A common Greenlandic Inuit RING domain founder mutation

Thomas V. O. Hansen (1) , Bent Ejlertsen (2) , Anders Albrechtsen (3) , Eva Bergsten (2) , Peter Bjerregaard (4) , Torben Hansen (5) , Torben Myrhøj (6) , Peter B. Nielsen (1) , Vera Timmermans-Wielenga (7) , Mette K. Andersen (8) , Lars Jønson (1) , Finn C. Nielsen (1)

1 Department of Clinical Biochemistry [Rigshospitalet]
2 Department of Oncology
3 Section of Biostatistics [Copenhagen]
4 National Institute of Public Health
5 Steno Diabetes Center
6 Department of Surgery
7 Department of Pathology
8 Department of Clinical Genetics

Germ-line mutations in the tumour suppressor proteins and predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in and . Whereas no mutations were identified in 19 families, 13 families exhibited a exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit, representing almost ~2% of the total Greenlandic Inuit population, showed that the frequency of the mutation was 1.0%. We conclude that the nucleotide 234 T > G is a common Greenlandic Inuit founder mutation. The relative high frequency in the general population, together with the ease of screening and possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.

Mots clés: RING domain; Cys39Gly; SNP array; Greenland; Inuit; Founder mutation

Thomas V. O. Hansen, Bent Ejlertsen, Anders Albrechtsen, Eva Bergsten, Peter Bjerregaard, et al.. A common Greenlandic Inuit RING domain founder mutation. Breast Cancer Research and Treatment, 2008, 115 (1), pp.69-76. ⟨10.1007/s10549-008-0060-z⟩. ⟨hal-00478231⟩