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Start Over Author "Downing, James R." Publisher american association for cancer research
23 results on '"Downing, James R."'

1. Abstract CT146: Prognostic and therapeutic significance of leukemia subtypes in the context of risk-directed therapy based on minimal residual disease levels in pediatric acute lymphoblastic leukemia

Author

Jeha, Sima, primary, Choi, John K., additional, Pei, Deqing, additional, Coustan-Smith, Elaine, additional, Inaba, Hiroto, additional, Rubnitz, Jeffrey E., additional, Ribiero, Raul C., additional, Gruber, Tanja A., additional, Raimondi, Susana C., additional, Karol, Seth E., additional, Roberts, Kathryn G., additional, Yang, Jun J., additional, Cheng, Cheng, additional, Downing, James R., additional, Evans, William E., additional, Relling, Mary V., additional, Campana, Dario, additional, Mullighan, Charles G., additional, and Pui, Ching-Hon, additional

Published
2021
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2. Abstract 642: Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer

Author

Wheeler, David A., primary, Newman, Scott, additional, Nakitandwe, Joy, additional, Kesserwan, Chimene A., additional, Azzato, Elizabeth M., additional, Rusch, Michael C., additional, Shurtleff, Sheila, additional, Bahrami, Armita, additional, Orr, Brent, additional, Klco, Jeffery M., additional, Hedges, Dale J., additional, Hamilton, Kayla V., additional, Foy, Scott G., additional, Edmonson, Michael N., additional, Thrasher, Andrew, additional, Gu, Jiali, additional, Harrison, Lynn W., additional, Wang, Lu, additional, Mostafavi, Roya, additional, Kubal, Manish, additional, Maciaszek, Jamie, additional, Clay, Michael, additional, Ouma, Annastasia, additional, Silkov, Antonina, additional, Liu, Yanling, additional, Zhang, Zhaojie, additional, Liu, Yu, additional, Brady, Samuel W., additional, Zhou, Xin, additional, Wilkinson, Mark, additional, Rahbarinia, Delaram, additional, Knight, Jay, additional, Wang, Jian, additional, Mullighan, Charles G., additional, McGee, Rose B., additional, Quinn, Emily A., additional, Gerhardt, Elsie L., additional, Taylor, Leslie M., additional, Nuccio, Regina, additional, Valdez, Jessica M., additional, Hines-Dowell, Stacy J., additional, Pappo, Alberto, additional, Robinson, Giles, additional, Johnson, Liza-Marie, additional, Pui, Ching-Hon, additional, Ellison, David W., additional, Downing, James R., additional, Zhang, Jinghui, additional, and Nichols, Kim E., additional

Published
2021
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3. Abstract 3671: Visualize 10,000 whole-genomes from pediatric cancer patients on St. Jude Cloud

Author

Zhou, Xin, primary, Mcleod, Clay, additional, Newman, Scott, additional, Wang, Zhaoming, additional, Rusch, Michael, additional, Birch, Kirby, additional, Macias, Michael, additional, Sunny, Jobin, additional, Wu, Gang, additional, Wang, Jian, additional, Sioson, Edgar, additional, Lei, Shaohua, additional, Michael, Robert J., additional, Patel, Aman, additional, Edmonson, Michael N., additional, Rice, Stephen V., additional, Frantz, Andrew, additional, Suh, Ed, additional, Perry, Keith, additional, Wilson, Carmen, additional, Robinson, Leslie L., additional, Yasui, Yutaka, additional, Nichols, Kim E., additional, Armstrong, Gregory T., additional, Downing, James R., additional, and Zhang, Jinghui, additional

Published
2019
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4. Abstract 4178: Germline mutations inBRCA2and pediatric/adolescent non-Hodgkin's lymphoma: A report from the St. Jude Lifetime (SJLIFE) and Childhood Cancer Survivor Study (CCSS) cohorts

Author

Wang, Zhaoming, primary, Chang, Ti-Cheng, additional, Wilson, Carmen L., additional, Kesserwan, Chimene A., additional, Gibson, Todd M., additional, Li, Nan, additional, Easton, John, additional, Mulder, Heather L., additional, Wu, Gang, additional, Edmonson, Michael N., additional, Rusch, Michael C., additional, Downing, James R., additional, Nichols, Kim E., additional, Bhatia, Smita, additional, Armstrong, Gregory T., additional, Hudson, Melissa M., additional, Zhang, Jinghui, additional, Yasui, Yutaka, additional, and Robison, Leslie L., additional

Published
2019
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5. Abstract 3651: Increased prevalence of germline monoallelicRECQL4mutations in children with cancer

Author

Maciaszek, Jamie L., primary, Wu, Gang, additional, Hamilton, Kayla, additional, McGee, Rose B., additional, Wang, Zhaoming, additional, Nuccio, Regina, additional, Hines-Dowell, Stacy, additional, Harrison, Lynn, additional, Gerhardt, Elsie L., additional, Ouma, Annastasia, additional, Newman, Scott, additional, Patel, Aman, additional, Nakitandwe, Joy, additional, Azzato, Elizabeth, additional, Pappo, Alberto S., additional, Shurtleff, Sheila A., additional, Ellison, David W., additional, Downing, James R., additional, Hudson, Melissa M., additional, Robison, Leslie L., additional, Santana, Victor, additional, Zhang, Jinghui, additional, Nichols, Kim E., additional, and Kesserwan, Chimene A., additional

Published
2019
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6. Abstract 3652: USP7 heterozygous loss-of-function affects T-cell differentiation in pediatric T-ALL

Author

Shaw, Timothy I., primary, Dong, Li, additional, High, Anthony, additional, Liu, Yu, additional, Ju, Bensheng, additional, Kavdia, Kanisha, additional, Pagala, Vishwajeeth, additional, Shaner, Bridget, additional, Easton, John, additional, Qian, Chenxi, additional, Yu, Jiyang, additional, Janke, Janke, additional, Choi, John Kim, additional, Peng, Junmin, additional, Gu, Wei, additional, Downing, James R., additional, and Zhang, Jinghui, additional

Published
2019
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7. Abstract 922: Access, visualize and analyze 5,000 whole-genomes from pediatric cancer patients on St. Jude Cloud

Author

Newman, Scott, primary, Zhou, Xin, additional, McLeod, Clay, additional, Rusch, Michael, additional, Wu, Gang, additional, Sioson, Edgar, additional, Wang, Shuoguo, additional, Michael, J. Robert, additional, Patel, Aman, additional, Edmonson, Michael N., additional, Frantz, Andrew, additional, Chang, Ti-Cheng, additional, Li, Yongjin, additional, Davidson, Robert I., additional, Ma, Singer, additional, McGuire, Irina, additional, Robison, Nedra, additional, Tang, Xing, additional, Palmer, Lance, additional, Suh, Ed, additional, Tanner, Leigh, additional, McMurry, James, additional, Perry, Keith, additional, Wang, Zhaoming, additional, Wilson, Carmen, additional, Cheng, Yong, additional, Weiss, Mitch, additional, Robison, Leslie L., additional, Yasui, Yutaka, additional, Nichols, Kim E., additional, Ellison, David W., additional, Downing, James R., additional, and Zhang, Jinghui, additional

Published
2018
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8. Abstract 3007: Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE)

Author

Wang, Zhaoming, primary, Wilson, Carmen L., additional, Liu, Qi, additional, Easton, John, additional, Mulder, Heather L., additional, Rusch, Michael, additional, Edmonson, Michael, additional, Levy, Shawn, additional, Patel, Aman, additional, Shao, Ying, additional, Chang, Ti-Cheng, additional, Rice, Stephen V., additional, Sapkota, Yadav, additional, Brooke, Russell J., additional, Moon, Wonjong, additional, Rampersaud, Evadnie, additional, Ma, Xiaotu, additional, Pepper, Cynthia, additional, Zhou, Xin, additional, Chen, Xiang, additional, Chen, Wenan, additional, Jones, Angela, additional, Boone, Braden, additional, Ehrhardt, Matthew J., additional, Howell, Rebecca M., additional, Phillips, Nicholas, additional, Lewis, Courtney, additional, Kesserwan, Chimene A., additional, Wu, Gang, additional, Nichols, Kim E., additional, Downing, James R., additional, Hudson, Melissa M., additional, Zhang, Jinghui, additional, Yasui, Yutaka, additional, and Robison, Leslie L., additional

Published
2018
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9. Abstract 4870: Mutational landscape and timing of resistant clone emergence in 104 Chinese pediatric patients with relapsed acute lymphoblastic leukemia

Author

Li, Benshang, primary, Li, Yongjin, additional, Shen, Shuhong, additional, Zhu, Xiaofan, additional, Ma, Xiaotu, additional, Wang, Ningling, additional, Liu, Yanling, additional, Liu, Yu, additional, Zhang, Hui, additional, Lin, Ting-Nien, additional, Rusch, Michael, additional, Edmonson, Michael, additional, Easton, John, additional, Zhang, Yingchi, additional, Zhang, Jingliao, additional, Cheng, Cheng, additional, Tang, Jingyan, additional, Downing, James R., additional, Pui, Ching-Hon, additional, Yang, Jun J., additional, and Zhang, Jinghui, additional

Published
2017
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10. Abstract 3001: Germline mutations in cancer predisposition genes and risk for subsequent neoplasms among long-term survivors of childhood cancer in the St. Jude Lifetime Cohort

Author

Wang, Zhaoming, primary, Wilson, Carmen L., additional, Easton, John, additional, Hedges, Dale, additional, Liu, Qi, additional, Wu, Gang, additional, Rusch, Michael, additional, Edmonson, Michael, additional, Levy, Shawn, additional, Lanctot, Jennifer Q., additional, Caron, Eric, additional, Shelton, Kyla, additional, Currie, Kelsey, additional, Lear, Matthew, additional, Mulder, Heather L., additional, Yergeau, Donald, additional, Rosencrance, Celeste, additional, Vadodaria, Bhavin, additional, Sapkota, Yadav, additional, Brooke, Russell J., additional, Moon, Wonjong, additional, Rampersaud, Evadnie, additional, Ma, Xiaotu, additional, Wang, Shuoguo, additional, Chang, Ti-Cheng, additional, Rice, Stephen, additional, Thrasher, Andrew, additional, Patel, Aman, additional, Pepper, Cynthia, additional, Zhou, Xin, additional, Chen, Xiang, additional, Chen, Wenan, additional, Jones, Angela, additional, Boone, Braden, additional, Srivastava, Deo Kumar, additional, Kesserwan, Chimene A., additional, Nichols, Kim E., additional, Downing, James R., additional, Hudson, Melissa M., additional, Yasui, Yutaka, additional, Robison, Leslie L., additional, and Zhang, Jinghui, additional

Published
2017
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12. Abstract 2628: Molecular diagnosis for pediatric cancer through integrative analysis of whole-genome, whole-exome and transcriptome sequencing

Author

Zhang, Jinghui, primary, Rusch, Michael, additional, Nakitandwe, Joy, additional, Zhang, Zhaojie, additional, Edmonson, Michael N., additional, Parker, Matthew, additional, Ma, Xiaotu, additional, Becksfort, Jared, additional, Thrasher, Andrew, additional, Gu, Jiali, additional, Li, Yongjin, additional, Hedlund, Erin, additional, Patel, Aman, additional, Easton, John, additional, Yergeau, Donald, additional, Vadodaria, Bhavin, additional, Chen, Xiang, additional, Gruber, Tanja A., additional, McGee, Rose, additional, Ellison, David, additional, Shurtleff, Sheila, additional, and Downing, James R., additional

Published
2016
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14. Abstract 4369: Rearrangements of the erythropoietin receptor are recurrent in Ph-like acute lymphoblastic leukemia and are sensitive to Jak2 inhibition

Author

Iacobucci, Ilaria, primary, Roberts, Kathryn G., additional, Li, Yongjin, additional, Zhang, Jinghui, additional, Harvey, Richard C., additional, Payne-Turner, Debbie, additional, Valentine, Marcus, additional, McCastlain, Kelly, additional, Easton, John, additional, Chen, I-Ming, additional, Rusch, Michael, additional, Kornblau, Steven M., additional, Konopleva, Marina, additional, Paietta, Elisabeth, additional, Rowe, Jacob M., additional, Pui, Ching-Hon, additional, Gastier-Foster, Julie M., additional, Reshmi, Shalini, additional, Loh, Mignon L., additional, Willman, Cheryl, additional, Downing, James R., additional, Hunger, Stephen P., additional, and Mullighan, Charles G., additional

Published
2015
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15. Abstract 2033: Germline mutations inETV6confer risk of thrombocytopenia and acute lymphocytic leukemia

Author

Joseph, Vijai, primary, Walsh, Michael F., additional, Topka, Sabine, additional, Wu, Gang, additional, McGee, Rose B., additional, Quinn, Emily, additional, Inaba, Hiroto, additional, Hartford, Christine, additional, Pui, Ching-Hon, additional, Pappo, Alberto S., additional, Edmonson, Michael, additional, Jacobs, Lauren, additional, Danylo, Villano, additional, Schrader, Kasmintan, additional, Gaddam, Pragna, additional, Stadler, Zsofia, additional, Zhang, Michael, additional, Stepensky, Polina, additional, Steinherz, Peter, additional, Bussel, James, additional, Harit, M, additional, Weintraub, Michael, additional, Shimamura, Akiko, additional, Zhang, Jinghui, additional, Downing, James R., additional, Offit, Kenneth, additional, and Nichols, Kim E., additional

Published
2015
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17. Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia.

Author

Umeda M, Ma J, Huang BJ, Hagiwara K, Westover T, Abdelhamed S, Barajas JM, Thomas ME, Walsh MP, Song G, Tian L, Liu Y, Chen X, Kolekar P, Tran Q, Foy SG, Maciaszek JL, Kleist AB, Leonti AR, Ju B, Easton J, Wu H, Valentine V, Valentine MB, Liu YC, Ries RE, Smith JL, Parganas E, Iacobucci I, Hiltenbrand R, Miller J, Myers JR, Rampersaud E, Rahbarinia D, Rusch M, Wu G, Inaba H, Wang YC, Alonzo TA, Downing JR, Mullighan CG, Pounds S, Babu MM, Zhang J, Rubnitz JE, Meshinchi S, Ma X, and Klco JM

Subjects
Adult, Child, Chromosome Aberrations, Exons, Genomics, Humans, Mutation, Recurrence, Leukemia, Myeloid, Acute genetics
Abstract

The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML., Significance: We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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18. Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing.

Author

Newman S, Nakitandwe J, Kesserwan CA, Azzato EM, Wheeler DA, Rusch M, Shurtleff S, Hedges DJ, Hamilton KV, Foy SG, Edmonson MN, Thrasher A, Bahrami A, Orr BA, Klco JM, Gu J, Harrison LW, Wang L, Clay MR, Ouma A, Silkov A, Liu Y, Zhang Z, Liu Y, Brady SW, Zhou X, Chang TC, Pande M, Davis E, Becksfort J, Patel A, Wilkinson MR, Rahbarinia D, Kubal M, Maciaszek JL, Pastor V, Knight J, Gout AM, Wang J, Gu Z, Mullighan CG, McGee RB, Quinn EA, Nuccio R, Mostafavi R, Gerhardt EL, Taylor LM, Valdez JM, Hines-Dowell SJ, Pappo AS, Robinson G, Johnson LM, Pui CH, Ellison DW, Downing JR, Zhang J, and Nichols KE

Subjects
Child, DNA, Humans, Mutation, Sequence Analysis, RNA, Exome Sequencing, Neoplasms genetics
Abstract

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers., Significance: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2021
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19. Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators.

Author

Fornerod M, Ma J, Noort S, Liu Y, Walsh MP, Shi L, Nance S, Liu Y, Wang Y, Song G, Lamprecht T, Easton J, Mulder HL, Yergeau D, Myers J, Kamens JL, Obeng EA, Pigazzi M, Jarosova M, Kelaidi C, Polychronopoulou S, Lamba JK, Baker SD, Rubnitz JE, Reinhardt D, van den Heuvel-Eibrink MM, Locatelli F, Hasle H, Klco JM, Downing JR, Zhang J, Pounds S, Zwaan CM, and Gruber TA

Subjects
Child, Gene Expression Profiling, Genomics, Humans, Mutation genetics, Prognosis, Leukemia, Myeloid, Acute diagnosis
Abstract

Genomic characterization of pediatric patients with acute myeloid leukemia (AML) has led to the discovery of somatic mutations with prognostic implications. Although gene-expression profiling can differentiate subsets of pediatric AML, its clinical utility in risk stratification remains limited. Here, we evaluate gene expression, pathogenic somatic mutations, and outcome in a cohort of 435 pediatric patients with a spectrum of pediatric myeloid-related acute leukemias for biological subtype discovery. This analysis revealed 63 patients with varying immunophenotypes that span a T-lineage and myeloid continuum designated as acute myeloid/T-lymphoblastic leukemia (AMTL). Within AMTL, two patient subgroups distinguished by FLT3 -ITD and PRC2 mutations have different outcomes, demonstrating the impact of mutational composition on survival. Across the cohort, variability in outcomes of patients within isomutational subsets is influenced by transcriptional identity and the presence of a stem cell-like gene-expression signature. Integration of gene expression and somatic mutations leads to improved risk stratification., Significance: Immunophenotype and somatic mutations play a significant role in treatment approach and risk stratification of acute leukemia. We conducted an integrated genomic analysis of pediatric myeloid malignancies and found that a combination of genetic and transcriptional readouts was superior to immunophenotype and genomic mutations in identifying biological subtypes and predicting outcomes. This article is highlighted in the In This Issue feature, p. 549 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2021
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20. Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy.

Author

Jeha S, Choi J, Roberts KG, Pei D, Coustan-Smith E, Inaba H, Rubnitz JE, Ribeiro RC, Gruber TA, Raimondi SC, Karol SE, Qu C, Brady SW, Gu Z, Yang JJ, Cheng C, Downing JR, Evans WE, Relling MV, Campana D, Mullighan CG, and Pui CH

Subjects
Child, Chromosome Aberrations, Humans, Neoplasm, Residual genetics, Prognosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Abstract

We evaluate clinical significance of recently identified subtypes of acute lymphoblastic leukemia (ALL) in 598 children treated with minimal residual disease (MRD)-directed therapy. Among the 16 B-ALL and 8 T-ALL subtypes identified by next generation sequencing, ETV6-RUNX1 , high-hyperdiploid and DUX4 -rearranged B-ALL had the best five-year event-free survival rates (95% to 98.4%); TCF3-PBX1 , PAX5alt, T-cell, ETP, iAMP21, and hypodiploid ALL intermediate rates (80.0% to 88.2%); and BCR-ABL1 , BCR-ABL1 -like and ETV6-RUNX1 -like and KMT2A -rearranged ALL the worst rates (64.1% to 76.2%). All but three of the 142 patients with day-8 blood MRD <0.01% remained in remission. Among new subtypes, intensified therapy based on day-15 MRD≥1% improved outcome of DUX4 -rearranged, BCR-ABL1 -like, and ZNF384 -rearranged ALL, and achievement of day-42 MRD<0.01% did not preclude relapse of PAX5alt, MEF2D -rearranged and ETV6-RUNX1 -like ALL. Thus, new subtypes including DUX4 -rearranged, PAX5alt, BCR-ABL1 -like, ETV6-RUNX1 -like, MEF2D -rearranged and ZNF384 -rearranged ALL have important prognostic and therapeutic implications., Competing Interests: Disclosure of Potential Conflicts of Interests. C.G.M. has received research funding from Loxo Oncology, Pfizer and AbbVie; compensation from Amgen and Illumina, and holds stock in Amgen. C.-H..P. is on scientific advisory board of Adaptive Biotechnology, Inc and Data Monitoring Committee of Novartis, and received honorarium from Amgen.

Published
2021
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21. St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem.

Author

McLeod C, Gout AM, Zhou X, Thrasher A, Rahbarinia D, Brady SW, Macias M, Birch K, Finkelstein D, Sunny J, Mudunuri R, Orr BA, Treadway M, Davidson B, Ard TK, Chiao A, Swistak A, Wiggins S, Foy S, Wang J, Sioson E, Wang S, Michael JR, Liu Y, Ma X, Patel A, Edmonson MN, Wilkinson MR, Frantz AM, Chang TC, Tian L, Lei S, Islam SMA, Meyer C, Thangaraj N, Tater P, Kandali V, Ma S, Nguyen T, Serang O, McGuire I, Robison N, Gentry D, Tang X, Palmer LE, Wu G, Suh E, Tanner L, McMurry J, Lear M, Pappo AS, Wang Z, Wilson CL, Cheng Y, Meshinchi S, Alexandrov LB, Weiss MJ, Armstrong GT, Robison LL, Yasui Y, Nichols KE, Ellison DW, Bangur C, Mullighan CG, Baker SJ, Dyer MA, Miller G, Newman S, Rusch M, Daly R, Perry K, Downing JR, and Zhang J

Subjects
Child, Ecosystem, Hospitals, Pediatric, Humans, Anemia, Sickle Cell genetics, Cloud Computing, Genomics, Information Dissemination, Neoplasms genetics
Abstract

Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. SIGNIFICANCE: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community. This article is highlighted in the In This Issue feature, p. 995 ., (©2021 American Association for Cancer Research.)

Published
2021
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22. The Clonal Evolution of Metastatic Osteosarcoma as Shaped by Cisplatin Treatment.

Author

Brady SW, Ma X, Bahrami A, Satas G, Wu G, Newman S, Rusch M, Putnam DK, Mulder HL, Yergeau DA, Edmonson MN, Easton J, Alexandrov LB, Chen X, Mardis ER, Wilson RK, Downing JR, Pappo AS, Raphael BJ, Dyer MA, and Zhang J

Subjects
Antineoplastic Agents pharmacology, Bone Neoplasms pathology, Cisplatin pharmacology, Clonal Evolution drug effects, DNA Mutational Analysis, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms secondary, Male, Models, Genetic, Mutagenesis drug effects, Neoplasm Metastasis, Osteosarcoma pathology, Whole Genome Sequencing, Bone Neoplasms drug therapy, Bone Neoplasms genetics, Cisplatin therapeutic use, Osteosarcoma drug therapy, Osteosarcoma genetics
Abstract

To investigate the genomic evolution of metastatic pediatric osteosarcoma, we performed whole-genome and targeted deep sequencing on 14 osteosarcoma metastases and two primary tumors from four patients (two to eight samples per patient). All four patients harbored ancestral (truncal) somatic variants resulting in TP53 inactivation and cell-cycle aberrations, followed by divergence into relapse-specific lineages exhibiting a cisplatin-induced mutation signature. In three of the four patients, the cisplatin signature accounted for >40% of mutations detected in the metastatic samples. Mutations potentially acquired during cisplatin treatment included NF1 missense mutations of uncertain significance in two patients and a KIT G565R activating mutation in one patient. Three of four patients demonstrated widespread ploidy differences between samples from the sample patient. Single-cell seeding of metastasis was detected in most metastatic samples. Cross-seeding between metastatic sites was observed in one patient, whereas in another patient a minor clone from the primary tumor seeded both metastases analyzed. These results reveal extensive clonal heterogeneity in metastatic osteosarcoma, much of which is likely cisplatin-induced. IMPLICATIONS: The extent and consequences of chemotherapy-induced damage in pediatric cancers is unknown. We found that cisplatin treatment can potentially double the mutational burden in osteosarcoma, which has implications for optimizing therapy for recurrent, chemotherapy-resistant disease., (©2019 American Association for Cancer Research.)

Published
2019
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23. Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE).

Author

Wang Z, Liu Q, Wilson CL, Easton J, Mulder H, Chang TC, Rusch MC, Edmonson MN, Rice SV, Ehrhardt MJ, Howell RM, Kesserwan CA, Wu G, Nichols KE, Downing JR, Hudson MM, Zhang J, Yasui Y, and Robison LL

Subjects
Age Factors, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Genetic Variation, Germ-Line Mutation, Humans, Incidence, Odds Ratio, Population Surveillance, Risk Assessment, Risk Factors, Sex Factors, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Cancer Survivors statistics & numerical data, Genetic Predisposition to Disease, Neoplasms, Second Primary epidemiology, Neoplasms, Second Primary etiology
Abstract

Purpose: The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population., Experimental Design: Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression., Results: The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1), and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2-8.3)., Conclusions: Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors., (©2018 American Association for Cancer Research.)

Published
2018
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