Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling

Waddell, Nic, Jonnalagadda, Jyoti, Marsh, Anna, Grist, Scott, Jenkins, Mark, Hobson, Karen, Taylor, Malcolm, Lindeman, Geoff J., Tavtigian, Sean V., Suthers, Graeme, Goldgar, David, Oefner, Peter J., kConFab Investigators, Taylor, Darrin, Grimmond, Sean, Khanna, Kum Kum and Chenevix-Trench, Georgia (2006) Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling. Genes Chromosomes and Cancer, 45 12: 1169-1181. doi:10.1002/gcc.20381


Author Waddell, Nic
Jonnalagadda, Jyoti
Marsh, Anna
Grist, Scott
Jenkins, Mark
Hobson, Karen
Taylor, Malcolm
Lindeman, Geoff J.
Tavtigian, Sean V.
Suthers, Graeme
Goldgar, David
Oefner, Peter J.
kConFab Investigators
Taylor, Darrin
Grimmond, Sean
Khanna, Kum Kum
Chenevix-Trench, Georgia
Title Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling
Formatted title
Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling
Journal name Genes Chromosomes and Cancer   Check publisher's open access policy
ISSN 1045-2257
1098-2264
Publication date 2006-12
Sub-type Article (original research)
DOI 10.1002/gcc.20381
Volume 45
Issue 12
Start page 1169
End page 1181
Total pages 13
Place of publication Hoboken, NJ, U.S.A.
Publisher John Wiley & Sons
Language eng
Subject 270000 Biological Sciences
Formatted abstract
Mutations in ATM are responsible for the autosomal recessive disorder ataxia telangiectasia. Heterozygous mutations in ATM have been associated with an elevated risk of breast cancer. We previously reported one breast cancer family in which ATM 7271T>G (V2424G) segregated with disease, and apparently acted in a dominant negative manner. We now report the screening of 782 multiple-case breast cancer families that identified two additional index cases with ATM 7271T>G. Phylogenetic sequence analysis showed that V2424 is a highly conserved residue, and that the 2424G variant is likely to interfere with function. To elucidate the consequences of this mutation, we expression profiled wild-type, heterozygous, and homozygous lymphoblastoid cell lines (LCLs) from Scottish and Australian families using an oligonucleotide microarray. Cluster analysis revealed 77 genes that were differentially expressed in homozygous and heterozygous V2424G cells (compared to wild-type) and 11 genes differentially expressed in the homozygous cells. We also evaluated the profiles of LCLs after exposure to ionizing radiation (IR) and identified 77 genes that were differentially expressed in wild-type cells, but not in homozygous or heterozygous V2424G cells. We validated the expression differences by RT-PCR in additional heterozygous V2424G LCLs from another breast cancer family. We found no consistent cytotoxicity or abrogation of ATM kinase activity after IR in seven heterozygous V2424G LCLs, compared to wild-type LCLs, but did find an increase in the number of chromosomal aberrations. These data suggest that the V2424G missense mutation acts largely as a dominant negative in terms of the associated expression profiles.
Keyword Oncology
Genetics & heredity
Ataxia-telangiectasia heterozygotes
Sequence variants
Protein function
DNA-damage
Risk
Missense
Carriers
Families
BRCA1
Susceptibility
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

 
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Created: Wed, 19 Sep 2007, 18:42:49 EST