No abstract

Our aim was to characterise the germline BRCA1 mutation profile in Latvian breast cancer and ovarian cancer patients, to develop an effective BRCA1 gene mutation detection strategy, and to document genotype-phenotype correlations in mutation carriers. The entire BRCA1 gene was analysed in 75 breast cancer and 30 ovarian cancer patients. Screening for three mutations (5382insC, 4154delA and 300T>G) was carried out in 55 breast cancer and 66 ovarian cancer patients, and for two mutations, 5382insC and 4154delA, in 376 unselected patients with any cancer (including 51 breast cancer and 29 ovarian cancers) and 215 women with any gynaecological tumour. Mutation detection techniques used were SSCP/HD analysis or F-SSCP (ABI PRISM 310). Five different deleterious mutations were detected by analysis of the entire BRCA1 gene. The proportion of cases with mutations amongst 50 breast cancer patients diagnosed before 48 years was 26.0% (95% CI: 14.6-40.3%). Two mutations (5382insC and 4154delA) made up more than 80% of all mutations identified by the analysis of the entire BRCA1 gene in Latvia, at present. Further screening for only the prevalent mutations in different cancer patient groups resulted in the identification of 53 more mutation carriers. We conclude that breast cancer diagnosed before the age of 48 years and ovarian cancer before 65 years are criteria for DNA testing to be offered to women in Latvia, regardless of cancer history in the family. The observed associations of specific prevalent mutations with cancer site and age at onset of disease are discussed.

Uncertainty exists whether the 4154delA mutation of the BRCA1 gene detected in unrelated individuals from Latvia, Poland and Russia is a founder mutation with a common ancestral origin. To trace back this problem we analysed the mutation-associated haplotype of the BRCA1 intragenic SNPs as well as intragenic and nearby STR markers in mutation carriers from the aforementioned populations. The mutation-associated SNP alleles were found to be "T-A-A-A-A-G" for six intragenic SNPs of the BRCA1 gene (IVS8-58delT, 3232A/G, 3667A/G, IVS16-68A/G, IVS16-92A/G, IVS18+66G/A, respectively). The alleles 195, 154, 210 and 181 were found to be associated with the 4154delA mutation for STR markers D17S1325, D17S855, D17S1328 and D17S1320, correspondingly. Further analysis of markers in the 4154delA mutation carriers from all three populations allows us to assert that all analysed mutation carriers share a common ancestry.