CORRESPONDENCE

Re: Dominant Negative ATM Mutations in Breast Cancer Families

Haixin Lei, Daria Pospisilova, Annika Lindblom, Igor Vorechovsky

Affiliations of authors: H. Lei, I. Vorechovsky, Karolinska Institute, Department of Biosciences at Novum, Huddinge, Sweden; D. Pospisilova, Department of Pathophysiology, Masaryk University, Brno, Czech Republic; A. Lindblom, Karolinska Hospital, Department of Clinical Genetics, Stockholm, Sweden.

Correspondence to: Igor Vorechovsky, M.D., Ph.D., Karolinska Institute, Department of Biosciences at Novum, 14157 Huddinge, Sweden (e-mail: igvo{at}biosci.ki.se).

Chenevix-Trench et al. (1) reported two ATM gene alterations associated with a risk of breast cancer in multiple-case families. The T7271G mutation was detected in one patient with breast cancer of 525 examined who were unselected for a family history of breast cancer and in four more affected family members (1). This transversion was previously found in two families with mild ataxia-telangiectasia (A-T) and a history of breast cancer (2) and in a sporadic T-cell leukemia (3). ATM IVS10-6T->G was not found in 262 unselected patients with breast cancer but was found in two of 76 index patients from multiple-case families with breast cancer (1) and, previously, in patients with A-T and in patients with breast cancer (4,5). Expression and activity analyses of ATM in heterozygous cell lines indicated a dominant negative effect for both mutations (1), a mechanism distinct from that previously proposed for ATM-mediated tumorigenesis in a sporadic T-cell leukemia (3), where the mutation pattern and the lack of wild-type alleles in most mutated samples were consistent with ATM acting as a tumor suppressor gene.

We examined germline DNA from patients with breast cancer and from control subjects in two European populations for the presence of both mutations (Table 1Go). The samples were ascertained as described (6,7). Genotyping was carried out by polymerase chain reaction, as reported (1), except for the forward primer [5`-TGAAAAGAGCCAAAaAGGAAG, the underlined nucleotide was guanine in (1)] in the T7271G assay. The amplified products and positive control DNA samples carrying T7271G (3) and IVS10-6T->G (a gift from T. Dörk, Medical School, Hannover, Germany) were digested with restriction enzymes (1) and separated on agarose gels.


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Table 1. Frequency of ATM T7271G and IVS10-6T -> G mutations in patients with breast cancer and control subjects
 
Although we did not detect the T7271G mutation among 612 patients, the IVS10-6T->G mutation was identified in one (0.3%) of 339 unselected Swedish patients and one (0.7%) of 138 selected Swedish familial patients without a detectable BRCA1/BRCA2 mutation (Table 1Go). We also found one (1.1%) such individual among 88 Czech female blood donors. The overall frequency of the IVS10-6G allele was 0.1%. No homozygote was found for either mutation. We also examined tumor DNA from the familial patient for allelic imbalance at the IVS10-6T->G polymorphism but found no loss of heterozygosity (LOH), consistent with the proposed dominant negative effect of the mutation. No DNA sample was available from the remaining family members.

If the loss of ATM alleles confers a detectable risk of breast cancer, then one would expect to see enrichment for ATM mutation/inactivation in tumor DNA samples with LOH at 11q22–q23. We selected 42 tumor DNA samples with LOH at 11q22–q23 from a larger number of paired normal and breast cancer DNA samples by use of polymorphic markers at and around ATM (D11S2179, D11S1778, D11S1391, D11S1347, D11S1345, D11S922, and D11S1318). We analyzed this material for mutations in exons 50–66 with single-strand conformation polymorphism, as described (3). No mutation was observed, including T7271G and IVS10-6T->G.

Additional studies in independent populations will help clarify the role of the two mutations as breast cancer risk modifiers, but we still need to reconcile a clear predominance of frame shift mutations among A-T alleles [(2,3) and references therein] and a putative lack of chain-terminating heterozygous mutations in the germline of patients with breast cancer in the context of original epidemiologic studies indicating an increased risk of breast cancer among A-T heterozygotes. In addition, more accurate proportions of mutations altering the correct splicing of ATM and dominant negative mutations remain to be shown in A-T.

NOTES

H. Lei and D. Pospisilova contributed equally to this work.

Supported by grant J07/98:141100002 from the Czech Ministry of Education, grant QLG2-CT-1999–00786 from the European Commission, and a Young Investigator Prize in Oncology from Bristol-Myers Squibb.

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.[Abstract/Free Full Text]

2 Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P, et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet 1998;62:334–45.[Medline]

3 Vorechovsky I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, et al. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet 1997;17:96–9.[Medline]

4 Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, et al. ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet 2000;66:494–500.[Medline]

5 Dork T, Bendix R, Bremer M, Rades D, Klopper K, Nicke M, et al. Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 2001;61:7608–15.[Abstract/Free Full Text]

6 Lei H, Sjoberg-Margolin S, Salahshor S, Werelius B, Jandakova E, Hemminki K, et al. CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk. Int J Cancer 2002;98:199–204.[Medline]

7 Luo L, Lei H, Du Q, von Wachenfeldt A, Kockum I, Luthman H, et al. No mutations in the BACH1 gene in BRCA1 and BRCA2 negative breast-cancer families linked to 17q22. Int J Cancer 2002;98:638–9.[Medline]


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