Genomic landscape of paediatric adrenocortical tumours.

Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome.

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D.

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.

Genomic analysis to define molecular basis of aggressiveness in a mouse model of oral cancer.

To investigate the molecular basis underlying aggressive behavior in oral squamous cell carcinoma (OSCC), our laboratory developed a carcinogen-induced mouse oral cancer (MOC) cell line model that encompasses the growth and metastasis spectrum of its human counterpart. We performed next-generation sequencing (NGS) and gene expression microarray profiles to explore the genomic and transcriptional backgrounds of the differential MOC line phenotypes, as well as, the cross-species relevance of the model. Here we describe the comparative analysis of NGS (www.

Cancer Genomics.

Modern cancer genomics has emerged from the combination of the Human Genome Reference, massively parallel sequencing, and the comparison of tumor to normal DNA sequences, revealing novel insights into the cancer genome and its amazing diversity. Recent developments in applying our knowledge of cancer genomics have focused on the utility of these data for clinical applications. The emergent results of this translation into the clinical setting already are changing the clinical care and monitoring of cancer patients.

Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.

Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis.

A central support system can facilitate implementation and sustainability of a Classroom-based Undergraduate Research Experience (CURE) in Genomics.

In their 2012 report, the President's Council of Advisors on Science and Technology advocated "replacing standard science laboratory courses with discovery-based research courses"-a challenging proposition that presents practical and pedagogical difficulties. In this paper, we describe our collective experiences working with the Genomics Education Partnership, a nationwide faculty consortium that aims to provide undergraduates with a research experience in genomics through a scheduled course (a classroom-based undergraduate research experience, or CURE). We examine the common barriers encountered in implementing a CURE, program elements of most value to faculty, ways in which a shared core support system can help, and the incentives for and rewards of establishing a CURE on our diverse campuses.

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.

The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells.

Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor.

Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation.

Estrogen receptor expression is high but is of lower intensity in tubular carcinoma than in well-differentiated invasive ductal carcinoma.

Context: Tubular carcinoma (TC) is a rare, luminal A subtype of breast carcinoma with excellent prognosis, for which adjuvant chemotherapy is usually contraindicated.

Objective: To examine the levels of estrogen receptor (ER) and progesterone receptor expression in cases of TC and well-differentiated invasive ductal carcinoma as compared to normal breast glands and to determine if any significant differences could be detected via molecular testing.

Design: We examined ER and progesterone receptor via immunohistochemistry in tubular (N = 27), mixed ductal/tubular (N = 16), and well-differentiated ductal (N = 27) carcinomas with comparison to surrounding normal breast tissue.

Caspase-9 is required for normal hematopoietic development and protection from alkylator-induced DNA damage in mice.

Apoptosis and the DNA damage responses have been implicated in hematopoietic development and differentiation, as well as in the pathogenesis of myelodysplastic syndromes (MDS) and leukemia. However, the importance of late-stage mediators of apoptosis in hematopoiesis and leukemogenesis has not been elucidated. Here, we examine the role of caspase-9 (Casp9), the initiator caspase of the intrinsic apoptotic cascade, in murine fetal and adult hematopoiesis.

Prioritizing targets for precision cancer medicine.

The implementation of cancer genomic testing into the clinical setting has brought major opportunities. However, as our understanding of cancer initiation, maintenance and progression improves through detailed cancer genomic studies, the challenges associated with driver identification and target classification in the clinical setting become clearer. Here, we review recent insights into cancer genomic testing in the clinical setting, and suggest a target classification approach that considers the levels of evidence supporting the prioritization of tumour drivers for therapeutic targeting in light of complex cancer clonal and sub-clonal structures and clinical successes and failures in the field.

Age-related mutations associated with clonal hematopoietic expansion and malignancies.

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age.

Sequencing the AML genome, transcriptome, and epigenome.

Leukemia is a disease that develops as a result of changes in the genomes of hematopoietic cells, a fact first appreciated by microscopic examination of the bone marrow cell chromosomes of affected patients. These studies revealed that specific subtypes of leukemia diagnoses correlated with specific chromosomal abnormalities, such as the t(15;17) of acute promyelocytic leukemia and the t(9;22) of chronic myeloid leukemia. Over time, our genomic characterization of hematologic malignancies has moved beyond the resolution of the microscope to that of individual nucleotides in the analysis of whole-genome sequencing (WGS) data using state-of-the-art massively parallel sequencing (MPS) instruments and algorithmic analyses of the resulting data.

The genomic landscape of childhood and adolescent melanoma.

Despite remarkable advances in the genomic characterization of adult melanoma, the molecular pathogenesis of pediatric melanoma remains largely unknown. We analyzed 15 conventional melanomas (CMs), 3 melanomas arising in congenital nevi (CNMs), and 5 spitzoid melanomas (SMs), using various platforms, including whole genome or exome sequencing, the molecular inversion probe assay, and/or targeted sequencing. CMs demonstrated a high burden of somatic single-nucleotide variations (SNVs), with each case containing a TERT promoter (TERT-p) mutation, 13/15 containing an activating BRAF V600 mutation, and >80% of the identified SNVs consistent with UV damage.

RNA-sequencing reveals oligodendrocyte and neuronal transcripts in microglia relevant to central nervous system disease.

Expression profiling of distinct central nervous system (CNS) cell populations has been employed to facilitate disease classification and to provide insights into the molecular basis of brain pathology. One important cell type implicated in a wide variety of CNS disease states is the resident brain macrophage (microglia). In these studies, microglia are often isolated from dissociated brain tissue by flow sorting procedures [fluorescence-activated cell sorting (FACS)] or from postnatal glial cultures by mechanic isolation.

Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.

Unlabelled: Ewing sarcoma is a primary bone tumor initiated by EWSR1-ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations.

Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma.

Background: Endometrioid endometrial carcinoma (EEC) is the most common form of endometrial carcinoma. The heterogeneous clinical course of EEC is an obstacle to individualized patient care.

Methods: We performed an integrated analysis on the multiple-dimensional data types including whole-exome and RNA sequencing, RPPA profiling, and clinical data from 271 EEC cases in The Cancer Genome Atlas (TCGA) to identify molecular fingerprints that may account for this clinical heterogeneity.

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.

Methods: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL.

SciClone: inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution.

The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena.

Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

Background: In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC).

Methods: Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested.

The translation of cancer genomics: time for a revolution in clinical cancer care.

The introduction of next-generation sequencing technologies has dramatically impacted the life sciences, perhaps most profoundly in the area of cancer genomics. Clinical applications of next-generation sequencing and associated methods are emerging from ongoing large-scale discovery projects that have catalogued hundreds of genes as having a role in cancer susceptibility, onset and progression. For example, discovery cancer genomics has confirmed that many of the same genes are altered by mutation, copy number gain or loss, or structural variation across multiple tumor types, resulting in a gain or loss of function that likely contributes to cancer development in these tissues.