Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients

Abstract

BackgroundGerm line mutations in BRCA1 and BRCA2 (BRCA1/2) and other susceptibility genes have been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for HBOC, we carried out a comprehensive screening of BRCA1/2, TP53 R337H, CHEK2 1100delC, followed by an analysis of copy number variations in 14 additional breast cancer susceptibility genes (PTEN, ATM, NBN, RAD50, RAD51, BRIP1, PALB2, MLH1, MSH2, MSH6, TP53, CDKN2A, CDH1 and CTNNB1).MethodsCapillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for detecting point mutations and copy number variations (CNVs), respectively, for the BRCA1 and BRCA2 genes; capillary sequencing was used for point mutation for both variants TP53 R337H and CHEK2 1100delC, and finally array comparative genomic hybridization (array-CGH) was used for identifying CNVs in the 14 additional genes.ResultsThe positive detection rate in our series was 26%. BRCA1 pathogenic mutations were found in 20 cases, including two cases with CNVs, whereas BRCA2 mutations were found in 7 cases. We also found three patients with the TP53 R337H mutation and one patient with the CHEK2 1100delC mutation. Seven (25%) pathogenic mutations in BRCA1/2 were firstly described, including a splice-site BRCA1 mutation for which pathogenicity was confirmed by the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. Microdeletions of exon 4 in ATM and exon 2 in PTEN were identified in BRCA2-mutated and BRCA1/2-negative patients, respectively.ConclusionsIn summary, our results showed a high frequency of BRCA1/2 mutations and a higher prevalence of BRCA1 (64.5%) gene. Moreover, the detection of the TP53 R337H variant in our series and the fact that this variant has a founder effect in our population prompted us to suggest that all female breast cancer patients with clinical criteria for HBOC and negative for BRCA1/2 genes should be tested for the TP53 R337H variant. Furthermore, the presence of genomic structural rearrangement resulting in CNVs in other genes that predispose breast cancer in conjunction with BRCA2 point mutations demonstrated a highly complex genetic etiology in Brazilian breast cancer families.

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

“…The most notable property of p53 is its action as a transcription factor [83]. We found three articles that studied variations in TP53, all in Brazilian populations [31,84,85]. These articles studied the c.1010G>A (p.R337H) mutation, which occurs at a high frequency in southern and southeastern Brazil [86][87][88][89][90].…”

“…The CHEK2 1100delC variant, which is associated with increased BC susceptibility among familial BC cases not attributable to mutations in BRCA1/2 [67], was studied in Brazilian (n = 120) [31] and Chilean (n = 196) patients with hereditary BC [67]. Only one of the Brazilian patients carried this mutation (0.83%), and it was not present is any of the Chilean cases (n = 196).…”

“…These articles studied the c.1010G>A (p.R337H) mutation, which occurs at a high frequency in southern and southeastern Brazil [86][87][88][89][90]. Silva et al [31] reported a frequency of 2.5% for this variant and suggested that all BRCA-negative female BC patients with clinical criteria for hereditary breast-ovarian cancer should be tested for the c.1010G>A variant. Giacomazzi et al [84] reported that the prevalence of p.R337H was higher in women diagnosed with BC at or before 45 years of age (12.1%) than in those diagnosed at 55 or older (5.1%).…”

“…In Brazil, 6 studies that collectively screened 1151 individuals with hereditary BC reported 34 different BRCA mutations (24 in BRCA1 and 10 in BRCA2) [30][31][32][33][34][35], including 7 recurrent mutations (5 in BRCA1 and 2 in BRCA2) (Additional file 1: Table S1). In cohort B, a study by Carraro et al [36] (n = 54) detected another 5 mutations (2 in BRCA1 and 3 in BRCA2), including the recurrent mutation c.5266dupC (3.7%), which was also a recurrent mutation in hereditary BC (Additional file 1: Table S1).…”

Frecuencia de las mutaciones en los genes BRCA en mujeres con agregación familiar de cáncer de glándula mamaria/ovario

“…Algunos estudios de familias con antecedentes de inicio de CGM a edad temprana sugieren que las mutaciones en el gen BRCA1 son responsables de aproximadamente el 50% de los casos de este tipo de cáncer, del 90 % de los casos de CO y hasta de un 95% de riesgo global para ambos tumores (Lynch et al, 2013;Seong et al, 2014). Los casos con mutaciones en dichos genes con un cáncer primario de mama tienen un riesgo de 64% de desarrollar una enfermedad colateral y un riesgo de 44% de desarrollar un cáncer de ovario a los 70 años (Saam et al, 2015;Silva et al, 2014). Además, "la frecuencia de las mutaciones en BRCA1 y BRCA2 varía de acuerdo con el país y el grupo étnico" (Narod & Rodríguez, 2011, p. 421).…”