Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse
University of New Mexico1, Ohio State University2, Nationwide Children's Hospital3, National University of Singapore4, University of Florida5, Johns Hopkins University6, University of California, San Francisco7, University of Texas Southwestern Medical Center8, Medical College of Wisconsin9, New York University10, University of Washington11, Pennsylvania State University12, National Institutes of Health13, University of Colorado Denver14
TL;DR: In a genome-wide association study of 511 ALL cases and 6,661 non-ALL controls, a susceptibility locus for Ph-like ALL is identified and genotype at the GATA3 SNP was associated with early treatment response and risk of ALL relapse, providing insights into interactions between inherited and somatic variants and their role in ALL pathogenesis and prognosis.
Abstract: Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a high-risk subtype with an expression signature resembling that of Philadelphia chromosome-positive ALL and poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a susceptibility locus for Ph-like ALL (GATA3, rs3824662; P = 2.17 × 10(-14), odds ratio (OR) = 3.85 for Ph-like ALL versus non-ALL; P = 1.05 × 10(-8), OR = 3.25 for Ph-like ALL versus non-Ph-like ALL), with independent validation. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (CRLF2 rearrangement, JAK gene mutation and IKZF1 deletion) and with variation in GATA3 expression. Finally, genotype at the GATA3 SNP was also associated with early treatment response and risk of ALL relapse. Our results provide insights into interactions between inherited and somatic variants and their role in ALL pathogenesis and prognosis.
Citations
More filters
••
TL;DR: The most common cancer in childhood is now curable in 90% of patients and the subsets of acute lymphoblastic leukemia that are most resistant to current therapy are being targeted.
Abstract: The most common cancer in childhood is now curable in 90% of patients. Current efforts are focused on devising molecular-based therapy for the subsets of acute lymphoblastic leukemia that are most resistant to current therapy.
1,339 citations
••
University of Tennessee Health Science Center1, University of Colorado Denver2, University of Kiel3, University of Milan4, University of Manchester5, Harvard University6, University of Copenhagen7, University of Hamburg8, Ghent University9, National University of Singapore10, Mackay Memorial Hospital11
TL;DR: The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.
Abstract: Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic p...
680 citations
••
University of California, San Francisco1, University of Michigan2, University of California, Davis3, University of Puerto Rico4, Cornell University5, University of Southern California6, Ponce Health Sciences University7, Cedars-Sinai Medical Center8, Georgetown University9, Fundación Instituto Leloir10, City of Hope National Medical Center11, Boston University12, National Institutes of Health13, St. Jude Children's Research Hospital14, LSU Health Sciences Center New Orleans15
TL;DR: To eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.
Abstract: There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA-African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.
383 citations
••
TL;DR: Evidence supporting the model that infections early in life reduce the risk of childhood common B cell precursor acute lymphoblastic leukaemia (BCP-ALL) development is described, given this evidence, paediatric BCP-ALL may be a preventable cancer.
Abstract: In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)–runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.
303 citations
••
TL;DR: Genome-wide association studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers, and deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS.
Abstract: Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS.
259 citations
References
More filters
••
TL;DR: Pritch et al. as discussed by the authors proposed a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations, which can be applied to most of the commonly used genetic markers, provided that they are not closely linked.
Abstract: We describe a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations. We assume a model in which there are K populations (where K may be unknown), each of which is characterized by a set of allele frequencies at each locus. Individuals in the sample are assigned (probabilistically) to populations, or jointly to two or more populations if their genotypes indicate that they are admixed. Our model does not assume a particular mutation process, and it can be applied to most of the commonly used genetic markers, provided that they are not closely linked. Applications of our method include demonstrating the presence of population structure, assigning individuals to populations, studying hybrid zones, and identifying migrants and admixed individuals. We show that the method can produce highly accurate assignments using modest numbers of loci— e.g. , seven microsatellite loci in an example using genotype data from an endangered bird species. The software used for this article is available from http://www.stats.ox.ac.uk/~pritch/home.html.
27,454 citations
••
Harvard University1, Broad Institute2, QIMR Berghofer Medical Research Institute3, Cardiff University4, North Carolina State University5, Trinity College, Dublin6, University of Edinburgh7, Karolinska Institutet8, Uppsala University9, University of Southern California10, University of North Carolina at Chapel Hill11, University College London12, National Health Service13, University of Oxford14, University of Aberdeen15, Strathclyde Institute of Pharmacy and Biomedical Sciences16, State University of New York Upstate Medical University17, University of Coimbra18
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Abstract: Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
4,573 citations
••
TL;DR: The method of “nearest shrunken centroids” identifies subsets of genes that best characterize each class, which was highly efficient in finding genes for classifying small round blue cell tumors and leukemias.
Abstract: We have devised an approach to cancer class prediction from gene expression profiling, based on an enhancement of the simple nearest prototype (centroid) classifier. We shrink the prototypes and hence obtain a classifier that is often more accurate than competing methods. Our method of "nearest shrunken centroids" identifies subsets of genes that best characterize each class. The technique is general and can be used in many other classification problems. To demonstrate its effectiveness, we show that the method was highly efficient in finding genes for classifying small round blue cell tumors and leukemias.
2,954 citations
••
TL;DR: This study presents a general framework for deciphering cis-regulatory connections and their roles in disease, and maps nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions.
Abstract: Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.
2,646 citations
••
TL;DR: LocusZoom is a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format that visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns and the positions of genes in the region.
Abstract: Summary: Genome-wide association studies (GWAS) have revealed hundreds of loci associated with common human genetic diseases and traits. We have developed a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format. LocusZoom visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns
2,454 citations