A Novel Method to Screen for Dominant Negative ATM Mutations in Familial Breast Cancer
Annual rept. 1 Apr 2002-31 Mar 2003
QUEENSLAND INST OF MEDICAL RESEARCH BRISBANE (AUSTRALIA)
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The aim of this proposal is to identify families carrying potentially pathogenic AIM mutations by assaying for ATM kinase activity in cell lines derived from individuals with multiple cases of breast cancer in their family but no pathogenic BRCA or BRCA2 mutation BRCAx families. If pathogenic mutations in AIM are found in these families it will substantiate the role of AIM in breast cancer susceptibility, allow us to characterize the functional effects of those mutations, and provide clinically valuable information for the families involved. We have analyzed 145 cell lines established from index cases from non-BRCAl2 breast cancer families for ATM expression and activity. 10145 6.9 cell lines showed markedly reduced ATM kinase activity, despite normal level of expression of ATM protein. DNA from the index cases with aberrant ATM kinase activity is currently being screened by D-HPLC to determine whether the lack of activity is due to mutations in AIM. Pathogenic ATM mutations T7271G, IVS 10 6T-G have been constructed in expression vectors. Functional analysis has been performed for V2424G base T7271G.
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