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Grant Details

Grant Number: 3P01CA034936-22S2 Interpret this number
Primary Investigator: Strong, Louise
Organization: University Of Tx Md Anderson Can Ctr
Project Title: A Mutational Model for Childhood Cancer
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): The overall goal of the program is to identify genes that predispose to childhood cancer, the molecular pathways to tumor development, and the clinical implications. We have focused on two model familial syndromes of childhood and adolescent cancers, sarcomas and Li Fraumeni Syndrome (LFS) and its variants, and Wilms' tumor of the kidney. We have developed a multidisciplinary program to investigate genetic susceptibility to childhood and associated cancer using integrated technology of genetic epidemiology, molecular genetics and genomics applied to the rich resources of cancer prone families and mouse models developed in this program. The hypotheses are based on a multi-stage model for cancer. For each tumor type, genetic loci have been identified that may be altered both as germline mutations and as tumor-specific mutations. There is also significant evidence for additional cancer susceptibility genes and risk modifiers, including an effect of generation, at least for LFS. The underlying themes of the program include identification of the underlying cancer susceptibility genes and risk modifiers, analysis of germline and somatic mutations by type and mechanism, determination of the molecular genetic anatomy of the tumors, development of animal models for human cancer susceptibility syndromes, determination of the role of telomere function in cancer risk in LFS and mouse models, and determination of the implications of germline mutations for the patients and their families. The findings from this program should provide insights into the mechanisms of carcinogenesis as well as guidelines for clinical programs for patients at high risk of cancer.

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Publications

?-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma.
Authors: Mokkapati S, Niopek K, Huang L, Cunniff KJ, Ruteshouser EC, deCaestecker M, Finegold MJ, Huff V
Source: Cancer Res, 2014 Aug 15;74(16), p. 4515-25.
EPub date: 2014 May 21.
PMID: 24848510
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Ubiquitin specific protease 18 (Usp18) is a WT1 transcriptional target.
Authors: Shahidul Makki M, Cristy Ruteshouser E, Huff V
Source: Exp Cell Res, 2013 Mar 10;319(5), p. 612-22.
EPub date: 2013 Jan 2.
PMID: 23291318
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Left-sided cryptorchidism in mice with Wilms' tumour 1 gene deletion in gubernaculum testis.
Authors: Kaftanovskaya EM, Neukirchner G, Huff V, Agoulnik AI
Source: J Pathol, 2013 May;230(1), p. 39-47.
EPub date: 2013 Mar 12.
PMID: 23288785
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Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor: a Children's Oncology Group Study.
Authors: Gadd S, Huff V, Huang CC, Ruteshouser EC, Dome JS, Grundy PE, Breslow N, Jennings L, Green DM, Beckwith JB, Perlman EJ
Source: Neoplasia, 2012 Aug;14(8), p. 742-56.
PMID: 22952427
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p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer.
Authors: Jackson JG, Pant V, Li Q, Chang LL, Quintás-Cardama A, Garza D, Tavana O, Yang P, Manshouri T, Li Y, El-Naggar AK, Lozano G
Source: Cancer Cell, 2012 Jun 12;21(6), p. 793-806.
PMID: 22698404
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Multiple stress signals activate mutant p53 in vivo.
Authors: Suh YA, Post SM, Elizondo-Fraire AC, Maccio DR, Jackson JG, El-Naggar AK, Van Pelt C, Terzian T, Lozano G
Source: Cancer Res, 2011 Dec 1;71(23), p. 7168-75.
EPub date: 2011 Oct 7.
PMID: 21983037
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Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation.
Authors: Wang Y, Suh YA, Fuller MY, Jackson JG, Xiong S, Terzian T, Quintás-Cardama A, Bankson JA, El-Naggar AK, Lozano G
Source: J Clin Invest, 2011 Mar;121(3), p. 893-904.
PMID: 21285512
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Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene.
Authors: Huff V
Source: Nat Rev Cancer, 2011 Feb;11(2), p. 111-21.
EPub date: 2011 Jan 20.
PMID: 21248786
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Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation.
Authors: Hu Q, Gao F, Tian W, Ruteshouser EC, Wang Y, Lazar A, Stewart J, Strong LC, Behringer RR, Huff V
Source: J Clin Invest, 2011 Jan;121(1), p. 174-83.
EPub date: 2010 Dec 1.
PMID: 21123950
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Methylation of the candidate biomarker TCF21 is very frequent across a spectrum of early-stage nonsmall cell lung cancers.
Authors: Richards KL, Zhang B, Sun M, Dong W, Churchill J, Bachinski LL, Wilson CD, Baggerly KA, Yin G, Hayes DN, Wistuba II, Krahe R
Source: Cancer, 2011 Feb 1;117(3), p. 606-17.
EPub date: 2010 Oct 13.
PMID: 20945327
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A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development.
Authors: Post SM, Quintás-Cardama A, Pant V, Iwakuma T, Hamir A, Jackson JG, Maccio DR, Bond GL, Johnson DG, Levine AJ, Lozano G
Source: Cancer Cell, 2010 Sep 14;18(3), p. 220-30.
PMID: 20832750
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Evolutionary evidence of the effect of rare variants on disease etiology.
Authors: Gorlov IP, Gorlova OY, Frazier ML, Spitz MR, Amos CI
Source: Clin Genet, 2011 Mar;79(3), p. 199-206.
EPub date: 2010 Sep 10.
PMID: 20831747
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Psychological functioning in persons considering genetic counseling and testing for Li-Fraumeni syndrome.
Authors: Peterson SK, Pentz RD, Marani SK, Ward PA, Blanco AM, LaRue D, Vogel K, Solomon T, Strong LC
Source: Psychooncology, 2008 Aug;17(8), p. 783-9.
PMID: 18688785
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The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss.
Authors: Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA, Van Pelt CS, Lozano G
Source: Genes Dev, 2008 May 15;22(10), p. 1337-44.
PMID: 18483220
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Wt1 negatively regulates beta-catenin signaling during testis development.
Authors: Chang H, Gao F, Guillou F, Taketo MM, Huff V, Behringer RR
Source: Development, 2008 May;135(10), p. 1875-85.
EPub date: 2008 Apr 9.
PMID: 18403409
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Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors.
Authors: Ruteshouser EC, Robinson SM, Huff V
Source: Genes Chromosomes Cancer, 2008 Jun;47(6), p. 461-70.
PMID: 18311776
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Statistical methods for anomalous discrete time series based on minimum cell count.
Authors: Wu CC, Grimson RC, Amos CI, Shete S
Source: Biom J, 2008 Feb;50(1), p. 86-96.
PMID: 17853406
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Successful design and conduct of genome-wide association studies.
Authors: Amos CI
Source: Hum Mol Genet, 2007 Oct 15;16 Spec No. 2, p. R220-5.
EPub date: 2007 Jun 27.
PMID: 17597095
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Mammary tumor modifiers in BALB/cJ mice heterozygous for p53.
Authors: Koch JG, Gu X, Han Y, El-Naggar AK, Olson MV, Medina D, Jerry DJ, Blackburn AC, Peltz G, Amos CI, Lozano G
Source: Mamm Genome, 2007 May;18(5), p. 300-9.
EPub date: 2007 Jun 8.
PMID: 17557176
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Crippling p53 activities via knock-in mutations in mouse models.
Authors: Iwakuma T, Lozano G
Source: Oncogene, 2007 Apr 2;26(15), p. 2177-84.
PMID: 17401426
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Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence.
Authors: Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, Chang S
Source: EMBO Rep, 2007 May;8(5), p. 497-503.
EPub date: 2007 Mar 30.
PMID: 17396137
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