Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico

Abstract

Background Frequent recurrent BRCA1 and BRCA2 gene (BRCA) mutations among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 ex9-12del), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economical screening for hereditary breast and ovarian cancer in Mexico. Methods In a multistage approach, 188 cancer cases unselected for family cancer history (92 ovarian cancer and 96 breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL®) of 115 recurrent mutations in a multiplex assay (114 on a mass spectroscopy platform, and a PCR assay for the BRCA1 ex9-12del mutation), followed by sequencing of all BRCA exons and adjacent intronic regions, and BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL negative cases. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. Results BRCA mutations were detected in 28% (26/92) of ovarian cancer cases and 15% (14/96) of breast cancer cases overall and 27% (9/33) of triple negative breast cancer. Most breast cancer cases were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of the BRCA-associated ovarian cancer cases and 29% of the BRCA-associated breast cancer cases. At 2% of the sequencing and MLPA cost, the HISPANEL detected 68% of all BRCA mutations. Conclusion In this study, we found a remarkably high prevalence of BRCA mutations among ovarian and breast cases not selected for family history, and BRCA1 ex9-12del explained one third of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer prevention.

Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations

“…Genomic DNA was obtained by standard methods from peripheral blood., All patients were screened for 114 BRCA mutations at a cost of <$20 USD, with a panel estimated to account for up to 75-80% of all Hispanic BRCA mutations (HISPANEL) [20]. Multiplex PCR fragments were genotyped on a Sequenom MassARRAY platform using MALDI-TOF (matrix-assisted laser desorption/ ionization -time-of-flight) mass spectrometry as previously described [11,20].…”

“…Multiplex PCR fragments were genotyped on a Sequenom MassARRAY platform using MALDI-TOF (matrix-assisted laser desorption/ ionization -time-of-flight) mass spectrometry as previously described [11,20].…”

Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations

“…Of these, 4 mutations in BRCA1 (c.548-?_4185+?del, c.2296-2297delAG, c.3598C>T and c.4327C>T) and 3 in BRCA2 (c.519+5_519+8delGTAA, c.1796-1800delTT-TAT and c.4111C>T) were present in women with earlyonset BC and no family history of the disease [48,50]. In the Mexican patients unselected for family history, 36 different BRCA mutations were described (20 in BRCA1 and 16 in BRCA2) [50,51]. Of these, 12 were also present in cohorts A or B (Table 3).…”

Genetics, Tumor Features and Treatment Response of Breast Cancer in Latinas

“…Villarreal-Garza et al found that 14 (15%) mutation cases including founder BRCA1 ex9-12del large rearrangement accounted for 29%, higher prevalence of other large rearrangement and HISPANEL panel accounted for 77% of all the BRCA mutations in 96 unselected Mexican women (Mexico DF) with BC [53], and in a later study Villarreal-Garza et al reported that seven mutations and BRCA1 ex9-12del accounted for 89 and 41% of a total of 44 BRCA mutations in 190 <50 years Mexican women (Mexico DF) with TNBC [54]. Three studies performed in Colombian (Bogotá city) in high risk for breast or ovarian cancer women described five recurrent founder mutations: BRCA1 c.3331 3334delCAAG (the most frequent), BRCA1 c.5123C>A, BRCA2 c.2808 2811del4, BRCA2 6076 delGTTA and BRCA2 c.6275 6276delTT [40][41]55].…”