Sequencing to Guide Cancer Care (CanSeq)
Ontology highlight
ABSTRACT: The overall goal of the CanSeq U01 project is to study the impact of whole-exome sequencing (WES) on the clinical care of cancer patients and oncology provider practices.
The aims of Project 1 are to implement and establish the feasibility of germline and somatic WES in patients with advanced solid tumors (lung and colon); to develop a framework for interpreting and reporting for exome sequencing data; to determine the proportion of patients with "actionable items" compared to existing technologies; and to report on the percentage of patients in whom unique WES findings led to a clinical action.
The aims of Project 2 are to implement a production-scale platform for WES from archival (FFPE) material; to identify biologically relevant somatic and germline alterations existing in tumor/normal DNA from individual patients; to produce an evidence-based list of clinically "actionable" genetic alterations; and to develop inferential models that predict the utility of tumor genomic data within the larger clinical context.
The goals of Project 3 are to describe the impact of information derived through WES on cancer patients; to test the hypothesis that patients will want to receive information about all potentially informative somatic and germline variants; to study patients' understanding of disclosed genomic information; and to describe the experiences of oncology providers as they implement WES into cancer care delivery.
SECONDARY ACCESSION(S): PRJNA312991PRJNA312992
REPOSITORIES: dbGaP
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Project description:Within the frame of inherited cancer predisposition, single gene carriers of pathogenic variants (PVs) have been extensively represented in the literature, whereas the oligogenic coinheritance of heterozygous PVs in cancer-related genes is a poorly studied event. Currently, due to the increment of cancer survivors, the probability of presenting multiple primary cancers (MPC) is higher. This study included MPC patients ≤45 years without known PVs in common cancer predisposition genes. We used whole exome sequencing (WES) of germline and tumoral DNA, chromosomal microarray analysis (CMA) on germline DNA (patient 1-7, and patient 9-10), and karyotype of patient 8to detect variants associated with the disease. The ten patients included in the study presented a mean of 3 cancers per patient. CMA showed two microduplications and one microdeletion, while WES of the germline DNA identified 1-3 single nucleotide variants of potential interest to the disease in each patient and two additional copy number variants. Most of the identified variants were classified as variants of uncertain significance. The mapping of the germline variants into their pathways showed a possible additive effect of these as the cause of the cancer. Twelve somatic samples from 5 patients were available for sequencing. All the germline variants were also present in the somatic samples, while no second hits were identified in the same genes. The sequencing of patients with early cancers, family history and multiple tumors is already a standard of care. However, the growing evidence suggests that patient´s assessment should not stop at the identification of one PV in a cancer predisposition gene.
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Project description:The overall goal of the Identification of recurrent mutations in Cushing’s disease project is to study the impact of whole-exome sequencing (WES) on the clinical care of cancer patients and oncology provider practices.
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Project description:The Pan-Cancer Analysis of Whole Genomes (PCAWG) study is an international collaboration to identify common patterns of mutation in more than 2,800 cancer whole genomes from the International Cancer Genome Consortium. Building upon previous work which examined cancer coding regions, this project is exploring the nature and consequences of somatic and germline variations in both coding and non-coding regions, with specific emphasis on cis-regulatory sites, non-coding RNAs, and large-scale structural alterations. Read more on the <a href=\"https://dcc.icgc.org/pcawg\" target=\"_blank\">project website</a>.<br>This is a subset featuring RNA-seq transcription profiling data of 27 cancer subtypes in 19 tissues. Some donors have matched normal tissue.<br>This is the alternative view of the experiment for Expression Atlas to show gene expression per donor.
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Project description:Among acute myeloid leukemias (AML) with normal karyotype (CN-AML), NPM1 and CEBPA mutations define WHO provisional entities accounting for ~60% of cases, but the remaining ~40% remains poorly characterized. By whole exome-sequencing (WES) of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3, MLL-PTD and IDH1, we newly identified a clonal somatic mutation in BCOR (BCL6 co-repressor), a gene located in chromosome X. Further analyses showed that BCOR mutations occurred in 11/262 (4.2%) CN-AML cases and represented a substantial fraction (14/82, 17.1%) of CN-AML patients showing the same genetic background as the index patient subjected to WES. BCOR somatic mutations were: i) disruptive events similar to germline BCOR mutations causing the oculo-cranio-facial-dental (OCFD) genetic syndrome; ii) associated with markedly decreased BCOR mRNA levels, absence of full-length BCOR and absent or low expression of a truncated BCOR protein; iii) almost mutually exclusive with NPM1 mutations and frequently associated with DNMT3A and RUNX1 mutations, pointing to a cooperation between these events. Finally, BCOR mutations correlated with poor outcome among a cohort of 160 CN-AML patients (28% versus 66% overall survival at 2 yrs, P=0.024). Our results implicate for the first time BCOR in the pathogenesis of CN-AML without NPM1 mutations. AML samples with normal karyotype were studied. Molecular analyses were performed for BCOR mutations. 12 BCOR wild-type cases and 12 BCOR mutated cases were hybridized to gene expression micro-arrays.
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Project description:Among acute myeloid leukemias (AML) with normal karyotype (CN-AML), NPM1 and CEBPA mutations define WHO provisional entities accounting for ~60% of cases, but the remaining ~40% remains poorly characterized. By whole exome-sequencing (WES) of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3, MLL-PTD and IDH1, we newly identified a clonal somatic mutation in BCOR (BCL6 co-repressor), a gene located in chromosome X. Further analyses showed that BCOR mutations occurred in 11/262 (4.2%) CN-AML cases and represented a substantial fraction (14/82, 17.1%) of CN-AML patients showing the same genetic background as the index patient subjected to WES. BCOR somatic mutations were: i) disruptive events similar to germline BCOR mutations causing the oculo-cranio-facial-dental (OCFD) genetic syndrome; ii) associated with markedly decreased BCOR mRNA levels, absence of full-length BCOR and absent or low expression of a truncated BCOR protein; iii) almost mutually exclusive with NPM1 mutations and frequently associated with DNMT3A and RUNX1 mutations, pointing to a cooperation between these events. Finally, BCOR mutations correlated with poor outcome among a cohort of 160 CN-AML patients (28% versus 66% overall survival at 2 yrs, P=0.024). Our results implicate for the first time BCOR in the pathogenesis of CN-AML without NPM1 mutations.
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