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s of the 7th International Workshop on AT, November, 1997, Clermont-Ferrand, France Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy J.M. Appleby, J.B.P. Barber, E. Levine, J.M. Varley, A.M.R. Taylor, T. Stankovic, J. Heighway, C. Warren and D. Scott CRC Section of Molecular Genetics, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 9BX, UK CRC Institute for Cancer Studies, University of Birmingham, Medical School, Birmingham, B15 2TA, UK In reviewing the available epidemiological data on A-T heterozygotes in 1994, Easton [1] produced best estimates of 0.5% for the population frequency, 3.9 for the increased relative risk of breast cancer and 3.8% for their frequency amongst breast cancer cases, but pointed out the wide confidence intervals on these estimates. The latter figure is intriguingly close to estimated proportion of 5% of breast cancer cases who sustain severe normal tissue damage after standard radiotherapy regimes [2]. It has also been shown that cultured cells from A-T heterozygotes and from some severely reacting (SR) patients show a modest increase in radiosensitivity in clonogenic assays utilising low dose rate or fractionated exposures [3]. The above observations have led to the prediction that a substantial proportion of SR patients may carry ATM mutations and that mutation screening could be used as a predictive test for adverse reactions to radiotherapy [4]. We have screened the complete coding sequence of the ATM gene in 16 SR breast cancer patients and 7 SR patients with other cancers, using the restriction endonuclease fingerprinting (REF) assay. Twelve of the breast cancer cases had shown severe acute reactions in our own prospective study of 202 unselected patients. In our hands the REF assay has a sensitivity of about 70% so, using figures of 5% for the incidence of SR reactions and 4% for the frequency of A-T heterozygotes amongst breast cancer cases, we would have expected to detect 9 ATM mutations amongst the 16 breast cancer patients tested if ATM mutations confer elevated clinical radiosensitivity. No mutations were detected (p<0.001 for observed v expected). Neither were there any mutations amongst the non breast cancer cases. A polymorphism at 5557GÆA (aspartic acidÆasparagine) was seen in 8 of the 23 patients. With respect to the function of the ATM gene this is not a significant change. Our results indicate either that ATM mutations do not lead to in vivo radiosensitivity or that the frequency of A-T heterozygotes amongst breast cancer cases is overestimated, or both. Recent estimates of the latter, since the review by Easton [1], are 3.4% (3/88) for patients with a family history of A-T type tumours, 0.5% (2/401) for early onset cases [6], and 6.6%, estimated indirectly from a study of breast Abstracts of the 7th International Workshop on AT 22s of the 7th International Workshop on AT 22 cancer incidence within 99 A-T families? There are also reports of 3 breast cancer patients with ATM mutations showing no adverse reactions to radiotherapy [6,8]. These early results suggest that screening for ATM mutations in cancer patients may not be of value in predicting complications from radiotherapy. Acknowledgment This study was funded by the Cancer Research Campaign and the National Radiological Protection Board, UK.

Abstracts of the 7th International Workshop on AT, November, 1997, Clermont-Ferrand, France