Sasi Arunachalam - Academia.edu (original) (raw)

Papers by Sasi Arunachalam

Research paper thumbnail of Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Blood cancer discovery, Mar 3, 2021

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoiet... more Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and precancer surveillance for both children and adults. SIgnIfICanCe: This study identifies frequently occurring mutations across several blood cancers that may drive hematologic malignancies and signal increased risk for cancer when detected in healthy persons. We find clonal mutations at these hotspots in a substantial number of individuals from noncancer cohorts, including children, showcasing potential for improved precancer surveillance.

Research paper thumbnail of Supplementary Table S2 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Bins for number of primary samples in COSMIC downloadable database having a protein-altering muta... more Bins for number of primary samples in COSMIC downloadable database having a protein-altering mutation at the locus in ALL, AML, CML, CMML, JMML, MPN, or MDS Bins for number of any sample type in the COSMIC web version for any mutation type at the locus for any cancer Gene* AA locus No. patients with protein-altering mutation in the 48 somatic landscape studies 0

Research paper thumbnail of A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A

ACS Chemical Biology, Dec 20, 2018

We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of m... more We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective cell death by specifically inducing cellular Zn 2+ uptake in transformed cells. ZNA's cancer selectivity was evaluated using metastatic, patient derived breast cancer cells, established human breast cancer cell lines, and three-dimensional organoid models derived from normal and transformed mouse mammary glands. Structural analysis of ZNA demonstrated that the compound interacts with zinc through the N 2-acyl-2 aminoimidazole core. Combination treatment with ZnSO 4 strongly potentiated ZNA's cancer specific cell death mechanism, an effect that was not observed with other transition metals. We show that Zn 2+-dyshomeostasis induced by ZNA is unique and markedly more selective than other known Zn 2+ interacting compounds such as clioquinol. The in vivo bioactivity of ZNA was also assessed and revealed that tumor-bearing mice treated with ZNA had improved survival outcomes. Collectively, these data demonstrate that the N 2-acyl-2aminoimidazole core of ZNA represents a powerful chemotype to induce cell death in cancer cells concurrently with a disruption in zinc homeostasis.

Research paper thumbnail of Data from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoiet... more Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and precancer surveillance for both children and adults.Significance:This study identifies frequently occurring mutations across several blood cancers that may drive hematologic malignancies and signal increased risk for cancer when detected in healthy persons. We find clonal mutations at these hotspots in a substantial number of individuals from noncancer cohorts, including children, showcasing potential for improved precancer surveillance.See related commentary by Spitzer and Levine, p. 192.

Research paper thumbnail of The Role of store operated calcium channels in human carcinoid cell lines

... Arunachalam, Sasi. ... culture method; tumorgenesis; migration; amoeboid; mesenchymal migrati... more ... Arunachalam, Sasi. ... culture method; tumorgenesis; migration; amoeboid; mesenchymal migration; multiphoton imaging; Fura-2AM; live cell imaging Committee / Advisors David Giovannucci, PhD (Committee Chair) Joseph Margiotta, PhD (Committee Member) Surya Nauli, PhD ...

Research paper thumbnail of Supplementary Table S4 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Convergent evolution and multi-wave clonal invasion in H3 K27-altered diffuse midline gliomas treated with a PDGFR inhibitor

Acta neuropathologica communications, May 31, 2022

The majority of diffuse midline gliomas, H3 K27-altered (DMG-H3 K27-a), are infiltrating pediatri... more The majority of diffuse midline gliomas, H3 K27-altered (DMG-H3 K27-a), are infiltrating pediatric brain tumors that arise in the pons with no effective treatment. To understand how clonal evolution contributes to the tumor's invasive spread, we performed exome sequencing and SNP array profiling on 49 multi-region autopsy samples from 11 patients with pontine DMG-H3 K27-a enrolled in a phase I clinical trial of PDGFR inhibitor crenolanib. For each patient, a phylogenetic tree was constructed by testing multiple possible clonal evolution models to select the one consistent with somatic mutations and copy number variations across all tumor regions. The tree was then used to deconvolute subclonal composition and prevalence at each tumor region to study convergent evolution and invasion patterns. Somatic variants in the PI3K pathway, a late event, are enriched in our cohort, affecting 70% of patients. Convergent evolution of PI3K at distinct phylogenetic branches was detected in 40% of the patients. 24 (~ 50%) of tumor regions were occupied by subclones of mixed lineages with varying molecular ages, indicating multiple waves of invasion across the pons and extrapontine. Subclones harboring a PDGFRA amplicon, including one that amplified a PDGR-FA Y849C mutant allele, were detected in four patients; their presence in extrapontine tumor and normal brain samples imply their involvement in extrapontine invasion. Our study expands the current knowledge on tumor invasion patterns in DMG-H3 K27-a, which may inform the design of future clinical trials.

Research paper thumbnail of Data-driven approaches to advance research and clinical care for pediatric cancer

Biochimica Et Biophysica Acta - Reviews On Cancer, Aug 1, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of The Genomic Landscape of Childhood Acute Lymphoblastic Leukemia

Blood, Nov 13, 2019

Introduction: Although recent studies have refined the classification of B-progenitor and T-linea... more Introduction: Although recent studies have refined the classification of B-progenitor and T-lineage acute lymphoblastic leukemia into gene-expression based subgroups, a comprehensive integration of significantly mutated genes and pathways for each subgroup is needed to understand disease etiology. Methods: We studied 2789 children, adolescents and young adults (AYA) with newly diagnosed B-ALL (n=2,322 cases) or T-ALL (n=467) treated on Children's Oncology Group (n=1,872) and St. Jude Children's Research Hospital trials (n=917). The cohort comprised childhood NCI standard-risk (41.8%; age range 1-9.99 yrs, WBC ≤ 50,000/ml), childhood NCI high-risk (44.5%; age range ≥10 to 15.99 yrs) and AYA (9.9%; age range 16-30.7 yrs). Genomic analysis was performed on tumor and matched-remission samples using whole transcriptome sequencing (RNA-seq; tumor only; n=1,922), whole exome sequencing (n=1,659), whole genome sequencing (n=757), and single nucleotide polymorphism array (n=1,909). Results: For B-ALL, 2104 cases (90.6%) were classified into 26 subgroups based on RNA-seq gene expression data and aneuploidy or other gross chromosomal abnormalities (iAMP21, Down syndrome, dicentric), deregulation of known transcription factors by rearrangement or mutation (PAX5 P80R, IKZF1 N159Y), or activation of kinase alterations (Ph+, Ph-like). For T-ALL, cases were classified into 9 previously described subtypes based on dysregulation of transcription factor genes and gene expression. In 1,659 cases subject to exome sequencing (1259 B-ALL, 405 T-ALL) we identified 18,954 nonsynonymous single nucleotide variants (SNV) and 2,329 insertion-deletion mutations (indels) in 8,985 genes. Overall, 161 potential driver genes were identified by the mutation-significance detection tool MutSigCV or by presence of pathogenic variants in known cancer genes. Integration of sequence mutations and DNA copy number alteration data in B-ALL identified 7 recurrently mutated pathways: transcriptional regulation (40.6%), cell cycle and tumor suppression (38.0%), B-cell development (34.5%), epigenetic regulation (24.7%), Ras signaling (33.0%), JAK-STAT signaling (12.0%) and protein modification (ubiquitination or SUMOylation, 5.0%). The top 10 genes altered by deletion or mutation in B-ALL were CDKN2A/B (30.1%), ETV6 (27.0%), PAX5 (24.6%), CDKN1B (20.3%), IKZF1 (17.6%), KRAS (16.5%), NRAS (14.6%), BTG1 (7.5%) histone genes on chromosome 6 (6.9%) and FLT3 (6.1%), and for T-ALL, CDKN2A/B (74.7%), NOTCH1 (68.2%), FBXW7 (21.3%), PTEN (20.5%) and PHF6 (18.2%) (Figure 1A). We identified 17 putative novel driver genes involved in ubiquitination (UBE2D3, UBE2A, UHRF1, and USP1), SUMOylation (SAE1, UBE2I), transcriptional regulation (ZMYM2, HMGB1), immune function (B2M), migration (CXCR4), epigenetic regulation (DOT1L) and mitochondrial function (LETM1). We also observed variation in the frequency of genes and pathways altered across B-ALL subtypes (Figure 1B). Interestingly, alteration of SAE1 and UBA2, novel genes that form a heterodimeric complex important for SUMOylation, and UHRF1 were enriched in ETV6-RUNX1 cases. Deletions of LETM1, ZMYM2 and CHD4 were associated with near haploid and low hypodiploid cases. Deletion of histone genes on chromosome 6 and alterations of HDAC7 were enriched in Ph+ and Ph-like ALL. Mutations in the RNA-binding protein ZFP36L2 were observed in PAX5alt, DUX4 and MEF2D subgroups. Genomic subtypes were prognostic. ETV6-RUNX1, hyperdiploid, DUX4 and ZNF384 ALL were associated with good outcome (5-yr EFS 91.1%, 87.2%, 91.9% and 85.7%, respectively), ETV6-RUNX1-like, iAMP21, low hyperdiploid, PAX5 P80R and PAX5alt were associated with intermediate outcome (5-yr EFS 68.6%, 72.2%, 70.8%, 77.0% and 70.9%, respectively), whilst KMT2A, MEF2D, Ph-like CRLF2 and Ph-like other conferred a poor prognosis (55.5%, 67.1%, 51.5% and 62.1%, respectively). TCF3-HLF and near haploid had the worst outcome with 5-yr EFS rates of 27.3% and 47.2%, respectively. Conclusions: These findings provide a comprehensive landscape of genomic alterations in childhood ALL. The associations of mutations with ALL subtypes highlights the need for specific patterns of cooperating mutations in the development of leukemia, which may help identify vulnerabilities for therapy intervention. Disclosures Gastier-Foster: Bristol Myers Squibb (BMS): Other: Commercial Research; Incyte Corporation: Other: Commercial Research. Willman:to come: Patents & Royalties; to come: Membership on an entity's Board of Directors or advisory committees; to come: Research Funding. Raetz:Pfizer: Research Funding. Borowitz:Beckman Coulter: Honoraria. Zweidler-McKay:ImmunoGen: Employment. Angiolillo:Servier Pharmaceuticals: Consultancy. Relling:Servier Pharmaceuticals: Research Funding. Hunger:Jazz: Honoraria; Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Novartis:…

Research paper thumbnail of XenoCP: Cloud-based BAM cleansing tool for RNA and DNA from Xenograft

bioRxiv (Cold Spring Harbor Laboratory), Nov 15, 2019

Xenografts are important models for cancer research and the presence of mouse reads in xenograft ... more Xenografts are important models for cancer research and the presence of mouse reads in xenograft next generation sequencing data can potentially confound interpretation of experimental results. We present an efficient, cloud-based BAM-to-BAM cleaning tool called XenoCP to remove mouse reads from xenograft BAM files. We show application of XenoCP in obtaining accurate gene expression quantification in RNA-seq and tumor heterogeneity in WGS of xenografts derived from brain and solid tumors.

Research paper thumbnail of Supplementary Information from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S8 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Supplementary Table 8. CHIP mutations not exclusive to hotspots identified in the three non-cance... more Supplementary Table 8. CHIP mutations not exclusive to hotspots identified in the three non-cancer cohorts. Listed are 189 CHIP mutations identified in 183 persons of the three non-cancer cohorts (N=4,530) occurring in hematopoietic-associated genes but not required to occur at a hematologic hotspot, identified as per the criteria used in Jaiswal et al. 14. These mutations were required to meet a variant allele frequency (VAF) threshold of 4%. Cohort* SRR ID # Chr. Start pos. (hg19) End pos. (hg19) Ref. Alt. Ref. reads Alt. reads VAF Ref./Alt. reads on both strands Transcript Mutation M/F † Age ‡ No. patients/ hemat. disorders/ studies hotspot observed in 48 studies § gnomAD allele frequency (exome) gnomAD allele frequency (genome)

Research paper thumbnail of Supplementary Table S1 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S6 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S4 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S3 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S5 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Supplementary Table 5. Unique mutations allowed at hotspots. Listed are 350 mutations reported ac... more Supplementary Table 5. Unique mutations allowed at hotspots. Listed are 350 mutations reported across the 48 somatic landscape studies that were not listed as queried variants for CHIP in Jaiswal et al. 14 (many of those 48 studies were published around or after that landmark CHIP paper). Columns show the number of mutations resulting in the exact protein exchange and for the total number of protein-altering mutations reported for each amino acid position or splice site locus across the 48 studies. Tallies are for the total number of patients with a reported mutation (No. patients), number of hematological malignancies having at least one reported patient with the mutation (No. hemat. disorders), and the number of studies reporting at least one patient with the mutation (No. studies).

Research paper thumbnail of Supplementary Table S7 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Additional mutations meeting the criteria for relaxed CHIP

Research paper thumbnail of Data from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoiet... more Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in ...

Research paper thumbnail of The genomic landscape of pediatric acute lymphoblastic leukemia and precision medicine opportunities

Seminars in Cancer Biology, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Blood cancer discovery, Mar 3, 2021

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoiet... more Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and precancer surveillance for both children and adults. SIgnIfICanCe: This study identifies frequently occurring mutations across several blood cancers that may drive hematologic malignancies and signal increased risk for cancer when detected in healthy persons. We find clonal mutations at these hotspots in a substantial number of individuals from noncancer cohorts, including children, showcasing potential for improved precancer surveillance.

Research paper thumbnail of Supplementary Table S2 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Bins for number of primary samples in COSMIC downloadable database having a protein-altering muta... more Bins for number of primary samples in COSMIC downloadable database having a protein-altering mutation at the locus in ALL, AML, CML, CMML, JMML, MPN, or MDS Bins for number of any sample type in the COSMIC web version for any mutation type at the locus for any cancer Gene* AA locus No. patients with protein-altering mutation in the 48 somatic landscape studies 0

Research paper thumbnail of A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A

ACS Chemical Biology, Dec 20, 2018

We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of m... more We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective cell death by specifically inducing cellular Zn 2+ uptake in transformed cells. ZNA's cancer selectivity was evaluated using metastatic, patient derived breast cancer cells, established human breast cancer cell lines, and three-dimensional organoid models derived from normal and transformed mouse mammary glands. Structural analysis of ZNA demonstrated that the compound interacts with zinc through the N 2-acyl-2 aminoimidazole core. Combination treatment with ZnSO 4 strongly potentiated ZNA's cancer specific cell death mechanism, an effect that was not observed with other transition metals. We show that Zn 2+-dyshomeostasis induced by ZNA is unique and markedly more selective than other known Zn 2+ interacting compounds such as clioquinol. The in vivo bioactivity of ZNA was also assessed and revealed that tumor-bearing mice treated with ZNA had improved survival outcomes. Collectively, these data demonstrate that the N 2-acyl-2aminoimidazole core of ZNA represents a powerful chemotype to induce cell death in cancer cells concurrently with a disruption in zinc homeostasis.

Research paper thumbnail of Data from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoiet... more Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and precancer surveillance for both children and adults.Significance:This study identifies frequently occurring mutations across several blood cancers that may drive hematologic malignancies and signal increased risk for cancer when detected in healthy persons. We find clonal mutations at these hotspots in a substantial number of individuals from noncancer cohorts, including children, showcasing potential for improved precancer surveillance.See related commentary by Spitzer and Levine, p. 192.

Research paper thumbnail of The Role of store operated calcium channels in human carcinoid cell lines

... Arunachalam, Sasi. ... culture method; tumorgenesis; migration; amoeboid; mesenchymal migrati... more ... Arunachalam, Sasi. ... culture method; tumorgenesis; migration; amoeboid; mesenchymal migration; multiphoton imaging; Fura-2AM; live cell imaging Committee / Advisors David Giovannucci, PhD (Committee Chair) Joseph Margiotta, PhD (Committee Member) Surya Nauli, PhD ...

Research paper thumbnail of Supplementary Table S4 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Convergent evolution and multi-wave clonal invasion in H3 K27-altered diffuse midline gliomas treated with a PDGFR inhibitor

Acta neuropathologica communications, May 31, 2022

The majority of diffuse midline gliomas, H3 K27-altered (DMG-H3 K27-a), are infiltrating pediatri... more The majority of diffuse midline gliomas, H3 K27-altered (DMG-H3 K27-a), are infiltrating pediatric brain tumors that arise in the pons with no effective treatment. To understand how clonal evolution contributes to the tumor's invasive spread, we performed exome sequencing and SNP array profiling on 49 multi-region autopsy samples from 11 patients with pontine DMG-H3 K27-a enrolled in a phase I clinical trial of PDGFR inhibitor crenolanib. For each patient, a phylogenetic tree was constructed by testing multiple possible clonal evolution models to select the one consistent with somatic mutations and copy number variations across all tumor regions. The tree was then used to deconvolute subclonal composition and prevalence at each tumor region to study convergent evolution and invasion patterns. Somatic variants in the PI3K pathway, a late event, are enriched in our cohort, affecting 70% of patients. Convergent evolution of PI3K at distinct phylogenetic branches was detected in 40% of the patients. 24 (~ 50%) of tumor regions were occupied by subclones of mixed lineages with varying molecular ages, indicating multiple waves of invasion across the pons and extrapontine. Subclones harboring a PDGFRA amplicon, including one that amplified a PDGR-FA Y849C mutant allele, were detected in four patients; their presence in extrapontine tumor and normal brain samples imply their involvement in extrapontine invasion. Our study expands the current knowledge on tumor invasion patterns in DMG-H3 K27-a, which may inform the design of future clinical trials.

Research paper thumbnail of Data-driven approaches to advance research and clinical care for pediatric cancer

Biochimica Et Biophysica Acta - Reviews On Cancer, Aug 1, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of The Genomic Landscape of Childhood Acute Lymphoblastic Leukemia

Blood, Nov 13, 2019

Introduction: Although recent studies have refined the classification of B-progenitor and T-linea... more Introduction: Although recent studies have refined the classification of B-progenitor and T-lineage acute lymphoblastic leukemia into gene-expression based subgroups, a comprehensive integration of significantly mutated genes and pathways for each subgroup is needed to understand disease etiology. Methods: We studied 2789 children, adolescents and young adults (AYA) with newly diagnosed B-ALL (n=2,322 cases) or T-ALL (n=467) treated on Children's Oncology Group (n=1,872) and St. Jude Children's Research Hospital trials (n=917). The cohort comprised childhood NCI standard-risk (41.8%; age range 1-9.99 yrs, WBC ≤ 50,000/ml), childhood NCI high-risk (44.5%; age range ≥10 to 15.99 yrs) and AYA (9.9%; age range 16-30.7 yrs). Genomic analysis was performed on tumor and matched-remission samples using whole transcriptome sequencing (RNA-seq; tumor only; n=1,922), whole exome sequencing (n=1,659), whole genome sequencing (n=757), and single nucleotide polymorphism array (n=1,909). Results: For B-ALL, 2104 cases (90.6%) were classified into 26 subgroups based on RNA-seq gene expression data and aneuploidy or other gross chromosomal abnormalities (iAMP21, Down syndrome, dicentric), deregulation of known transcription factors by rearrangement or mutation (PAX5 P80R, IKZF1 N159Y), or activation of kinase alterations (Ph+, Ph-like). For T-ALL, cases were classified into 9 previously described subtypes based on dysregulation of transcription factor genes and gene expression. In 1,659 cases subject to exome sequencing (1259 B-ALL, 405 T-ALL) we identified 18,954 nonsynonymous single nucleotide variants (SNV) and 2,329 insertion-deletion mutations (indels) in 8,985 genes. Overall, 161 potential driver genes were identified by the mutation-significance detection tool MutSigCV or by presence of pathogenic variants in known cancer genes. Integration of sequence mutations and DNA copy number alteration data in B-ALL identified 7 recurrently mutated pathways: transcriptional regulation (40.6%), cell cycle and tumor suppression (38.0%), B-cell development (34.5%), epigenetic regulation (24.7%), Ras signaling (33.0%), JAK-STAT signaling (12.0%) and protein modification (ubiquitination or SUMOylation, 5.0%). The top 10 genes altered by deletion or mutation in B-ALL were CDKN2A/B (30.1%), ETV6 (27.0%), PAX5 (24.6%), CDKN1B (20.3%), IKZF1 (17.6%), KRAS (16.5%), NRAS (14.6%), BTG1 (7.5%) histone genes on chromosome 6 (6.9%) and FLT3 (6.1%), and for T-ALL, CDKN2A/B (74.7%), NOTCH1 (68.2%), FBXW7 (21.3%), PTEN (20.5%) and PHF6 (18.2%) (Figure 1A). We identified 17 putative novel driver genes involved in ubiquitination (UBE2D3, UBE2A, UHRF1, and USP1), SUMOylation (SAE1, UBE2I), transcriptional regulation (ZMYM2, HMGB1), immune function (B2M), migration (CXCR4), epigenetic regulation (DOT1L) and mitochondrial function (LETM1). We also observed variation in the frequency of genes and pathways altered across B-ALL subtypes (Figure 1B). Interestingly, alteration of SAE1 and UBA2, novel genes that form a heterodimeric complex important for SUMOylation, and UHRF1 were enriched in ETV6-RUNX1 cases. Deletions of LETM1, ZMYM2 and CHD4 were associated with near haploid and low hypodiploid cases. Deletion of histone genes on chromosome 6 and alterations of HDAC7 were enriched in Ph+ and Ph-like ALL. Mutations in the RNA-binding protein ZFP36L2 were observed in PAX5alt, DUX4 and MEF2D subgroups. Genomic subtypes were prognostic. ETV6-RUNX1, hyperdiploid, DUX4 and ZNF384 ALL were associated with good outcome (5-yr EFS 91.1%, 87.2%, 91.9% and 85.7%, respectively), ETV6-RUNX1-like, iAMP21, low hyperdiploid, PAX5 P80R and PAX5alt were associated with intermediate outcome (5-yr EFS 68.6%, 72.2%, 70.8%, 77.0% and 70.9%, respectively), whilst KMT2A, MEF2D, Ph-like CRLF2 and Ph-like other conferred a poor prognosis (55.5%, 67.1%, 51.5% and 62.1%, respectively). TCF3-HLF and near haploid had the worst outcome with 5-yr EFS rates of 27.3% and 47.2%, respectively. Conclusions: These findings provide a comprehensive landscape of genomic alterations in childhood ALL. The associations of mutations with ALL subtypes highlights the need for specific patterns of cooperating mutations in the development of leukemia, which may help identify vulnerabilities for therapy intervention. Disclosures Gastier-Foster: Bristol Myers Squibb (BMS): Other: Commercial Research; Incyte Corporation: Other: Commercial Research. Willman:to come: Patents & Royalties; to come: Membership on an entity's Board of Directors or advisory committees; to come: Research Funding. Raetz:Pfizer: Research Funding. Borowitz:Beckman Coulter: Honoraria. Zweidler-McKay:ImmunoGen: Employment. Angiolillo:Servier Pharmaceuticals: Consultancy. Relling:Servier Pharmaceuticals: Research Funding. Hunger:Jazz: Honoraria; Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Novartis:…

Research paper thumbnail of XenoCP: Cloud-based BAM cleansing tool for RNA and DNA from Xenograft

bioRxiv (Cold Spring Harbor Laboratory), Nov 15, 2019

Xenografts are important models for cancer research and the presence of mouse reads in xenograft ... more Xenografts are important models for cancer research and the presence of mouse reads in xenograft next generation sequencing data can potentially confound interpretation of experimental results. We present an efficient, cloud-based BAM-to-BAM cleaning tool called XenoCP to remove mouse reads from xenograft BAM files. We show application of XenoCP in obtaining accurate gene expression quantification in RNA-seq and tumor heterogeneity in WGS of xenografts derived from brain and solid tumors.

Research paper thumbnail of Supplementary Information from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S8 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Supplementary Table 8. CHIP mutations not exclusive to hotspots identified in the three non-cance... more Supplementary Table 8. CHIP mutations not exclusive to hotspots identified in the three non-cancer cohorts. Listed are 189 CHIP mutations identified in 183 persons of the three non-cancer cohorts (N=4,530) occurring in hematopoietic-associated genes but not required to occur at a hematologic hotspot, identified as per the criteria used in Jaiswal et al. 14. These mutations were required to meet a variant allele frequency (VAF) threshold of 4%. Cohort* SRR ID # Chr. Start pos. (hg19) End pos. (hg19) Ref. Alt. Ref. reads Alt. reads VAF Ref./Alt. reads on both strands Transcript Mutation M/F † Age ‡ No. patients/ hemat. disorders/ studies hotspot observed in 48 studies § gnomAD allele frequency (exome) gnomAD allele frequency (genome)

Research paper thumbnail of Supplementary Table S1 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S6 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S4 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S3 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Research paper thumbnail of Supplementary Table S5 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Supplementary Table 5. Unique mutations allowed at hotspots. Listed are 350 mutations reported ac... more Supplementary Table 5. Unique mutations allowed at hotspots. Listed are 350 mutations reported across the 48 somatic landscape studies that were not listed as queried variants for CHIP in Jaiswal et al. 14 (many of those 48 studies were published around or after that landmark CHIP paper). Columns show the number of mutations resulting in the exact protein exchange and for the total number of protein-altering mutations reported for each amino acid position or splice site locus across the 48 studies. Tallies are for the total number of patients with a reported mutation (No. patients), number of hematological malignancies having at least one reported patient with the mutation (No. hemat. disorders), and the number of studies reporting at least one patient with the mutation (No. studies).

Research paper thumbnail of Supplementary Table S7 from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Additional mutations meeting the criteria for relaxed CHIP

Research paper thumbnail of Data from Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoiet... more Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in ...

Research paper thumbnail of The genomic landscape of pediatric acute lymphoblastic leukemia and precision medicine opportunities

Seminars in Cancer Biology, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.