Comprehensive Analysis of BRCA1, BRCA2 and TP53 Germline Mutation and Tumor Characterization: A Portrait of Early-Onset Breast Cancer in Brazil

Abstract

Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

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

“…Finally, in Uruguay, 17% of 42 patients selected by family history carried a pathogenic germline mutation in Page 7 of 17 one of the BRCA genes [33]. Only two smaller studies (combined n=174) have performed comprehensive BRCA sequencing among Brazilian patients fulfilling NCCN criteria from the Brazilian State of São Paulo, wherein the HISPANEL detection rate would have been 7-11%, which corresponds to more than one third of the mutations detected by complete sequencing (detection rate 20-21%) [24,25]. The BRCA1 c.5266dupC mutation (also known as 5382insC) was the most prevalent mutation identified in this study.…”

“…The HISPANEL is organized into 5 multiplex PCR reactions and detects 59 BRCA1 and 55 BRCA2 mutations, including 15 mutations already described in Brazilian patients [21][22][23][24][25][26]. Results of the HISPANEL analyses were compared to data from an independent cohort of 193 unrelated probands from the same Page 5 of 17 region who met the same inclusion criteria and had full BRCA testing by either Sanger or next generation sequencing at commercial diagnostic laboratories.…”

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

“…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). Another 3 mutations not seen in cohorts A or B were detected in cohort C (n = 402) (1 in BRCA1 and 2 in BRCA2), including the recurrent mutation c.6405_6409delCTTAA (0.5%) [37].…”

Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G Variations in Breast Carcinoma

“…An important role of gene polymorphisms related to the risk of developing BC has been reported but results are still controversial. Approximately 25% of breast cancers are inherited by germ-line mutations in functional and/or oncogenes (Akbari et al, 2013;Carraro et al, 2013;Sohail et al, 2013). As claimed by Bonache et al there are various involvement of additional genetic susceptibility in BC (Bonache et al, 2013).…”