment: hospital clinic-based followed by registry-based. Hospital based cases will be identified within the Univeristy of Pennsylvania Health System and the University of Pennsylvania Cancer Network. All cases identified through this mechanism will be recruited irregardless of diagnosis date. The remaining cases will be identified through the New Jersey and Pennsylvania cancer registries and contacted following their protocols. Controls will be identified through random digit dialing and address based sampling. Both cases and controls will complete a questionnaire addressing known, presumed, and hypothesized risk factors for TGCT and provide a biospecimen. Pathological slides will be reviewed to cases to confirm diagnostic sub-type of TGCT. Haplotypes and functional SNPs will be typed in the genes of interest, as well as throughout the genome. Analyses will be conducted for specific variants, common haplotypes, alone and in conjunction with each other and exposure data after appropriate adjustment for potential confounders. The findings from this study will greatly contribute to our understanding of determinants of TGCT susceptibility.

  Study phs001307

• Whole Exome Sequencing of Colorectal Cancer Patients from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS)

  Colorectal cancer is a molecularly heterogeneous disease. Whole Exome Sequencing from patients diagnosed with colorectal cancer in the NHS and HPFS cohorts will extend our understanding of the genetic changes occurring in specific clinical contexts in the disease. This effort has the potential to discover novel recurrently mutated genes and pathways in colorectal cancer that can be functionally validated and give further insights to colorectal cancer pathogenesis. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000.

  Study phs000722

• Targeted Sequencing of Primary ER-positive Breast Tumors Treated with 5 Years of Tamoxifen

  Targeted massively parallel sequencing analysis was conducted on DNA extracted from archived 22-28 year old, formalin-fixed primary breast tumors from 625 patents from British Columbia treated with five years of adjuvant tamoxifen monotherapy and followed for over 10 years. Genes were selected for targeted sequencing by review of existing large-scale breast cancer sequencing studies and breast cancer literature. In total, 83 genes were identified and 3,029 probes were designed to tile across all known exons. Illumina sequencing libraries were constructed, indexed, pooled, and enriched for target sequences by hybrid-capture followed by sequencing of paired-end 100bp reads. All samples met minimum quality controls of 80% targeted space covered at 20X or greater. On average, each sample had 336M aligned bases and a mean coverage of 135.8X.

  Study phs001234

• New England-Based Case-Control Study of Ovarian Cancer

  The case-control data provided to dbGaP were collected under NCI grant number CA54419 which had 3 enrollment phases: I (1992-1997), II (1998-2002) and III (2003-2008). Altogether, CA54419 funded 15 years of data and specimen collection, resulting in one of the longest running population based case-control studies of ovarian cancer. The study goal was to examine reproductive factors, lifestyle exposures, and genetic background in relation to ovarian cancer risk. The project recruited cases from Eastern Massachusetts and New Hampshire, and became known as the New England-based Case-Control study (NECC) of ovarian cancer. 3957 ovarian cancer cases diagnosed at ages 18-80 and residing in Eastern Massachusetts and New Hampshire were identified through tumor boards and registries. Of these, 3083 (78%) were eligible and among those eligible, 2203 (71%) were enrolled. After excluding 127 non-epithelial and 35 mixed mesodermal tumors, 2041 cases with epithelial tumors of ovarian, primary peritoneal, and fallopian tube origin, including borderline malignancies were included. On average, cases were interviewed 10 months after their diagnosis. A pathologist reviewed pathology reports and recorded histologic subtype, grade, and stage. Mixed ovarian cancers described as predominantly one type were classified as that type. Undifferentiated, transitional cell tumors, or mixed serous/transitional cell tumors were counted as serous. Other mixed epithelial, malignant Brenner, and unspecified epithelial tumors were classified as other. 2100 controls were identified through random digit dialing (RDD), driver-license lists, and town-resident lists. During the first funding phase from 1992 to 1997, 420 (72%) controls identified through RDD and 102 (51%) through town-resident lists agreed to participate. From 1998 to 2008, only town-resident lists were used to identify potential controls. 4366 controls were identified, of whom 1426 (33%) were ineligible if they had died, moved, or were seriously ill or if they did not have a working telephone, speak English, or have at least one ovary. Of eligible controls, 1362 (46%) declined to participate by phone or via 'opt-out' postcard and 1578 (54%) were enrolled. Controls were frequency matched to cases by 5-year age groups and region of residence. In all phases, after written informed consent, demographic information, reproductive and medical history, and habits were assessed by in-person or telephone interview (in a few instances). All of the questions were framed with respect to a reference date defined as 1 year before the diagnosis date for women in the case group and the date of interview for those in the control group. This study was approved by institutional review boards at Dana Farber Harvard Cancer Center and Dartmouth Medical Center.

  Study phs001034

• The genomic complexity of early T-cell progenitor acute lymphoblastic leukemia

  CREST The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, >80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution. T-ALL Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  Study phs000340

• Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (UC-GENOME): a Bladder Cancer Advocacy Network (BCAN)-Led Collaborative Research Pilot Study - for Samples Collected at Johns Hopkins

  UC-GENOME is a real-world cohort of patients with metastatic urothelial carcinoma (UC). The study consisted of two co-equal aims: 1) to provide targeted DNA sequencing for clinical decision making at no cost to patients; and 2) to create a resource for collaborative translational science including a clinically annotated biobank. The submitted data represents the foundational analysis of 218 patients accrued at 7 academic medical centers. The analysis includes 176 patients with both targeted DNA sequencing and RNA sequencing. The genomic data was combined with clinical variables to model response to chemotherapy and immune checkpoint inhibitors (ICI).The larger dataset for this study can be found in dbGaP study phs003066.

  Study phs003094

• 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

• Pathways Study

  The Pathways Study (NCI R01 CA105274, PI: Kushi), is a prospective cohort study of a diverse population of recently diagnosed breast cancer survivors in KPNC. The aims are to examine the effect on recurrence and survival of 1) lifestyle factors such as diet, physical activity, and use of complementary and alternative therapies and 2) molecular factors such as biomarkers of inflammation and tumor DNA methylation profiles. Recruitment into the cohort was from January 2006 to May 2013. Baseline data collection was by in-person interview (on average two months post-diagnosis), with follow-up via mailed or phone questionnaires at 6, 24, and 72 months and outcomes and comorbidities at 12, 24, 48, 72, and 96 months post-enrollment. The Pathways Study is now funded through May 2021 as a cancer cohort infrastructure grant (U01 CA195565, MPI: Kushi/Ambrosone). The Pathways baseline interview consists of interviewer- and self-administered questionnaires. Interviewer-administered questionnaires collected information including demographics, family health history, pregnancy health history, menstrual history, history of breast care screening procedures, smoking history, hormone use, medication history, and vitamin and mineral use. Self-administered questionnaires collected information on diet, physical activity, CAM use, lymphedema, and psychosocial and quality of life measures.

  Study phs001534

• Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes

  Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past few decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated. However, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present an orthotopic xenotransplantation model of human patient-derived PDAC organoids in which organoids are grafted via direct injection into the pancreatic duct of immunocompromised (NSG) mice. Tumors that arise from these intraductally grafted organoids (IGOs) enable the distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively, depending on which organoid they originate from. RNA-sequencing was used to characterize the tumors that resulted from IGO xenografts, and to compare the fast- and slow-progressing IGO tumors. Tumors generated using a traditional orthotopic xenograft model, in which organoids are injected into the parenchyma of the pancreas (i.e. orthotopically grafted organoids, or OGOs), were also sequenced for comparison with the IGO tumors. To further characterize the model, laser-capture microdissection followed by RNA-sequencing was used to compare intraductal to invasive lesions resulting from IGOs. To better understand the connection between KRAS signaling and the fast-progressing phenotype, RNA-sequencing was used to compare cultured organoids in which oncogenic KRAS (GeneID: 3845) was hyperactivated to control organoids, and to compare laser-capture microdissected lesions derived from IGOs of KRAS-hyperactivated organoids to lesions derived from control organoids. To ascertain copy number, low-coverage, whole genome DNA-sequencing was performed on organoids cultured in vitro, and on laser-capture microdissected lesions derived from IGO tumors.

  Study phs002045

• Characterization of Neoantigen-reactive T cells by Single-Cell Analysis

  Through CITE-seq and TCR-seq analysis of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TIL), we developed a neoantigen-reactive T-cell signature based on clonotype frequency and CD39 protein and CXCL13 mRNA expression. There are four datasets from four NSCLC cases. Each dataset includes (1) Transcriptome of tumor infiltrating lymphocytes (TIL), (2) Cell surface protein expression on TIL by Feature barcoding, (3) T-cell receptor analysis of TIL, and (4) Reference file for feature-barcoding antibodies.

  Study phs002792

• Using Genomics to Reduce Breast Cancer Disparities in the African Diaspora

  Differences in breast cancer incidence and mortality rates between North American Caucasian and African American women are well-described and transcend socioeconomic issues. Black women are diagnosed with breast cancer at a younger median age; have more clinically aggressive disease and stage-for-stage; and have higher mortality rates than age-matched Caucasian women. Black women in West Africa, the origin of the slave trade in the US in the 19th century and thus the founder population for most African Americans, have even higher rates of early-onset, poor-prognosis breast cancer than African American women. Racial difference in the distribution of intrinsic molecular subtypes has been well characterized in the US and throughout the African Diaspora as well. Despite the large efforts on characterizing racial/ethnic differences, however, the reasons women of African ancestry are disproportionately affected by breast cancer incidence and mortality remain poorly understood - largely due to paucity of data on inherent genomic differences that contribute to the disparities in incidence and progression of breast cancer across populations. West Africa Breast Cancer Study (WABCS) is an initiative that aims to comprehensively understand the genetic architecture of breast cancer in West Africans, the founder population of a large proportion of black women in the United States. The objective of the study was to provide a better understanding of the molecular genetic factors that influence prognosis in Nigerian breast cancer patients, and determine which of these alterations may be amenable to available therapy. To that end, we examined the molecular features of breast cancers of indigenous African women using a combination of whole-genome, whole-exome, and transcriptome sequencing (WGS, WES, and RNA-seq) on 194 tumors from Nigerian patients. The goal of this project was to obtain answers to two related research questions using an unscreened population without genetic admixture in Nigeria: 1) why are women of African ancestry more likely to develop aggressive young onset breast cancer? 2) What are the associated genomic and non-genomic risk factors? We hypothesize that the genomic determinants of breast cancer molecular subtypes in women of African ancestry are also molecular drivers of tumor progression and represent targets for interventions to improve clinical outcomes and close the mortality gap. By identifying causal links between genetic variants that promote aggressive tumor progression in Nigerian women in comparison to women from different population found in TCGA and ICGC, the present dataset will have significant public health impact on millions of women in the African Diaspora. The potential to identify novel pathways for interventions to reduce the increasing mortality gap between women of African and European ancestry is huge

  Study phs001687