title: A common Greenlandic Inuit BRCA1 RING domain founder mutation.
abstract: Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 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(2+) 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 BRCA1 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 BRCA1 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.
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. tvoh@rh.dk
authors.forename: Thomas V O
authors.initials: TV
authors.lastname: Hansen
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: Eva
authors.initials: E
authors.lastname: Bergsten
authors.forename: Peter
authors.initials: P
authors.lastname: Bjerregaard
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Torben
authors.initials: T
authors.lastname: Myrhøj
authors.forename: Peter B
authors.initials: PB
authors.lastname: Nielsen
authors.forename: Vera
authors.initials: V
authors.lastname: Timmermans-Wielenga
authors.forename: Mette K
authors.initials: MK
authors.lastname: Andersen
authors.forename: Lars
authors.initials: L
authors.lastname: Jønson
authors.forename: Finn C
authors.initials: FC
authors.lastname: Nielsen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006116:Greenland; D006801:Humans; D004930:Inuit; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid