germline mutations in women with familial breast cancer and a relative with haematological malignancy

Laura La Paglia (1, 2) , Anthony Laugé (1) , Jérémie Weber (3) , Jérôme Champ (1, 3, 4, 5) , Eve Cavaciuti (6, 7, 8) , Antonio Russo (2) , Jean-Louis Viovy (4, 5) , Dominique Stoppa-Lyonnet (1, 9, 10)

1 Service de Génétique
2 Department of Surgery and Oncology
3 Fluigent
4 Centre de Recherche
5 PCC - Physico-Chimie-Curie
6 Service de Biostatistiques
7 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
8 École des Mines de Paris
9 U830 - Unité de génétique et biologie des cancers
10 UPD5 - Université Paris Descartes - Paris 5

Biallelic inactivation of the gene causes ataxia–telangiectasia (A–T), a complex neurological disease associated with a high risk of leukaemias and lymphomas. Mothers of A–T children, obligate heterozygote mutation carriers, have a breast cancer (BC) relative risk of about 3. The frequency of carriers in BC women with a BC family history has been estimated to be 2.70%. To further our clinical understanding of familial BC and examine whether haematological malignancies are predictive of germline mutation, we estimated the frequency of heterozygote mutation carriers in a series of 122 BC women with a family history of both BC and haematological malignancy and without mutation. The gene screening was performed with a new high throughput method, EMMA (enhanced mismatch mutation analysis). Amongst 28 different variants, eight mutations have been identified in eight patients: two mutations leading to a putative truncated protein and six being likely deleterious mutations. One of the truncating mutations was initially interpreted as a missense mutation, p.Asp2597Tyr, but is actually a splice mutation (c.7789G>T/p.Asp2597_Lys2643>LysfsX3). The estimated frequency of heterozygote mutation carriers in our series is 6.56% (95% CI: 2.16–10.95), a significantly higher figure than that observed in the general population, estimated to be between 0.3 and 0.6%. Although a trend towards an increased frequency of carriers was observed, it was not different from that observed in a population of familial BC women not selected for haematological malignancy as the frequency of carriers was 2.70%, a value situated in the confidence interval of our study.

Mots clés: Ataxia–telangiectasia; Breast cancer; EMMA

Laura La Paglia, Anthony Laugé, Jérémie Weber, Jérôme Champ, Eve Cavaciuti, et al.. germline mutations in women with familial breast cancer and a relative with haematological malignancy. Breast Cancer Research and Treatment, 2009, 119 (2), pp.443-452. ⟨10.1007/s10549-009-0396-z⟩. ⟨hal-00535361⟩