Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse
Virginia Perez-Andreu,Kathryn G. Roberts,Richard C. Harvey,Wenjian Yang,Cheng Cheng,Deqing Pei,Heng Xu,Julie M. Gastier-Foster,Julie M. Gastier-Foster,Shuyu E,Joshua Yew Suang Lim,I. Ming Chen,Yiping Fan,Meenakshi Devidas,Michael J. Borowitz,Colton Smith,Geoffrey Neale,Esteban G. Burchard,Dara G. Torgerson,Federico Antillon Klussmann,Cesar Rolando Najera Villagran,Naomi J. Winick,Bruce M. Camitta,Elizabeth A. Raetz,Brent L. Wood,Feng Yue,William L. Carroll,Eric Larsen,W. Paul Bowman,Mignon L. Loh,Michael Dean,Deepa Bhojwani,Ching-Hon Pui,William E. Evans,Mary V. Relling,Stephen P. Hunger,Cheryl L. Willman,Charles G. Mullighan,Jun J. Yang +38 more
TLDR
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.read more
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Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.
TL;DR: Analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse, and targeting recurrent pathways implicated in relapse is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic.
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Genetic abnormalities associated with acute lymphoblastic leukemia.
Takafumi Yokota,Yuzuru Kanakura +1 more
TL;DR: Philadelphia chromosome‐like B‐lineage ALL is one of the new high‐risk subtypes characterized by genetic alterations that activate various signaling pathways, including those involving cytokine receptors, tyrosine kinases, and epigenetic modifiers.
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The treatment of childhood acute lymphoblastic leukemia in Guatemala: Biologic features, treatment hurdles, and results.
Federico Antillon,Jessica G. Blanco,Patricia D. Valverde,Mauricio Castellanos,Claudia Garrido,Verónica Girón,Tomas R. Letona,Emilia J. Osorio,Dyna A. Borrayo,Ricardo Mack,Mario Melgar,Rodolfo Lorenzana,Raul C. Ribeiro,Monika L. Metzger,Valentino Conter,Valentino Conter,Emanuela Rossi,Maria Grazia Valsecchi +17 more
TL;DR: The National Pediatric Oncology Unit (UNOP) is the only pediatric hemato‐oncology center in Guatemala.
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A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros.
Joseph L. Wiemels,A J de Smith,Jianqiao Xiao,Seung-Tae Lee,Marcus O. Muench,Marina E. Fomin,Mi Zhou,Helen M. Hansen,Amanda M. Termuhlen,Catherine Metayer,Kyle M. Walsh +10 more
TL;DR: A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros.
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Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia
Ching-Hon Pui,Ching-Hon Pui +1 more
TL;DR: Deeper characterization of leukemic cell genetic abnormalities has discovered new subtypes of leukemia such as early T-cell precursor ALL and Philadelphia chromosome-like ALL, and identified many genomic alterations that have diagnostic, prognostic, or therapeutic implications.
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