Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families

Abstract

Early studies of genetic predisposition due to the BRCA1 and BRCA2 genes have focused largely on sequence alterations, but it has now emerged that 4-28% of inherited mutations in the BRCA genes may be due to large genomic rearrangements of these genes. However, to date, there have been relatively few studies of large genomic rearrangements in Asian populations. We have conducted a full sequencing and large genomic rearrangement analysis (using Multiplex Ligation-dependent Probe Amplification, MLPA) of 324 breast cancer patients who were selected from a multi-ethnic hospital-based cohort on the basis of age of onset of breast cancer and/or family history. Three unrelated individuals were found to have large genomic rearrangements: 2 in BRCA1 and 1 in BRCA2, which accounts for 2/24 (8%) of the total mutations detected in BRCA1 and 1/23 (4%) of the mutations in BRCA2 detected in this cohort. Notably, the family history of the individuals with these mutations is largely unremarkable suggesting that family history alone is a poor predictor of mutation status in Asian families. In conclusion, this study in a multi-ethnic (Malay, Chinese, Indian) cohort suggests that large genomic rearrangements are present at a low frequency but should nonetheless be included in the routine testing for BRCA1 and BRCA2.

Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin

“…For instance, LGRs account for 2% of all BRCA2 and 12.5% of all BRCA1 disease-causing mutations detected in a Danish cohort [4]. Similar findings are observed in Australian (2.3% vs. 14.9%), Malaysian (4% vs. 8%), Italian (0% vs. 10.5%), Czech Republic (0% vs. 12.3%), or USA (6% vs. 22%) cohorts [5][6][7][8][9]. In Spain, previous studies detected BRCA2 LGRs in 1.5%, and BRCA1 LGRs in 2.8% of the families analyzed [10,11].…”

“…Overall, we have detected BRCA2 LGRs in 7 out of 836 HBOC families analyzed, supporting a low proportion of these alterations in our population. Indeed, a low proportion (ranging from 0 to 2.5%) has been reported in most populations analyzed [3,[5][6][7][8][9]30]. Some authors have reported male breast cancer patients in most families harboring BRCA2 LGRs, thus suggesting a strong association with this malignancy [4,5,21].…”

“…LGRs fully characterized at the molecular level [4,6,9,[15][16][17][18][19][20][21][22][23][24]. Here, we describe the molecular characterization of four additional LGRs indentified in Spanish HBOC families.…”

BRCA1/2 Mutation Frequency is HIGH in Japanese Triple-Negative Breast Cancer Patients

“…In patients from high-risk families, an intragenic rearrangement prevalence of 2 and 12 for each mutation has been suggested [22][23][24][25] . In 2011, Sluiter and van Rensburg reported that 81 rearrangements of BRCA1 had been found worldwide 22 .…”

“…The frequency of these rearrangement mutations varies in different races. Notably, although rearrangement mutations in Asian and Hispanic populations have been reported, they are relatively more frequent in Caucasians [23][24][25] . Although direct sequencing is the standard method used for BRCA1 / 2 genetic testing, this method cannot detect rearrangement mutations.…”