© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 12, 952,
June 19, 2002
© 2002 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Dominant Negative ATM Mutations in Breast Cancer Families
Affiliations of authors: G. Chenevix-Trench, Queensland Institute of Medical Research, Brisbane, Australia; T. Dörk, Medical School, Hannover, Germany; C. Scott, Walter and Eliza Hall Institute, Melbourne, Australia; J. Hopper, Centre for Genetic Epidemiology, University of Melbourne, Australia.
Correspondence to: Georgia Chenevix-Trench, Ph.D., Queensland Institute of Medical Research, c/o RBH Post Office, Brisbane, Queensland 4029, Australia (e-mail: georgiaT{at}qimr.edu.au).
Lei et al. have determined the frequency of two ATM mutations in a large number of unselected and familial breast cancer case patients, and random control subjects, from Sweden and the Czech Republic. The IVS10-6T
G ATM mutation was identified in two case patients of a total of 768 case patients (one of whom had a family history of breast cancer) and one control subject of a total of 557 control subjects, confirming the fact that it is a relatively common mutation in Caucasians. Although it is interesting to note that the IVS10-6TG mutation occurs in the Swedish and Czech populations, this observation does not contribute to the estimation of the penetrance of the IVS10-6TG mutation, because no family members of the affected case patients were available for genotyping, and the personal and family breast cancer history of the control carrier is not known. However, these data emphasize that to estimate penetrance with any precision, it is necessary to carry out such studies in multiple-case families in which many DNA samples are available from unaffected and affected family members or in a large population-based series of case families with similar DNA sampling. If the variant is likely to confer only low risks for breast cancer, well-characterized control subjects will also need to be studied.
The authors also use single-strand conformational polymorphism analysis to examine 42 tumors for ATM mutations that were selected for having loss of heterozygosity (LOH) around the ATM locus, and they found no somatic mutations. However, if breast cancer-causing ATM mutations act as dominant negative mutations, as our functional data on T7271G and IVS10-6TG suggest (1), then this null result is not surprising. Mutation analysis of breast tumors without LOH might uncover somatic mutations although, of course, for reasons that are not clear, such mutations are exceedingly rare in BRCA1 and BRCA2 genes and would, therefore, not necessarily be expected in ATM (2). As Lei et al. suggest, the mechanism of action of ATM mutations may be different in T-cell leukemia, where both alleles appear to be inactivated (3), compared with breast tumors where a dominant negative effect on BRCA1 phosphorylation may be critical.
Finally, we thank Lei et al. for pointing out the error in our published primer sequence.
REFERENCES
1
Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, et al. Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 2002;94:205–15.
2
Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet 2001;10:705–13.
3
Boultwood J. Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J Clin Pathol 2001;54:512–6.
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