A common Greenlandic Inuit BRCA1 RING domain founder mutation

Area of Science:

• Genetics
• Oncology
• Population Health

Background:

• Germline mutations in BRCA1 and BRCA2 tumor suppressor genes are linked to hereditary breast and ovarian cancers.
• Investigating genetic predispositions in isolated populations can reveal founder mutations and inform public health strategies.

Purpose of the Study:

• To identify BRCA1 and BRCA2 mutations in Greenlandic patients with breast and/or ovarian cancer.
• To characterize a novel BRCA1 mutation and determine its prevalence and origin within the Greenlandic Inuit population.

Main Methods:

• Screening of 32 breast/ovarian cancer patient families for BRCA1 and BRCA2 mutations.
• Mutation characterization, including functional impact on BRCA1 ubiquitin ligase activity.
• SNP array analysis to identify shared genomic regions and confirm founder effect.
• Population-based genetic screening of 1152 Inuit individuals.

Main Results:

• A previously unreported BRCA1 exon 3 nucleotide 234 T > G mutation was identified in 13 of 32 families.
• This mutation affects a conserved cysteine in the BRCA1 RING domain, crucial for its ligase activity.
• SNP array analysis confirmed a common 4.5 Mb genomic fragment in affected families, indicating a founder mutation.
• The BRCA1 234 T > G mutation was found in 1.0% of the screened Inuit population, suggesting a founder effect.

Conclusions:

• The BRCA1 nucleotide 234 T > G mutation is a common founder mutation in the Greenlandic Inuit population.
• The mutation's high frequency and potential for mortality reduction warrant population screening.
• Screening could potentially prevent approximately 5% of breast and 13% of ovarian cancers in this population.