Abstract P3-06-01: ATM Heterozygosity as a Breast Cancer-Susceptibility Factor in the General Population
Authors: Soddu S , Prodosmo A , Nistico’ C , Pinnaro’ P , Strigari L , Cundari E , De Amicis A , Chessa L. 
Published: April 2011

Abstract
Background: Do ATM heterozygous (ATM-htz) carriers have an increased risk of developing breast cancer? Do they have an increased sensitivity to ionizing radiation (IR)? Definitive information does not yet exist to answer these questions. Case-control studies have suggested a link between single copy ATM gene mutation and increased breast cancer risk. Lymphoblasts and skin fibroblasts from ATM-htz carriers are less sensitive to IR than cells from Ataxia Telangiectasia (AT) patients, but more sensitive than cells from the general population. Because of the clinical and environmental implication of these aspects, large studies are in progress to better understand the interaction between ATM-htz and increased breast cancer risk or radio-sensitivity. However, to be performed on the general population rather than on the obligate ATM-htz carriers, i.e., the rare parents of children affected by AT, these studies must relay on the expensive sequencing of the entire ATM gene (approximately 160Kb of genomic DNA, a 13Kb transcript of 66 exons, and more than 400 unique mutations that extend across the full length of the gene). Materials and Methods: Based on a serendipitous discovery, we have development of a new, non-invasive, easy, quick, and inexpensive test to identify AT patients and, more interestingly, the ATM-htz carriers. In particular, we found that, in mitosis, p53 localizes at centrosomes, the cytoplasmic organelles that organize the interphase cytoskeleton and contribute to bipolar spindle formation during mitotic cell division. In addition, we demonstrated that ATM is required for p53 localization at centrosome. These findings allowed us to identify a particular phenotype of peripheral blood lymphocytes (PBL) from AT patients or their parents, the obligate ATM-htz that should allow to easily discriminate the ATM-htz carries in the general population with a very high statistical significance (P&lt;0.001). We have employed this new test to assess the contribution of ATM heterozygosity in the risk to develop breast cancer. Results: The frequency of ATM-htz in breast cancer patients and in healthy individuals was assessed by our new test and compared with the Italian theoretical frequency (between 1.69 and 3.43%; Italian AT Registry). At present, we have found 6 ATM-htz out of 80 breast cancer patients (7.5%) and 1 ATM-htz out of 70 healthy donors (1.4%) supporting the proposed link between single copy ATM gene mutation and increased breast cancer risk. In addition, an initial individual evaluation of the 6 ATM-Htz patients showed the following common characteristics: 1) early onset of tumor appearance (37-42 years of age); 2) ER and PgR positive and HER negative breast cancers.
Discussion: Beside an accurate assessment of the relative contribution of ATM heterozygosity to tumor susceptibility, this study will open the possibility of performing large screening for ATM-htz carries in the general population for different clinical aspects, such as IR sensitivity, genetic counseling, cancer predisposition, or selection for specific targeted therapies.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-06-01.