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Grant Details

Grant Number: 5R21CA087691-02 Interpret this number
Primary Investigator: Haber, Daniel
Organization: Massachusetts General Hospital
Project Title: Mutational Analysis of P53 Related Genes
Fiscal Year: 2001
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Abstract

DESCRIPTION: (Applicant's Description) Germline mutations in p53 account for 60-70 percents of cases of Li-Fraumeni Syndrome (LFS), a familial cancer phenotype associated with breast cancer, sarcomas and other tumors. We hypothesize that LFS cases without p53 mutations may harbor mutations in other components of this DNA damage response pathway. Recent molecular studies have identified kinases that are involved in the phosphorylation and activation of p53, as well as other genes that modulate p53 stability, and its ability to mediate apoptosis. Cellular homologs of p53 have recently been identified, as have mammalian homologs of yeast cell cycle checkpoint genes that are critical to the DNA damage response pathway. The small size of LFS families makes classical linkage analysis difficult, and we therefore propose a candidate gene approach to identify the additional gene (s) responsible for LFS, using high throughput mutational detection techniques. We note that such gene (s) may be involved in both genetic predisposition to cancer and somatic tumorigenesis, but as for BRCAl and BRCA2, absence of somatic mutations does not exclude the possibility of gennline mutations, requiring mutational analysis both in germline and tumor specimens. We propose a phased approach: initially we will undertake mutational analysis in a highly selected cohort of patients with LFS or variant multi-cancer syndromes that do not have mutations in p53. The absence of p53 mutations in such families enhances the likelihood of detecting mutations in related genes required for genomic stability. As a second step, we will expand the mutational analysis to subsets of the general population at high risk for breast cancer, but without the extraordinary risk factors demonstrated by LFS and related families. Finally, we will examine a collection of tumor cell lines for the frequency of mutations in these candidate genes.

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Publications

Prevalence and functional analysis of sequence variants in the ATR checkpoint mediator Claspin.
Authors: Zhang J. , Song Y.H. , Brannigan B.W. , Wahrer D.C. , Schiripo T.A. , Harris P.L. , Haserlat S.M. , Ulkus L.E. , Shannon K.M. , Garber J.E. , et al. .
Source: Molecular cancer research : MCR, 2009 Sep; 7(9), p. 1510-6.
EPub date: 2009-09-08.
PMID: 19737971
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Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts.
Authors: Bell D.W. , Kim S.H. , Godwin A.K. , Schiripo T.A. , Harris P.L. , Haserlat S.M. , Wahrer D.C. , Haiman C.A. , Daly M.B. , Niendorf K.B. , et al. .
Source: International journal of cancer, 2007-12-15; 121(12), p. 2661-7.
PMID: 17721994
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salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.
Authors: Tapon N. , Harvey K.F. , Bell D.W. , Wahrer D.C. , Schiripo T.A. , Haber D. , Hariharan I.K. .
Source: Cell, 2002-08-23; 110(4), p. 467-78.
PMID: 12202036
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Selective loss of heterozygosity in multiple breast cancers from a carrier of mutations in both BRCA1 and BRCA2.
Authors: Bell D.W. , Erban J. , Sgroi D.C. , Haber D.A. .
Source: Cancer research, 2002-05-15; 62(10), p. 2741-3.
PMID: 12019146
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