Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients

Blood relatives of patients with the inherited disease ataxia telanglectasi a (A-T) have an increased susceptibility for breast cancer. We therefore lo oked for sequence alterations of the ATM gene in a large hospital-based ser ies of unselected breast cancer patients. The whole ATM coding sequence was analyzed in genomic DNA samples from a core group of 192 consecutive breas t cancer cases to define the spectrum of ATM gene mutations. Common sequenc e alterations were then screened in the whole series of 1000 breast cancer patients and in 500 random individuals. In the core group, 21 distinct sequ ence alterations were identified throughout the ATM coding region, and 1 co mmon splicing mutation was uncovered in intron 10. Almost half of the breas t cancer patients (46%) were heterozygotes for 1 of 16 different amino acid substitutions, and three patients (1.6%) carried a truncating mutation. Th ese data indicate that similar to1 in 50 German breast cancer patients is h eterozygous for an A-T-causing mutation. In our extended series, the most c ommon A-T mutation 1066-6T -->G was disclosed in 7 of 1000 (0.7%) breast ca ncer patients. Transcript analyses indicated that the loss of exon 11 in th e ATM mRNA was the pathogenic consequence of this splicing mutation, which produced a < 10% of full-length ATM mRNA and ATM protein in a homozygous A- T patient. We also found an excess of rare missense substitutions in the br east cancer cohort compared with random individuals (7.9% versus 5.3% of al leles; odds ratio = 1.6; P < 0.01). One missense substitution, S707P in exo n 15, was two times more frequent in breast cancer patients (odds ratio = 2 .4; 95% confidence interval, 1.0-5.8) and five times more frequent in patie nts with bilateral disease than in random individuals (P < 0.001). We concl ude that a large variety of distinct ATM mutations and variants exist among breast cancer patients, some of which can contribute to the etiology and p rogression of the malignancy. Screening for frequent A-T mutations such as the 1066-6 -->G splice site substitution can be effective to prospectively identify A-T heterozygotes in an unselected cancer patient population.