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
Citations
More filters
Journal ArticleDOI
Acute Lymphoblastic Leukemia in Children
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.
Journal ArticleDOI
Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration
Ching-Hon Pui,Jun J. Yang,Stephen P. Hunger,Rob Pieters,Martin Schrappe,Andrea Biondi,Ajay Vora,André Baruchel,Lewis B. Silverman,Kjeld Schmiegelow,Gabriele Escherich,Keizo Horibe,Yves Benoit,Shai Izraeli,Allen Eng Juh Yeoh,Der Cherng Liang,James R. Downing,William E. Evans,Mary V. Relling,Charles G. Mullighan +19 more
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.
Journal ArticleDOI
Cancer health disparities in racial/ethnic minorities in the United States
Valentina A. Zavala,Paige M. Bracci,John M. Carethers,Luis G. Carvajal-Carmona,Nicole B. Coggins,Marcia Cruz-Correa,Melissa Davis,Adam J. de Smith,Julie Dutil,Jane C. Figueiredo,Rena K. Fox,Kristi D. Graves,Scarlett Lin Gomez,Andrea S. Llera,Susan L. Neuhausen,Lisa A. Newman,Tung T. Nguyen,Julie R. Palmer,Nynikka R. Palmer,Eliseo J. Pérez-Stable,Sorbarikor Piawah,Erik J. Rodriquez,María Carolina Sanabria-Salas,Stephanie L. Schmit,Silvia J. Serrano-Gomez,Mariana C. Stern,Jeffrey N. Weitzel,Jun J. Yang,Jovanny Zabaleta,Elad Ziv,Laura Fejerman +30 more
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.
Journal ArticleDOI
A causal mechanism for childhood acute lymphoblastic leukaemia.
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.
Journal ArticleDOI
Genome-wide association studies of cancer: current insights and future perspectives
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.
References
More filters
Journal ArticleDOI
DNase I sensitivity QTLs are a major determinant of human expression variation
Jacob F. Degner,Athma A. Pai,Roger Pique-Regi,Jean Baptiste Veyrieras,Daniel J. Gaffney,Daniel J. Gaffney,Joseph K. Pickrell,Sherryl De Leon,Katelyn Michelini,Noah Lewellen,Gregory E. Crawford,Matthew Stephens,Yoav Gilad,Jonathan K. Pritchard,Jonathan K. Pritchard +14 more
TL;DR: It is shown that genetic variants that modify chromatin accessibility and transcription factor binding are a major mechanism through which genetic variation leads to gene expression differences among humans.
Journal ArticleDOI
Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia
Kathryn G. Roberts,Ryan D. Morin,Jinghui Zhang,Martin Hirst,Yongjun Zhao,Xiaoping Su,Shann-Ching Chen,Debbie Payne-Turner,Michelle L. Churchman,Richard C. Harvey,Xiang Chen,Corynn Kasap,Chunhua Yan,Jared Becksfort,Richard Finney,David T. Teachey,Shannon L. Maude,Kane Tse,Richard A. Moore,Steven J.M. Jones,Karen Mungall,Inanc Birol,Michael N. Edmonson,Ying Hu,Kenneth E Buetow,I-Ming Chen,William L. Carroll,Lei Wei,Jing Ma,Maria Kleppe,Ross L. Levine,Guillermo Garcia-Manero,Eric Larsen,Neil P. Shah,Meenakshi Devidas,Gregory H. Reaman,Malcolm A. Smith,Steven W. Paugh,William E. Evans,Stephan A. Grupp,Sima Jeha,Ching-Hon Pui,Daniela S. Gerhard,James R. Downing,Cheryl L. Willman,Mignon L. Loh,Stephen P. Hunger,Marco A. Marra,Marco A. Marra,Charles G. Mullighan +49 more
TL;DR: Several genetic alterations that activate kinase signaling in Ph-like ALL induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.
Journal ArticleDOI
Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia
Christopher N. Hahn,Christopher N. Hahn,Chan-Eng Chong,Chan-Eng Chong,Catherine Carmichael,Ella J Wilkins,Ella J Wilkins,Peter J. Brautigan,Xiaochun Li,Milena Babic,Ming-Chih Lin,Amandine Carmagnac,Young Koung Lee,Chung H. Kok,Lucia Gagliardi,Kathryn Friend,Paul G Ekert,Carolyn M. Butcher,Anna L. Brown,Ian D. Lewis,Ian D. Lewis,L. Bik To,L. Bik To,Andrew E. Timms,Jan Storek,Sarah Moore,Meryl Altree,Robert Escher,Robert Escher,Peter Bardy,Graeme Suthers,Graeme Suthers,Richard J D'Andrea,Richard J D'Andrea,Marshall S. Horwitz,Hamish S. Scott +35 more
TL;DR: The discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene is reported and differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression are shown.
Journal ArticleDOI
Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia
Richard C. Harvey,Richard C. Harvey,Charles G. Mullighan,I-Ming Chen,I-Ming Chen,Walker Wharton,Fady M. Mikhail,Andrew J. Carroll,Andrew J. Carroll,Huining Kang,Wei Liu,Kevin K. Dobbin,Malcolm A. Smith,William L. Carroll,William L. Carroll,Meenakshi Devidas,Meenakshi Devidas,W. Paul Bowman,Bruce M. Camitta,Bruce M. Camitta,Gregory H. Reaman,Gregory H. Reaman,Stephen P. Hunger,Stephen P. Hunger,James R. Downing,Cheryl L. Willman,Cheryl L. Willman +26 more
TL;DR: Observations suggest that activation of CRLF2 expression, mutation of JAK kinases, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis and identify these pathways as important therapeutic targets in this disease.
Journal ArticleDOI
Common genetic variants account for differences in gene expression among ethnic groups
Richard S. Spielman,Laurel A Bastone,Joshua T. Burdick,Michael Morley,Warren J. Ewens,Vivian G. Cheung,Vivian G. Cheung +6 more
TL;DR: The results show that specific genetic variation among populations contributes appreciably to differences in gene expression phenotypes, and suggest that allele frequency differences at regulatory polymorphisms also account for some population differences in prevalence of complex diseases.
Related Papers (5)
Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
Charles G. Mullighan,Xiaoping Su,Jinghui Zhang,Ina Radtke,Letha A. Phillips,Christopher B. Miller,Jing Ma,Wei Liu,Cheng Cheng,Brenda A. Schulman,Brenda A. Schulman,Richard C. Harvey,Richard C. Harvey,I-Ming Chen,I-Ming Chen,Robert J. Clifford,William L. Carroll,Gregory H. Reaman,W. Paul Bowman,Meenakshi Devidas,Daniela S. Gerhard,Wenjian Yang,Mary V. Relling,Sheila A. Shurtleff,Dario Campana,Michael J. Borowitz,Ching-Hon Pui,Malcolm A. Smith,Stephen P. Hunger,Cheryl L. Willman,Cheryl L. Willman,James R. Downing +31 more
Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia
Kathryn G. Roberts,Yongjin Li,Debbie Payne-Turner,Richard C. Harvey,Yung-Li Yang,Dehua Pei,Kelly McCastlain,Li Ding,Li Ding,Changxue Lu,Changxue Lu,Guangchun Song,Jing Ma,Jared Becksfort,Michael Rusch,S. C. Chen,John Easton,J. Cheng,Kristy Boggs,Natalia Santiago-Morales,Ilaria Iacobucci,Robert S. Fulton,Robert S. Fulton,Ji Wen,Marcus B. Valentine,Cheng Cheng,Steven W. Paugh,Meenakshi Devidas,Meenakshi Devidas,I-Ming Chen,S. Reshmi,S. Reshmi,Amy Smith,Erin Hedlund,Pankaj Gupta,Panduka Nagahawatte,Gang Wu,Xiang Chen,Donald Yergeau,Bhavin Vadodaria,Heather L. Mulder,Naomi J. Winick,Eric Larsen,William L. Carroll,William L. Carroll,Nyla A. Heerema,Andrew J. Carroll,G. Grayson,Sarah K. Tasian,Andrew S. Moore,F. Keller,Melissa Frei-Jones,J. A. Whitlock,Elizabeth A. Raetz,Deborah L. White,Timothy P. Hughes,J. M. Guidry Auvil,Malcolm A. Smith,Malcolm A. Smith,Guido Marcucci,Clara D. Bloomfield,Krzysztof Mrózek,Jessica Kohlschmidt,Jessica Kohlschmidt,Wendy Stock,Steven M. Kornblau,Marina Konopleva,Elisabeth Paietta,Ching-Hon Pui,Sima Jeha,Mary V. Relling,William E. Evans,Daniela S. Gerhard,Julie M. Gastier-Foster,Julie M. Gastier-Foster,Elaine R. Mardis,Richard K. Wilson,Mignon L. Loh,Mignon L. Loh,James R. Downing,James R. Downing,Stephen P. Hunger,Stephen P. Hunger,Cheryl L. Willman,Cheryl L. Willman,Jinghui Zhang,Charles G. Mullighan,Charles G. Mullighan +87 more
A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study
Monique L. den Boer,Marjon van Slegtenhorst,Renee X. de Menezes,Renee X. de Menezes,Meyling Cheok,Jessica Buijs-Gladdines,Susan T C J M Peters,Laura J. C. M. van Zutven,H. Berna Beverloo,Peter J. van der Spek,Gaby Escherich,Martin A. Horstmann,Gritta Janka-Schaub,Willem A. Kamps,William E. Evans,Rob Pieters +15 more
Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia
Richard C. Harvey,Richard C. Harvey,Charles G. Mullighan,I-Ming Chen,I-Ming Chen,Walker Wharton,Fady M. Mikhail,Andrew J. Carroll,Andrew J. Carroll,Huining Kang,Wei Liu,Kevin K. Dobbin,Malcolm A. Smith,William L. Carroll,William L. Carroll,Meenakshi Devidas,Meenakshi Devidas,W. Paul Bowman,Bruce M. Camitta,Bruce M. Camitta,Gregory H. Reaman,Gregory H. Reaman,Stephen P. Hunger,Stephen P. Hunger,James R. Downing,Cheryl L. Willman,Cheryl L. Willman +26 more
The genomic landscape of hypodiploid acute lymphoblastic leukemia
Linda Holmfeldt,Lei Wei,Ernesto Diaz-Flores,Michael Walsh,Jinghui Zhang,Li Ding,Debbie Payne-Turner,Michelle L. Churchman,Anna Andersson,Shann Ching Chen,Kelly McCastlain,Jared Becksfort,Jing Ma,Gang Wu,Samir Patel,Susan L. Heatley,Letha A. Phillips,Guangchun Song,John Easton,Matthew Parker,Xiang Chen,Michael Rusch,Kristy Boggs,Bhavin Vadodaria,Erin Hedlund,Christina D. Drenberg,Sharyn D. Baker,Deqing Pei,Cheng Cheng,Robert Huether,Charles Lu,Robert S. Fulton,Lucinda Fulton,Yashodhan Tabib,David J. Dooling,Kerri Ochoa,Mark D. Minden,Ian D. Lewis,L. Bik To,Paula Marlton,Andrew W. Roberts,Gordana Raca,Wendy Stock,Geoffrey Neale,Hans G. Drexler,Ross A. Dickins,David W. Ellison,Sheila A. Shurtleff,Ching-Hon Pui,Raul C. Ribeiro,Meenakshi Devidas,Andrew J. Carroll,Nyla A. Heerema,Brent L. Wood,Michael J. Borowitz,Julie M. Gastier-Foster,Julie M. Gastier-Foster,Susana C. Raimondi,Elaine R. Mardis,Richard K. Wilson,James R. Downing,Stephen P. Hunger,Mignon L. Loh,Charles G. Mullighan +63 more