Loss of heterozygosity (LOH) in the chromosome band 11q23, where the ATM gene is located, has been reported in several types of tumours including breast carcinomas.
We present a simple and rapid polymerase chain reaction (PCR)-based assay for this dimorphism that should be useful to trace the inheritance of ATM alleles in ataxia telangiectasia and breast cancer families and to study loss of heterozygosity in primary tumours.
To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations.
We report, in two A-T families, an ATM mutation (7271T-->G) that may be associated with an increased risk of breast cancer in both homozygotes and heterozygotes (relative risk 12.7; P=.
To further examine the possibility that ATM is correlated to breast cancer, we screened for ATM germ-line mutations in another 100 breast cancer patients with a family history of breast cancer.
The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age > or = 45 years (RR = 2.48, P = 0.08).
A common assumption has been that the target for the LOH at 11q23.1 in breast carcinoma is the ATM gene, but the area studied has been too large, the density of markers too low, and the number of tumors studied has been too small to draw any firm conclusions.
Thus, our procedure identified at least one allelic variant of ATM associated with breast cancer, and indicated that the ATM locus may interact with HRAS1.
This high rate of somatic inactivation of ATM may indicate either that these rare variants play a role in breast cancer development or alternatively that a neighboring tumor suppressor gene is important for tumorigenesis.
Our understanding of the molecular basis of familial breast cancer has advanced significantly through investigation of the tumor suppressor gene BRCA1, as has our knowledge of the role of the ATM gene and predisposition to breast cancer in ataxia-telangiectasia carriers.
Thus, phosphorylation of Brca1 by the checkpoint kinase ATM may be critical for proper responses to DNA double-strand breaks and may provide a molecular explanation for the role of ATM in breast cancer.
ATM was chosen for evaluation because of the increased radiosensitivity of cells derived from AT patients and obligate heterozygotes and the epidemiologic observation that AT carriers are at increased risk for radiation-induced breast cancer.