The Importance of ATM Mutations and Polymorphisms in Breast Cancer and Radiation Sensitivity

The primary objective of my 4-year career development award is to determine whether ATM heterozygosity is a significant contributor to both breast cancer risk and normal tissue injury resulting from radiation treatments of breast cancer. During the past year, we have begun full-length sequencing of ATM cDNA in these two patient cohorts. Our 3-year goal is to enroll 200 breast cancer patients and 50 breast cancer patients with injury. Over the first year, we have completed the sequencing of 89 breast cancer patients 21 with radiation injuries . Results of the sequencing studies have failed to find any protein truncating mutations that are known to be associated with the disease of ataxia telangiectasia. However, the sequencing has revealed a number of single base changes in the gene, the majority of which result in a change in an amino acid in the protein. It is not clear whether these changes affect the function of the protein or the stability of the mRNA. To evaluate this, we compiled a 960 individual control set of DNAs obtained from healthy volunteers. We have developed and validated allele specific oligonucleotide ASO assays to test the frequency of the polymorphisms in the patients and controls. The results of the ASO for the most prevalent polymorphisms are currently being analyzed.