Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation

Abstract

The BRCA1 and BRCA2 genes are the strongest susceptibility genes identified for breast cancer worldwide. However, BRCA1/BRCA2 have been incompletely investigated due to their large size and the genomic rearrangements that occasionally occur within them. Here we performed a comprehensive mutational analysis for BRCA1/BRCA2 in 206 Korean patients with breast cancer. We analyzed all exons and flanking regions of BRCA1/BRCA2 by direct sequencing and screened deletions or duplications involving BRCA1/BRCA2 by multiplex ligation-dependent probe amplification. We reconstructed haplotypes using intragenic single nucleotide polymorphisms (SNPs) to investigate the possibility of a founder effect among recurrent mutations. In our series, 38 patients (18.4%) had one or more BRCA1/BRCA2 mutations including 10 novel ones. Three additional patients carried novel distinct unclassified variants with potentially harmful effects. No large deletions or duplications involving BRCA1/BRCA2 were identified in our series. Haplotype analyses and allele separation suggested that the most frequent mutation in Koreans, BRCA2:c.7480C>T, might have originated from a common ancestor. BRCA1/BRCA2 mutations were more frequent in a group with family history, bilateral cancer or multiple site cancer than in a group without the risk factors described or an unknown risk group. In contrast, mutation frequencies in the early-onset cancer group were not higher than in the unknown risk group. Our results will be helpful to understand the mutation spectrum in BRCA1/BRCA2 genes and establish a genetic screening strategy. In addition, this study suggests the possibility of the first true founder mutation of BRCA1/BRCA2 identified in the Korean population.

Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: the importance of whole-gene sequencing

“…These variations have not been reported in the SNP database (http://www.ncbi.nlm.nih.gov/snp) and eight have been reported in the BIC database but are of unknown clinical importance. Among the 13 unclassified variations, 11 variations have been found in previous normal control studies 8,10 and/or in the present study, but there is not reliable functional assay at present. Four different protein prediction programs (PolyPhen, SIFT, PANTHER and SVM) were used to predict the functional consequences of the mutations and obtain diverse results.…”

“…Ahn et al 9 reported that the combination of seven common mutations (BRCA1: c.2433delC, c.3627dupA, c.4065_4068delTCAA, c.5470_5477del8 and c.5496_5506del11insA; BRCA2: c.1399A4T and c.7480C4T) accounted for 62.5% and this suggests the possibility of founder effect. Seong et al 10 analyzed data from previous two large studies 7,9 and reported that another set of seven common mutations (BRCA1: c.390C4A, c.2433delC, c.3627dupA, c.4065_4068delTCAA and c.5496_ 5506del11insA; BRCA2: c.3744_3747delTGAG and c.7480C4T) was recurrent and accounted for up to 43.9% in the pooled population.…”

“…Most previous studies of BRCA1/BRCA2 genes in Korea used performed two-step approaches, in which mutations are first scanned in a rapid manner, and then subjected to sequencing analysis when sequence alterations are detected. [6][7][8][9][10] Table 3 shows the mutation detection rates in the BRCA1/BRCA2 genes from each study in Korea. Compared with the two studies using similar inclusion criteria for the high-risk group of Korean breast cancer patients, mutation detection rates of whole-gene sequencing exceeded 20%.…”

“…The study was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2000. Selection of patients was based on the following criteria as previously described 9,10 and at least one of the following: (F) at least one first-or seconddegree relative with breast and/or ovarian cancer diagnosed at any age, (E) early-onset breast cancer diagnosed at age 35 or before, (B) bilateral breast cancer and (M) multiple organ cancer, including breast cancer. The study subjects consisted of 134 unrelated Korean breast cancer patients who were identified as being at high risk of carrying BRCA1/BRCA2 mutations; 116 (87%) familial cases, 29 (22%) early-onset cancer cases, 13 (10%) bilateral cancer cases and 10 (7%) multiple organ cancer cases.…”

“…5 To date, only a few studies have examined the frequencies and spectra of mutations in large series of Korean breast cancer patients. [6][7][8][9][10] Several mutations are considered to be founder mutations, as they account for the majority of detected BRCA1/BRCA2 mutations in Korea. Although some of these recurrent mutations are unique to Koreans, their effects vary across studies.…”