Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families

Anne Laure Renault, Noura Mebirouk, Eve Cavaciuti, Dorothée Le Gal, Julie Lecarpentier, Catherine Dubois d'Enghien, Anthony Laugé, Marie Gabrielle Dondon, Martine Labbé, Gaetan Lesca, Dominique Leroux, Laurence Gladieff, Claude Adenis, Laurence Faivre, Brigitte Gilbert-Dussardier, Alain Lortholary, Jean Pierre Fricker, Karin Dahan, Jacques Olivier Bay, Michel LongyBruno Buecher, Nicolas Janin, Hélène Zattara, Pascaline Berthet, Audrey Combès, Isabelle Coupier, CoF-AT study collaborators, Janet Hall, Dominique Stoppa-Lyonnet, Nadine Andrieu, Fabienne Lesueur

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families. The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies. HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women. Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families.

Original languageEnglish
Article numberbgx074
Pages (from-to)994-1003
Number of pages10
JournalCarcinogenesis
Volume38
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017
Externally publishedYes

Cite this

Renault, A. L., Mebirouk, N., Cavaciuti, E., Le Gal, D., Lecarpentier, J., Dubois d'Enghien, C., Laugé, A., Dondon, M. G., Labbé, M., Lesca, G., Leroux, D., Gladieff, L., Adenis, C., Faivre, L., Gilbert-Dussardier, B., Lortholary, A., Fricker, J. P., Dahan, K., Bay, J. O., ... Lesueur, F. (2017). Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families. Carcinogenesis, 38(10), 994-1003. [bgx074]. https://doi.org/10.1093/carcin/bgx074