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1.  Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study 
The Lancet. Oncology  2015;16(16):1659-1666.
Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukemia (ALL). Recent studies identified germline ETV6 variations associated with marked familial clustering of hematologic malignancies, pointing to this gene as a potentially important genetic determinant for ALL susceptibility. The aims of the current study are to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contribute to the overall risk of childhood ALL.
Whole-exome sequencing of an index family with multiple cases of ALL was performed to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in 4,405 children from the Children's Oncology Group (COG) and St. Jude Children's Research Hospital frontline ALL trials. Patients were included in this study on the basis of their enrollment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterized bioinformatically and correlated with clinical and demographic features in 2,021 children with ALL.
We identified a novel nonsense ETV6 variant (p.R359X) with a high penetrance of familial ALL. Subsequent targeted sequencing of ETV6 in 4,405 childhood ALL cases discovered 31 exonic variants (4 nonsense, 21 missense, 1 splice site, and 5 frame shift variants) that are potentially related to ALL risk in 35 cases (0.79%). Fifteen (48%) of the 31 ALL-related ETV6 variants clustered in the ETS domain and predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukemia diagnosis than others (10.2 years [IQR 5.3-13.8] vs 4.7 years [IQR 3.0-8.7], P=0.017). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (9 of 14 cases [64.3%] vs 538 of 2,007 cases [26.8%]; P=0.0050).
Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL.
This study was supported by the National Institutes of Health and by the American Lebanese Syrian Associated Charities.
PMCID: PMC4684709  PMID: 26522332
2.  Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia 
Nature Communications  2016;7:13331.
Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.
Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.
PMCID: PMC5105166  PMID: 27824051
3.  Comprehensive Molecular Characterization of Papillary Renal Cell Carcinoma 
Linehan, W. Marston | Spellman, Paul T. | Ricketts, Christopher J. | Creighton, Chad J. | Fei, Suzanne S. | Davis, Caleb | Wheeler, David A. | Murray, Bradley A. | Schmidt, Laura | Vocke, Cathy D. | Peto, Myron | Al Mamun, Abu Amar M. | Shinbrot, Eve | Sethi, Anurag | Brooks, Samira | Rathmell, W. Kimryn | Brooks, Angela N. | Hoadley, Katherine A. | Robertson, A. Gordon | Brooks, Denise | Bowlby, Reanne | Sadeghi, Sara | Shen, Hui | Weisenberger, Daniel J. | Bootwalla, Moiz | Baylin, Stephen B. | Laird, Peter W. | Cherniack, Andrew D. | Saksena, Gordon | Haake, Scott | Li, Jun | Liang, Han | Lu, Yiling | Mills, Gordon B. | Akbani, Rehan | Leiserson, Mark D.M. | Raphael, Benjamin J. | Anur, Pavana | Bottaro, Donald | Albiges, Laurence | Barnabas, Nandita | Choueiri, Toni K. | Czerniak, Bogdan | Godwin, Andrew K. | Hakimi, A. Ari | Ho, Thai | Hsieh, James | Ittmann, Michael | Kim, William Y. | Krishnan, Bhavani | Merino, Maria J. | Mills Shaw, Kenna R. | Reuter, Victor E. | Reznik, Ed | Shelley, Carl Simon | Shuch, Brian | Signoretti, Sabina | Srinivasan, Ramaprasad | Tamboli, Pheroze | Thomas, George | Tickoo, Satish | Burnett, Kenneth | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Mallery, David | Morris, Scott | Paulauskis, Joseph D. | Penny, Robert J. | Shelton, Candace | Shelton, W. Troy | Sherman, Mark | Thompson, Eric | Yena, Peggy | Avedon, Melissa T. | Bowen, Jay | Gastier-Foster, Julie M. | Gerken, Mark | Leraas, Kristen M. | Lichtenberg, Tara M. | Ramirez, Nilsa C. | Santos, Tracie | Wise, Lisa | Zmuda, Erik | Demchok, John A. | Felau, Ina | Hutter, Carolyn M. | Sheth, Margi | Sofia, Heidi J. | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean C. | Zhang, Jiashan (Julia) | Ayala, Brenda | Baboud, Julien | Chudamani, Sudha | Liu, Jia | Lolla, Laxmi | Naresh, Rashi | Pihl, Todd | Sun, Qiang | Wan, Yunhu | Wu, Ye | Ally, Adrian | Balasundaram, Miruna | Balu, Saianand | Beroukhim, Rameen | Bodenheimer, Tom | Buhay, Christian | Butterfield, Yaron S.N. | Carlsen, Rebecca | Carter, Scott L. | Chao, Hsu | Chuah, Eric | Clarke, Amanda | Covington, Kyle R. | Dahdouli, Mahmoud | Dewal, Ninad | Dhalla, Noreen | Doddapaneni, HarshaVardhan | Drummond, Jennifer | Gabriel, Stacey B. | Gibbs, Richard A. | Guin, Ranabir | Hale, Walker | Hawes, Alicia | Hayes, D. Neil | Holt, Robert A. | Hoyle, Alan P. | Jefferys, Stuart R. | Jones, Steven J.M. | Jones, Corbin D. | Kalra, Divya | Kovar, Christie | Lewis, Lora | Li, Jie | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Meng, Shaowu | Meyerson, Matthew | Mieczkowski, Piotr A. | Moore, Richard A. | Morton, Donna | Mose, Lisle E. | Mungall, Andrew J. | Muzny, Donna | Parker, Joel S. | Perou, Charles M. | Roach, Jeffrey | Schein, Jacqueline E. | Schumacher, Steven E. | Shi, Yan | Simons, Janae V. | Sipahimalani, Payal | Skelly, Tara | Soloway, Matthew G. | Sougnez, Carrie | Tam, Angela | Tan, Donghui | Thiessen, Nina | Veluvolu, Umadevi | Wang, Min | Wilkerson, Matthew D. | Wong, Tina | Wu, Junyuan | Xi, Liu | Zhou, Jane | Bedford, Jason | Chen, Fengju | Fu, Yao | Gerstein, Mark | Haussler, David | Kasaian, Katayoon | Lai, Phillip | Ling, Shiyun | Radenbaugh, Amie | Van Den Berg, David | Weinstein, John N. | Zhu, Jingchun | Albert, Monique | Alexopoulou, Iakovina | Andersen, Jeremiah J | Auman, J. Todd | Bartlett, John | Bastacky, Sheldon | Bergsten, Julie | Blute, Michael L. | Boice, Lori | Bollag, Roni J. | Boyd, Jeff | Castle, Erik | Chen, Ying-Bei | Cheville, John C. | Curley, Erin | Davies, Benjamin | DeVolk, April | Dhir, Rajiv | Dike, Laura | Eckman, John | Engel, Jay | Harr, Jodi | Hrebinko, Ronald | Huang, Mei | Huelsenbeck-Dill, Lori | Iacocca, Mary | Jacobs, Bruce | Lobis, Michael | Maranchie, Jodi K. | McMeekin, Scott | Myers, Jerome | Nelson, Joel | Parfitt, Jeremy | Parwani, Anil | Petrelli, Nicholas | Rabeno, Brenda | Roy, Somak | Salner, Andrew L. | Slaton, Joel | Stanton, Melissa | Thompson, R. Houston | Thorne, Leigh | Tucker, Kelinda | Weinberger, Paul M. | Winemiller, Cythnia | Zach, Leigh Anne | Zuna, Rosemary
The New England journal of medicine  2015;374(2):135-145.
Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal cell carcinoma; no effective forms of therapy for advanced disease exist.
We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas.
Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene.
Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features.
PMCID: PMC4775252  PMID: 26536169
4.  Safe Integration of Nelarabine into Intensive Chemotherapy in Newly Diagnosed T-cell Acute Lymphoblastic Leukemia: Children’s Oncology Group Study AALL0434 
Pediatric blood & cancer  2015;62(7):1176-1183.
Nelarabine has shown impressive single agent clinical activity in T-cell acute lymphoblastic leukemia (T-ALL), but has been associated with significant neurotoxicities in heavily pre-treated patients. We showed previously that it was safe to add nelarabine to a BFM-86 chemotherapy backbone (AALL00P2). Children’s Oncology Group (COG) AALL0434 is a Phase III study designed to test the safety and efficacy of nelarabine when incorporated into a COG augmented BFM-based regimen, which increases exposure to agents with potential neurotoxicity compared to the historical AALL00P2 regimen.
AALL0434 included a safety phase to assess nelarabine toxicity. Patients with high-risk (HR) T-ALL were randomized to receive Capizzi-style escalating methotrexate (MTX) plus pegaspargase or high dose (HD) MTX with/without six five-day courses of nelarabine. We report results from 94 patients who participated in the initial safety phase of the study.
There were no differences in the incidence of peripheral motor neuropathies, sensory neuropathies or central neurotoxicities among those randomized to the nelarabine (n = 47) and non-nelarabine arms (n = 47).
The addition of nelarabine to COG-augmented BFM chemotherapy regimen is safe and feasible. The ongoing AALL0434 Efficacy Phase will determine whether the addition of nelarabine treatment improves outcome for patients with T-ALL.
PMCID: PMC4433576  PMID: 25755211
Nelarabine; T-ALL; BFM chemotherapy regimen
5.  Germline TP53 Variants and Susceptibility to Osteosarcoma 
The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ2 tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants.
PMCID: PMC4651039  PMID: 25896519
6.  Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Study AALL07P4 
Journal of Clinical Oncology  2014;32(34):3874-3882.
Asparaginase is a critical agent used to treat acute lymphoblastic leukemia (ALL). Pegaspargase (SS-PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker, is the first-line asparaginase product used in Children's Oncology Group (COG) ALL trials. Calaspargase pegol (SC-PEG) replaces the SS linker in SS-PEG with a succinimidyl carbamate linker, creating a more stable molecule. COG AALL07P4 was designed to determine the pharmacokinetic and pharmacodynamic comparability of SC-PEG to SS-PEG in patients with newly diagnosed high-risk (HR) B-cell ALL.
Patients and Methods
A total of 165 evaluable patients were randomly assigned at a 2:1 ratio to receive SC-PEG at 2,100 (SC-PEG2100; n = 69) or 2,500 IU/m2 (SC-PEG2500; n = 42) versus SS-PEG 2,500 IU/m2 (SS-PEG2500; n = 54) as part of an otherwise identical chemotherapy regimen. The groups were similar demographically, except more female patients received SC-PEG2500.
The mean half-life of plasma asparaginase activity for both SC-PEG doses was approximately 2.5× longer than that of SS-PEG2500. The total systemic exposure, as defined by induction area under the curve from time 0 to 25 days, was greater with SC-PEG2500 than with SS-PEG2500 or SC-PEG2100. The proportion of patients with plasma asparaginase activity ≥ 100 mIU/mL and ≥ 400 mIU/mL was higher in patients who received SC-PEG as compared with SS-PEG2500. After one dose of pegylated asparaginase on induction day 4, plasma asparagine was undetectable for 11 days for SS-PEG2500 and 18 days for both SC-PEG groups.
SC-PEG2500 achieves a significantly longer period of asparaginase activity above defined thresholds and asparagine depletion compared with SS-PEG2500 and has a comparable toxicity profile in children with HR B-cell ALL.
PMCID: PMC4239306  PMID: 25348002
7.  Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations 
Nature genetics  2015;47(8):864-871.
The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK signaling pathway. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide the rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.
PMCID: PMC4775079  PMID: 26121087
8.  Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors 
Cancer cell  2015;27(2):286-297.
We report the most common single nucleotide substitution/deletion mutations in Favorable Histology Wilms Tumors (FHWT) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPG) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG-mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.
PMCID: PMC4800737  PMID: 25670082
9.  A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma 
Cancer discovery  2015;5(9):920-931.
Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified a SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P=1.2×10−9, OR 2.43, 95% CI 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had lowered Nfib expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis, and that NFIB is an osteosarcoma metastasis susceptibility gene.
PMCID: PMC4560660  PMID: 26084801
osteosarcoma; metastasis; genome-wide association study
10.  MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours 
Nature Communications  2015;6:10013.
Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour.
Wilms tumour is a rare renal neoplasm that primarily affects children but the genomic changes responsible for its development are currently largely unknown. In this study, the authors identify somatic mutations of the MLLT1 gene that are potentially involved in the aetiology of a subset of Wilms tumours.
PMCID: PMC4686660  PMID: 26635203
11.  Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33 
Wang, Zhaoming | Zhu, Bin | Zhang, Mingfeng | Parikh, Hemang | Jia, Jinping | Chung, Charles C. | Sampson, Joshua N. | Hoskins, Jason W. | Hutchinson, Amy | Burdette, Laurie | Ibrahim, Abdisamad | Hautman, Christopher | Raj, Preethi S. | Abnet, Christian C. | Adjei, Andrew A. | Ahlbom, Anders | Albanes, Demetrius | Allen, Naomi E. | Ambrosone, Christine B. | Aldrich, Melinda | Amiano, Pilar | Amos, Christopher | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Arici, Cecilia | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Beane Freeman, Laura E. | Berg, Christine D. | Berndt, Sonja I. | Bertazzi, Pier Alberto | Biritwum, Richard B. | Black, Amanda | Blot, William | Boeing, Heiner | Boffetta, Paolo | Bolton, Kelly | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brennan, Paul | Brinton, Louise A. | Brotzman, Michelle | Bueno-de-Mesquita, H. Bas | Buring, Julie E. | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Cao, Guangwen | Caporaso, Neil E. | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chang, Gee-Chen | Chang, I-Shou | Chang-Claude, Jenny | Che, Xu | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chung-Hsing | Chen, Constance | Chen, Kuan-Yu | Chen, Yuh-Min | Chokkalingam, Anand P. | Chu, Lisa W. | Clavel-Chapelon, Francoise | Colditz, Graham A. | Colt, Joanne S. | Conti, David | Cook, Michael B. | Cortessis, Victoria K. | Crawford, E. David | Cussenot, Olivier | Davis, Faith G. | De Vivo, Immaculata | Deng, Xiang | Ding, Ti | Dinney, Colin P. | Di Stefano, Anna Luisa | Diver, W. Ryan | Duell, Eric J. | Elena, Joanne W. | Fan, Jin-Hu | Feigelson, Heather Spencer | Feychting, Maria | Figueroa, Jonine D. | Flanagan, Adrienne M. | Fraumeni, Joseph F. | Freedman, Neal D. | Fridley, Brooke L. | Fuchs, Charles S. | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Garcia-Closas, Reina | Gastier-Foster, Julie M. | Gaziano, J. Michael | Gerhard, Daniela S. | Giffen, Carol A. | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gonzalez, Carlos | Gorlick, Richard | Greene, Mark H. | Gross, Myron | Grossman, H. Barton | Grubb, Robert | Gu, Jian | Guan, Peng | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Hartge, Patricia | Hattinger, Claudia | Hayes, Richard B. | He, Qincheng | Helman, Lee | Henderson, Brian E. | Henriksson, Roger | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hosgood, H. Dean | Hsiao, Chin-Fu | Hsing, Ann W. | Hsiung, Chao Agnes | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Hunter, David J. | Inskip, Peter D. | Ito, Hidemi | Jacobs, Eric J. | Jacobs, Kevin B. | Jenab, Mazda | Ji, Bu-Tian | Johansen, Christoffer | Johansson, Mattias | Johnson, Alison | Kaaks, Rudolf | Kamat, Ashish M. | Kamineni, Aruna | Karagas, Margaret | Khanna, Chand | Khaw, Kay-Tee | Kim, Christopher | Kim, In-Sam | Kim, Jin Hee | Kim, Yeul Hong | Kim, Young-Chul | Kim, Young Tae | Kang, Chang Hyun | Jung, Yoo Jin | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert | Kogevinas, Manolis | Koh, Woon-Puay | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kratz, Christian P. | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kurucu, Nilgun | Lan, Qing | Lathrop, Mark | Lau, Ching C. | Lecanda, Fernando | Lee, Kyoung-Mu | Lee, Maxwell P. | Le Marchand, Loic | Lerner, Seth P. | Li, Donghui | Liao, Linda M. | Lim, Wei-Yen | Lin, Dongxin | Lin, Jie | Lindstrom, Sara | Linet, Martha S. | Lissowska, Jolanta | Liu, Jianjun | Ljungberg, Börje | Lloreta, Josep | Lu, Daru | Ma, Jing | Malats, Nuria | Mannisto, Satu | Marina, Neyssa | Mastrangelo, Giuseppe | Matsuo, Keitaro | McGlynn, Katherine A. | McKean-Cowdin, Roberta | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Meltzer, Paul S. | Mensah, James E. | Miao, Xiaoping | Michaud, Dominique S. | Mondul, Alison M. | Moore, Lee E. | Muir, Kenneth | Niwa, Shelley | Olson, Sara H. | Orr, Nick | Panico, Salvatore | Park, Jae Yong | Patel, Alpa V. | Patino-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Pu, Xia | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Riboli, Elio | Risch, Harvey A. | Rodabough, Rebecca J. | Rothman, Nathaniel | Ruder, Avima M. | Ryu, Jeong-Seon | Sanson, Marc | Schned, Alan | Schumacher, Fredrick R. | Schwartz, Ann G. | Schwartz, Kendra L. | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Severi, Gianluca | Shen, Hongbing | Shen, Min | Shete, Sanjay | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesumaga, Luis | Sierri, Sabina | Loon Sihoe, Alan Dart | Silverman, Debra T. | Simon, Matthias | Southey, Melissa C. | Spector, Logan | Spitz, Margaret | Stampfer, Meir | Stattin, Par | Stern, Mariana C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael Z. | Stram, Daniel O. | Strom, Sara S. | Su, Wu-Chou | Sund, Malin | Sung, Sook Whan | Swerdlow, Anthony | Tan, Wen | Tanaka, Hideo | Tang, Wei | Tang, Ze-Zhang | Tardon, Adonina | Tay, Evelyn | Taylor, Philip R. | Tettey, Yao | Thomas, David M. | Tirabosco, Roberto | Tjonneland, Anne | Tobias, Geoffrey S. | Toro, Jorge R. | Travis, Ruth C. | Trichopoulos, Dimitrios | Troisi, Rebecca | Truelove, Ann | Tsai, Ying-Huang | Tucker, Margaret A. | Tumino, Rosario | Van Den Berg, David | Van Den Eeden, Stephen K. | Vermeulen, Roel | Vineis, Paolo | Visvanathan, Kala | Vogel, Ulla | Wang, Chaoyu | Wang, Chengfeng | Wang, Junwen | Wang, Sophia S. | Weiderpass, Elisabete | Weinstein, Stephanie J. | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolk, Alicja | Wolpin, Brian M. | Wong, Maria Pik | Wrensch, Margaret | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Yang, Hannah P. | Yang, Pan-Chyr | Yatabe, Yasushi | Ye, Yuanqing | Yeboah, Edward D. | Yin, Zhihua | Ying, Chen | Yu, Chong-Jen | Yu, Kai | Yuan, Jian-Min | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Mirabello, Lisa | Savage, Sharon A. | Kraft, Peter | Chanock, Stephen J. | Yeager, Meredith | Landi, Maria Terese | Shi, Jianxin | Chatterjee, Nilanjan | Amundadottir, Laufey T.
Human Molecular Genetics  2014;23(24):6616-6633.
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
PMCID: PMC4240198  PMID: 25027329
12.  PAX-FOXO1 Fusion Status Drives Unfavorable Outcome for Children With Rhabdomyosarcoma: A Children’s Oncology Group Report 
Pediatric blood & cancer  2013;60(9):1411-1417.
Rhabdomyosarcoma (RMS) is divided into two major histological subtypes: alveolar (ARMS) and embryonal (ERMS), with most ARMS expressing one of two oncogenic genes fusing PAX3 or PAX7 with FOXO1 (P3F and P7F, respectively). The Children’s Oncology Group (COG) carried out a multi-institutional clinical trial to evaluate the prognostic value of PAX-FOXO1 fusion status.
Study participants were treated on COG protocol D9803 for intermediate risk ARMS or ERMS using multi-agent chemotherapy, radiotherapy, and surgery. Central diagnostic pathology review and molecular testing for fusion genes were carried out on prospectively collected specimens. Event-free (EFS) and overall survival (OS) at 5 years were correlated with histological subtype and PAX-FOXO1 status.
Of 616 eligible D9803 enrollees, 434 cases had adequate clinical, molecular, and pathology data for definitive classification as ERMS, ARMS P3F+ or P7F+, or ARMSn (without detectable fusion). EFS was worse for those with ARMS P3F+ (54%) and P7F+ (65%) than those with ERMS (77%; P < 0.001). EFS for ARMSn and ERMS were not statistically different (90% vs. 77%, P = 0.15). ARMS P3F+had poorer OS (64%) than ARMS P7F+ (87%), ARMSn (89%), and ERMS (82%; P = 0.006).
ARMSn has an outcome similar to ERMS and superior EFS compared to ARMS with either P3F or P7F, when given therapy designed for children with intermediate risk RMS. This prospective analysis supports incorporation of PAX-FOXO1 fusion status into risk stratification and treatment allocation.
PMCID: PMC4646073  PMID: 23526739
PAX-FOXO1; rhabdomyosarcoma; survival
13.  Intrachromosomal Amplification of Chromosome 21 Is Associated With Inferior Outcomes in Children With Acute Lymphoblastic Leukemia Treated in Contemporary Standard-Risk Children's Oncology Group Studies: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2013;31(27):3397-3402.
Five-year overall survival (OS) for children with B-cell precursor acute lymphoblastic leukemia (B-ALL) exceeds 90% with risk-adapted therapy. Age, initial WBC count, genetic aberrations, and minimal residual disease (MRD) are used for risk stratification. Intrachromosomal amplification of a region of chromosome 21 (iAMP21; three or more extra copies of RUNX1 on an abnormal chromosome 21) is a recently identified recurrent genomic lesion associated with inferior outcome in some studies. We investigated the impact of iAMP21 in a large cohort treated in contemporary Children's Oncology Group (COG) ALL trials.
Patients and Methods
Fluorescent in situ hybridization for specific genetic aberrations was required at diagnosis. MRD was measured by flow cytometry at end induction. Outcome was measured as event-free survival (EFS) and OS.
iAMP21 was found in 158 (2%) of 7,793 patients with B-ALL age ≥ 1 year; 74 (1.5%) of 5,057 standard-risk (SR) patients, and 84 (3.1%) of 2,736 high-risk (HR) patients. iAMP21 was associated with age ≥ 10 years, WBC less than 50,000/μL, female sex, and detectable MRD at day 29. Four-year EFS and OS were significantly worse for patients with iAMP21 and SR B-ALL, but iAMP21 was not a statistically significant prognostic factor in HR patients. There was no interaction between MRD and iAMP21. Among SR patients, day 29 MRD ≥ 0.01% and iAMP21 were associated with the poorest EFS and OS; absence of both was associated with the best outcome.
iAMP21 is associated with inferior outcome in pediatric B-ALL, particularly SR patients who require more intensive therapy and are now treated on HR COG ALL protocols.
PMCID: PMC3770866  PMID: 23940221
14.  Dense Pattern of Embryonal Rhabdomyosarcoma, a Lesion Easily Confused With Alveolar Rhabdomyosarcoma 
To examine whether the frequency of fusion-negative alveolar rhabdomyosarcoma (ARMSn) increased coincident with changes in the definition of alveolar histology.
We re-reviewed alveolar rhabdomyosarcoma (ARMS) in the Children’s Oncology Group study D9803, comparing histopathology with fusion status.
Our review of 255 original ARMS cases (compared with a control group of 38 embryonal rhabdomyosarcomas [ERMS] cases) revealed that many had an ARMS-like densely cellular pattern with cytologic features and myogenin expression more typical of ERMS. Following re-review, 84 (33%) cases of original ARMS were rediagnosed as ERMS. All reclassified ERMS, including dense ERMS, were fusion negative, whereas 82% of confirmed ARMS cases were fusion positive. Total ARMS diagnoses returned to historic rates of 25% to 30% of all rhabdomyosarcomas, and ARMSn decreased from 37% to 18% of ARMS cases. The outcome of reclassified ERMS was similar to confirmed ERMS.
To address the role of fusion status in risk stratification, pathologists should include both a histologic diagnosis and an evaluation of fusion status for all new ARMS diagnoses.
PMCID: PMC4624292  PMID: 23765537
Alveolar rhabdomyosarcoma; Embryonal rhabdomyosarcoma; Histologic classification; Rhabdomyosarcoma; Myogenin
15.  Integrated Genomic Characterization of Papillary Thyroid Carcinoma 
Agrawal, Nishant | Akbani, Rehan | Aksoy, B. Arman | Ally, Adrian | Arachchi, Harindra | Asa, Sylvia L. | Auman, J. Todd | Balasundaram, Miruna | Balu, Saianand | Baylin, Stephen B. | Behera, Madhusmita | Bernard, Brady | Beroukhim, Rameen | Bishop, Justin A. | Black, Aaron D. | Bodenheimer, Tom | Boice, Lori | Bootwalla, Moiz S. | Bowen, Jay | Bowlby, Reanne | Bristow, Christopher A. | Brookens, Robin | Brooks, Denise | Bryant, Robert | Buda, Elizabeth | Butterfield, Yaron S.N. | Carling, Tobias | Carlsen, Rebecca | Carter, Scott L. | Carty, Sally E. | Chan, Timothy A. | Chen, Amy Y. | Cherniack, Andrew D. | Cheung, Dorothy | Chin, Lynda | Cho, Juok | Chu, Andy | Chuah, Eric | Cibulskis, Kristian | Ciriello, Giovanni | Clarke, Amanda | Clayman, Gary L. | Cope, Leslie | Copland, John | Covington, Kyle | Danilova, Ludmila | Davidsen, Tanja | Demchok, John A. | DiCara, Daniel | Dhalla, Noreen | Dhir, Rajiv | Dookran, Sheliann S. | Dresdner, Gideon | Eldridge, Jonathan | Eley, Greg | El-Naggar, Adel K. | Eng, Stephanie | Fagin, James A. | Fennell, Timothy | Ferris, Robert L. | Fisher, Sheila | Frazer, Scott | Frick, Jessica | Gabriel, Stacey B. | Ganly, Ian | Gao, Jianjiong | Garraway, Levi A. | Gastier-Foster, Julie M. | Getz, Gad | Gehlenborg, Nils | Ghossein, Ronald | Gibbs, Richard A. | Giordano, Thomas J. | Gomez-Hernandez, Karen | Grimsby, Jonna | Gross, Benjamin | Guin, Ranabir | Hadjipanayis, Angela | Harper, Hollie A. | Hayes, D. Neil | Heiman, David I. | Herman, James G. | Hoadley, Katherine A. | Hofree, Matan | Holt, Robert A. | Hoyle, Alan P. | Huang, Franklin W. | Huang, Mei | Hutter, Carolyn M. | Ideker, Trey | Iype, Lisa | Jacobsen, Anders | Jefferys, Stuart R. | Jones, Corbin D. | Jones, Steven J.M. | Kasaian, Katayoon | Kebebew, Electron | Khuri, Fadlo R. | Kim, Jaegil | Kramer, Roger | Kreisberg, Richard | Kucherlapati, Raju | Kwiatkowski, David J. | Ladanyi, Marc | Lai, Phillip H. | Laird, Peter W. | Lander, Eric | Lawrence, Michael S. | Lee, Darlene | Lee, Eunjung | Lee, Semin | Lee, William | Leraas, Kristen M. | Lichtenberg, Tara M. | Lichtenstein, Lee | Lin, Pei | Ling, Shiyun | Liu, Jinze | Liu, Wenbin | Liu, Yingchun | LiVolsi, Virginia A. | Lu, Yiling | Ma, Yussanne | Mahadeshwar, Harshad S. | Marra, Marco A. | Mayo, Michael | McFadden, David G. | Meng, Shaowu | Meyerson, Matthew | Mieczkowski, Piotr A. | Miller, Michael | Mills, Gordon | Moore, Richard A. | Mose, Lisle E. | Mungall, Andrew J. | Murray, Bradley A. | Nikiforov, Yuri E. | Noble, Michael S. | Ojesina, Akinyemi I. | Owonikoko, Taofeek K. | Ozenberger, Bradley A. | Pantazi, Angeliki | Parfenov, Michael | Park, Peter J. | Parker, Joel S. | Paull, Evan O. | Pedamallu, Chandra Sekhar | Perou, Charles M. | Prins, Jan F. | Protopopov, Alexei | Ramalingam, Suresh S. | Ramirez, Nilsa C. | Ramirez, Ricardo | Raphael, Benjamin J. | Rathmell, W. Kimryn | Ren, Xiaojia | Reynolds, Sheila M. | Rheinbay, Esther | Ringel, Matthew D. | Rivera, Michael | Roach, Jeffrey | Robertson, A. Gordon | Rosenberg, Mara W. | Rosenthall, Matthew | Sadeghi, Sara | Saksena, Gordon | Sander, Chris | Santoso, Netty | Schein, Jacqueline E. | Schultz, Nikolaus | Schumacher, Steven E. | Seethala, Raja R. | Seidman, Jonathan | Senbabaoglu, Yasin | Seth, Sahil | Sharpe, Samantha | Mills Shaw, Kenna R. | Shen, John P. | Shen, Ronglai | Sherman, Steven | Sheth, Margi | Shi, Yan | Shmulevich, Ilya | Sica, Gabriel L. | Simons, Janae V. | Sipahimalani, Payal | Smallridge, Robert C. | Sofia, Heidi J. | Soloway, Matthew G. | Song, Xingzhi | Sougnez, Carrie | Stewart, Chip | Stojanov, Petar | Stuart, Joshua M. | Tabak, Barbara | Tam, Angela | Tan, Donghui | Tang, Jiabin | Tarnuzzer, Roy | Taylor, Barry S. | Thiessen, Nina | Thorne, Leigh | Thorsson, Vésteinn | Tuttle, R. Michael | Umbricht, Christopher B. | Van Den Berg, David J. | Vandin, Fabio | Veluvolu, Umadevi | Verhaak, Roel G.W. | Vinco, Michelle | Voet, Doug | Walter, Vonn | Wang, Zhining | Waring, Scot | Weinberger, Paul M. | Weinstein, John N. | Weisenberger, Daniel J. | Wheeler, David | Wilkerson, Matthew D. | Wilson, Jocelyn | Williams, Michelle | Winer, Daniel A. | Wise, Lisa | Wu, Junyuan | Xi, Liu | Xu, Andrew W. | Yang, Liming | Yang, Lixing | Zack, Travis I. | Zeiger, Martha A. | Zeng, Dong | Zenklusen, Jean Claude | Zhao, Ni | Zhang, Hailei | Zhang, Jianhua | Zhang, Jiashan (Julia) | Zhang, Wei | Zmuda, Erik | Zou., Lihua
Cell  2014;159(3):676-690.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
PMCID: PMC4243044  PMID: 25417114
16.  Neuroblastoma - Undifferentiated Subtype, Prognostic Significance of Prominent Nucleolar Formation and MYC/MYCN Protein Expression: A Report from the Children’s Oncology Group 
Cancer  2013;119(20):3718-3726.
To investigate biological/clinicopathological characteristics of neuroblastoma, undifferentiated subtype (NBUD).
Patients and Methods
157 NBUD cases filed at the Children’s Oncology Group Neuroblastoma Pathology Reference Laboratory were studied, and survival rates of the patients were analyzed with known prognostic factors. Immunostainings for MYCN and MYC protein were performed on 68 tumors.
NBUD cases had a poor prognosis (48.4±5.0% 3-year event-free survival [EFS]; 56.5±5.0% overall survival), and were often associated with high Mitosis-Karyorrhexis Index (MKI, 65%), prominent nucleoli (PN, 83%), ≥18months of age (75%), MYCN amplification (MYCN-A, 83%), diploid pattern (63%), and 1pLOH (loss of heterozygosity, 72%). However, these prognostic indicators, except for MYCN status, had no significant impact on survival. Surprisingly, EFS for patients with MYCN-A tumors (53.4±5.6%) was significantly better (P=0.0248) than for patients with MYCN-Non-Amplified (MYCN-NA) tumors (31.7±11.7%), with MYCN-NA and PN (+) tumors having the worst prognosis (9.3+8.8%, p=0.0045). Immunohistochemically, MYCN expression was found in 42/48 MYCN-A tumors. In contrast, MYC expression was almost exclusively found in the MYCN-NA tumors (9/20) especially when they had PN (8/11). Those patients with only MYC-positive tumors had the worst EFS (N=8, 12.5±11.7%) compared with only MYCN-positive (N=39, 49.9±17.7%) and both negative tumors (N=15, 70.0±17.1%) (P=0.0029). High MKI was often found in only MYCN-positive (30/38) but rarely in only MYC-positive (2/8) tumors.
NBUD represents a unique subtype of neuroblastoma associated with a poor prognosis. In this subtype, MYC protein expression may be a new prognostic factor indicating more aggressive clinical behavior than MYCN amplification and subsequent MYCN protein expression.
PMCID: PMC4554323  PMID: 23901000
Neuroblastoma; undifferentiated subtype; MYCN Amplification; MYC/MYCN expression; prognostic factors; MYC gene expression
17.  Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children 
Nature Communications  2015;6:7553.
There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10−23, odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16INK4A, increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A–CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A–CDKN2B tumour suppressors in leukaemogenesis.
Genome-wide association studies indicate a strong genetic susceptibility to acute lymphoblastic leukaemia in children, though the effect on protein-coding genes is not fully understood. Here Xu and Zhang et al. identify a missense variant in CDKN2A which reduces tumour suppression.
PMCID: PMC4544058  PMID: 26104880
18.  TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney 
Oncotarget  2015;6(18):15828-15841.
Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified. One tumor with t(10;17)(q22;p13) involving fusion of YHWAE with NUTM2B was identified. Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10;17)(q22;p13). TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples. The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. Future studies are needed to functionally verify a tumorigenic role of TCF21 down-regulation and to tie this to the unique gene expression pattern of CCSK.
PMCID: PMC4599240  PMID: 26158413
clear cell sarcoma of the kidney; whole genome sequencing; methylation; TCF21; TARID
19.  Myogenin, AP2β, NOS-1 and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma 
Pediatric rhabdomyosarcoma (RMS) is traditionally classified by histologic appearance into alveolar (ARMS) and embryonal (ERMS) subtypes. The majority of ARMS contain a PAX3-FOXO1 or PAX7-FOXO1 gene fusion, but about 20% do not. Intergroup Rhabdomyosarcoma Study (IRS) Stage and group-matched ARMS typically behaves more aggressively than the embryonal subtype, but recent studies have shown that it is, in fact, fusion status that drives outcome for RMS. Gene expression microarray data indicate that several genes discriminate between fusion positive and fusion negative RMS with high specificity. Using tissue microarrays containing a series of both ARMS and ERMS, we identified a panel of four immunohistochemical markers, myogenin, AP2β, NOS-1 and HMGA2, which can be used as surrogate markers of fusion status in RMS. These antibodies provide an alternative to molecular methods for identification of fusion positive RMS, particularly in cases where there is scant or poor quality material. Additionally, these antibodies, may be useful in fusion negative ARMS as an indicator that a variant gene fusion may be present.
PMCID: PMC4010390  PMID: 24618610
rhabdomyosarcoma; fusion status; immunohistochemistry
20.  Rise and fall of subclones from diagnosis to relapse in Pediatric B-Acute Lymphoblastic Leukemia 
Nature communications  2015;6:6604.
There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of leukemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in 9 cases, with mutations in 4 cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
PMCID: PMC4377644  PMID: 25790293
21.  Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia 
Nature Communications  2015;6:6604.
There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
Genetic heterogeneity and clonal evolution contribute to cancer progression. Here Ma et al. use deep whole-exome sequencing to identify recurrently mutated pathways and clonal architecture in pediatric acute lymphoblastic leukaemia, shedding light on the evolutionary trajectory from diagnosis to relapse
PMCID: PMC4377644  PMID: 25790293
22.  Variability in pathogenicity prediction programs: impact on clinical diagnostics 
Current practice by clinical diagnostic laboratories is to utilize online prediction programs to help determine the significance of novel variants in a given gene sequence. However, these programs vary widely in their methods and ability to correctly predict the pathogenicity of a given sequence change. The performance of 17 publicly available pathogenicity prediction programs was assayed using a dataset consisting of 122 credibly pathogenic and benign variants in genes associated with the RASopathy family of disorders and limb-girdle muscular dystrophy. Performance metrics were compared between the programs to determine the most accurate program for loss-of-function and gain-of-function mechanisms. No one program correctly predicted the pathogenicity of all variants analyzed. A major hindrance to the analysis was the lack of output from a significant portion of the programs. The best performer was MutPred, which had a weighted accuracy of 82.6% in the full dataset. Surprisingly, combining the results of the top three programs did not increase the ability to predict pathogenicity over the top performer alone. As the increasing number of sequence changes in larger datasets will require interpretation, the current study demonstrates that extreme caution must be taken when reporting pathogenicity based on statistical online protein prediction programs in the absence of functional studies.
PMCID: PMC4367082  PMID: 25802880
Diagnostics; pathogenicity; prediction; sequencing; variants
23.  Age-Dependent Prognostic Effect by Mitosis-Karyorrhexis Index in Neuroblastoma: A Report from the Children’s Oncology Group 
Prognostic effects of Mitosis-Karyorrhexis Index (MKI) used in the International Neuroblastoma Pathology Classification (INPC) are age-dependent. A total of 4,282 neuroblastomas reviewed at the Children’s Oncology Group Neuroblastoma Pathology Reference Laboratory (8/1/2001–3/31/2012) included 2,365 low-MKI (L-MKI), 1,068 intermediate-MKI (I-MKI), and 849 high-MKI (H-MKI) tumors. Cox proportional hazards models were fit to determine age cut-offs at which the relative risk of event/death was maximized in each MKI class. Backward-selected Cox models were fit to determine the prognostic strength of the age cut-offs for survival in the presence of other prognostic factors. The age cut-offs used in the INPC for L-MKI tumors (<60 months, n = 2,710, 84.0% ± 1.0% event-free survival [EFS], 93.8 ± 0.7% overall survival [OS] vs ≥60 months, n = 195, 49.8% ± 4.6% EFS, 71.7% ± 4.1% OS; P < 0.0001) and I-MKI tumors (<18 months, n = 568, 83.8% ± 2% EFS, 93.7% ± 1.3% OS vs ≥18 months, n = 500, 51.4% ± 2.9% EFS, 66.7% ± 2.7% OS; P < 0.0001) were within the effective range for distinguishing prognostic groups. As for H-MKI tumors (no cut-off age in the INPC, 51.0% ± 2.2% EFS, 64.4% ± 2.1% OS), a new cut-off of 3–4 months was suggested (<4 months, n = 38, 82.3% ± 8.4% EFS, 81.8% ± 8.5% OS vs ≥4 months, n = 811, 49.6% ± 2.2% EFS, 63.7% ± 2.1% OS, P = 0.0034 and 0.0437, respectively). Multivariate analyses revealed that cut-offs of 60 and 18 months for L-MKI and I-MKI tumors, respectively, were independently prognostic. However, the cut-off of 4 months for H-MKI tumors did not reach statistical significance in the presence of other factors. The age cut-offs for MKI classes (60 months for L-MKI, 18 months for I-MKI, no cut-off for H-MKI) in the current INPC are reasonable and effective for distinguishing prognostic groups with increased risk of event/death for older patients.
PMCID: PMC4340697  PMID: 25207821
age cut-off; International Neuroblastoma Pathology Classification; mitosis-karyorrhexis index; neuroblastoma; prognosis
24.  Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster 
Recent studies have shown that certain copy number variations (CNV) are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorders (ASD), bipolar disorder and intellectual disabilities. Implicated regions and genes have comprised a variety of post synaptic complex proteins and neurotransmitter receptors, including gamma-amino butyric acid A (GABAA). Clusters of GABAA receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. We describe a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array comparative genomic hybridization, that contains 13 genes including a cluster of four GABAA receptor subunit genes. Fluorescent in-situ hybridization was used to confirm the duplication. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). In addition, we identified and describe another individual unrelated to this family, with a similar duplication, who was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. We hypothesize that the duplication acts through a dosage effect of GABAA receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders.
PMCID: PMC3865421  PMID: 23695283
autism; bipolar disorder; chromosome disorders; DNA copy number variation; intellectual disabilities; GABAA
25.  A novel algorithm for simplification of complex gene classifiers in cancer 
Cancer research  2013;73(18):5625-5632.
The clinical application of complex molecular classifiers as diagnostic or prognostic tools has been limited by the time and cost needed to apply them to patients. Using an existing fifty-gene expression signature known to separate two molecular subtypes of the pediatric cancer rhabdomyosarcoma, we show that an exhaustive iterative search algorithm can distill this complex classifier down to two or three features with equal discrimination. We validated the two-gene signatures using three separate and distinct data sets, including one that uses degraded RNA extracted from formalin-fixed, paraffin-embedded material. Finally, to demonstrate the generalizability of our algorithm, we applied it to a lung cancer data set to find minimal gene signatures that can distinguish survival. Our approach can easily be generalized and coupled to existing technical platforms to facilitate the discovery of simplified signatures that are ready for routine clinical use.
PMCID: PMC4233649  PMID: 23913937

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