|Grant Number:||5R01CA089032-06 Interpret this number|
|Primary Investigator:||Wiemels, Joseph|
|Organization:||University Of California, San Francisco|
|Project Title:||Backtracking Translocations in Childhood Leukemia|
DESCRIPTION (provided by applicant): Leukemia is the most common cancer among children and a significant cause of morbidity, stress, and long-term sequelae. Despite advances in treatment that permit a cure in the majority of leukemias, we still know very little about the causes of the disease, thwarting any attempt at prevention. Our focus is to describe in molecular detail the chromosomal and mutational changes that occur in leukemias, and use these genetic aberrations to develop tools to study the timing and causality of these events. Hitherto we have focused on translocations, finding that most but not all translocation subtypes have an in utero origin. The most common childhood translocation, t(12;21) TEL-AML1, occurs in 25% of childhood acute lymphocytic leukemia and usually, if not always, occurs before birth in children who later contract leukemia with this genetic aberration. We now propose to describe the secondary genetic events in TEL-AMLI+ leukemia, focusing first on the 12p deletion, which is a common (~75%) event in TEL-AMLI+ leukemia. We will use array-Comparative Genomic Hybridization (array-CGH) to define the exact breakpoints of 12p chromosomal deletions, allowing their cloning at the genomic nucleotide level. Next, we will use the cloned fusion junction as a probe to "backtrack" leukemia to birth, by searching for the presence of this genetic marker on neonatal heel-prick Guthrie cards from the same children that we have also sequenced and "backtracked" the genomic TEL-AML 1 translocation sequence. Thirdly, we will use 12p deletions along with TEL-AML 1 translocations to track the fate of the leukemia clone in children after therapy, thereby completing the story of the "natural history" of these genomic fusions and determining clinical utility of the novel markers. Lastly, we will assess the presence of putative tumor suppressor allele(s) that are indicated as allelic loss in array-CGH experiments. Preliminary results suggest the presence of more than one distinct deletion on 12p in some patients, demonstrating the complexity and discovery potential of this analysis. Our results will inform and guide the Northern California Childhood Leukemia Study, an epidemiological project from which all of our samples are derived. We are ultimately working to elucidate the origin and causes of a cancer that might be preventable.
TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a.
Authors: Diakos C, Zhong S, Xiao Y, Zhou M, Vasconcelos GM, Krapf G, Yeh RF, Zheng S, Kang M, Wiencke JK, Pombo-de-Oliveira MS, Panzer-Grümayer R, Wiemels JL
Source: Blood, 2010 Dec 2;116(23), p. 4885-93.
EPub date: 2010 Aug 31.
IgE, allergy, and risk of glioma: update from the San Francisco Bay Area Adult Glioma Study in the temozolomide era.
Authors: Wiemels JL, Wilson D, Patil C, Patoka J, McCoy L, Rice T, Schwartzbaum J, Heimberger A, Sampson JH, Chang S, Prados M, Wiencke JK, Wrensch M
Source: Int J Cancer, 2009 Aug 1;125(3), p. 680-7.
Chromosome 12p deletions in TEL-AML1 childhood acute lymphoblastic leukemia are associated with retrotransposon elements and occur postnatally.
Authors: Wiemels JL, Hofmann J, Kang M, Selzer R, Green R, Zhou M, Zhong S, Zhang L, Smith MT, Marsit C, Loh M, Buffler P, Yeh RF
Source: Cancer Res, 2008 Dec 1;68(23), p. 9935-44.
Adenovirus detection in Guthrie cards from paediatric leukaemia cases and controls.
Authors: Vasconcelos GM, Kang M, Pombo-de-Oliveira MS, Schiffman JD, Lorey F, Buffler P, Wiemels JL
Source: Br J Cancer, 2008 Nov 18;99(10), p. 1668-72.
EPub date: 2008 Oct 28.
The molecular anatomy of the FIP1L1-PDGFRA fusion gene.
Authors: Walz C, Score J, Mix J, Cilloni D, Roche-Lestienne C, Yeh RF, Wiemels JL, Ottaviani E, Erben P, Hochhaus A, Baccarani M, Grimwade D, Preudhomme C, Apperley J, Martinelli G, Saglio G, Cross NC, Reiter A, European LeukemiaNet
Source: Leukemia, 2009 Feb;23(2), p. 271-8.
EPub date: 2008 Nov 6.
NQO1 polymorphisms and de novo childhood leukemia: a HuGE review and meta-analysis.
Authors: Guha N, Chang JS, Chokkalingam AP, Wiemels JL, Smith MT, Buffler PA
Source: Am J Epidemiol, 2008 Dec 1;168(11), p. 1221-32.
EPub date: 2008 Oct 22.
Reproductive factors and hormone use and risk of adult gliomas.
Authors: Felini MJ, Olshan AF, Schroeder JC, Carozza SE, Miike R, Rice T, Wrensch M
Source: Cancer Causes Control, 2009 Feb;20(1), p. 87-96.
EPub date: 2008 Sep 3.
Pathway analysis of single-nucleotide polymorphisms potentially associated with glioblastoma multiforme susceptibility using random forests.
Authors: Chang JS, Yeh RF, Wiencke JK, Wiemels JL, Smirnov I, Pico AR, Tihan T, Patoka J, Miike R, Sison JD, Rice T, Wrensch MR
Source: Cancer Epidemiol Biomarkers Prev, 2008 Jun;17(6), p. 1368-73.
Allergy-related polymorphisms influence glioma status and serum IgE levels.
Authors: Wiemels JL, Wiencke JK, Kelsey KT, Moghadassi M, Rice T, Urayama KY, Miike R, Wrensch M
Source: Cancer Epidemiol Biomarkers Prev, 2007 Jun;16(6), p. 1229-35.
Nonsynonymous coding single-nucleotide polymorphisms spanning the genome in relation to glioblastoma survival and age at diagnosis.
Authors: Wrensch M, McMillan A, Wiencke J, Wiemels J, Kelsey K, Patoka J, Jones H, Carlton V, Miike R, Sison J, Moghadassi M, Prados M
Source: Clin Cancer Res, 2007 Jan 1;13(1), p. 197-205.
Serum IgE, tumor epidermal growth factor receptor expression, and inherited polymorphisms associated with glioma survival.
Authors: Wrensch M, Wiencke JK, Wiemels J, Miike R, Patoka J, Moghadassi M, McMillan A, Kelsey KT, Aldape K, Lamborn KR, Parsa AT, Sison JD, Prados MD
Source: Cancer Res, 2006 Apr 15;66(8), p. 4531-41.
Diagnostic, treatment, and demographic factors influencing survival in a population-based study of adult glioma patients in the San Francisco Bay Area.
Authors: Wrensch M, Rice T, Miike R, McMillan A, Lamborn KR, Aldape K, Prados MD
Source: Neuro Oncol, 2006 Jan;8(1), p. 12-26.
DNA topoisomerase II in therapy-related acute promyelocytic leukemia.
Authors: Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B, Parry A, Walz C, Wiemels JL, Segal MR, Adès L, Blair IA, Osheroff N, Peniket AJ, Lafage-Pochitaloff M, Cross NC, Chomienne C, Solomon E, Fenaux P, Grimwade D
Source: N Engl J Med, 2005 Apr 14;352(15), p. 1529-38.
RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia.
Authors: Wiemels JL, Zhang Y, Chang J, Zheng S, Metayer C, Zhang L, Smith MT, Ma X, Selvin S, Buffler PA, Wiencke JK
Source: Leukemia, 2005 Mar;19(3), p. 415-9.
Reduced immunoglobulin E and allergy among adults with glioma compared with controls.
Authors: Wiemels JL, Wiencke JK, Patoka J, Moghadassi M, Chew T, McMillan A, Miike R, Barger G, Wrensch M
Source: Cancer Res, 2004 Nov 15;64(22), p. 8468-73.
Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16).
Authors: McHale CM, Wiemels JL, Zhang L, Ma X, Buffler PA, Feusner J, Matthay K, Dahl G, Smith MT
Source: Blood, 2003 Jun 1;101(11), p. 4640-1.
Real-time quantitative PCR: standardized detection of minimal residual disease in pediatric acute lymphoblastic leukemia. Polymerase chain reaction.
Authors: Pine SR, Moy FH, Wiemels JL, Gill RK, Levendoglu-Tugal O, Ozkaynak MF, Sandoval C, Jayabose S
Source: J Pediatr Hematol Oncol, 2003 Feb;25(2), p. 103-8.
TEL-AML1 fusion precedes differentiation to pre-B cells in childhood acute lymphoblastic leukemia.
Authors: Pine SR, Wiemels JL, Jayabose S, Sandoval C
Source: Leuk Res, 2003 Feb;27(2), p. 155-64.
Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia.
Authors: Reiter A, Saussele S, Grimwade D, Wiemels JL, Segal MR, Lafage-Pochitaloff M, Walz C, Weisser A, Hochhaus A, Willer A, Reichert A, Büchner T, Lengfelder E, Hehlmann R, Cross NC
Source: Genes Chromosomes Cancer, 2003 Feb;36(2), p. 175-88.
In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia.
Authors: Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, Smith MT, Zhang L, Feusner J, Wiencke J, Pritchard-Jones K, Kempski H, Greaves M
Source: Blood, 2002 May 15;99(10), p. 3801-5.
History of allergies among adults with glioma and controls.
Authors: Wiemels JL, Wiencke JK, Sison JD, Miike R, McMillan A, Wrensch M
Source: Int J Cancer, 2002 Apr 1;98(4), p. 609-15.
Molecular characterization of genomic AML1-ETO fusions in childhood leukemia.
Authors: Xiao Z, Greaves MF, Buffler P, Smith MT, Segal MR, Dicks BM, Wiencke JK, Wiemels JL
Source: Leukemia, 2001 Dec;15(12), p. 1906-13.