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

<div><p>Germline mutations in <i>BRCA1</i>, <i>BRCA2</i> and <i>TP53</i> 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 <i>BRCA1, BRCA2</i>, <i>CHEK2</i> (c.1100delC<i>)</i> and <i>TP53</i> 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 <i>BRCA1</i> (13%), 4 in <i>BRCA2</i> (7%) and one in <i>TP53</i> (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 <i>BRCA1</i> and in 6.2% in the <i>BRCA2</i> genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried <i>BRCA1</i> 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 <i>BRCA1/2</i>-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of <i>BRCA1/2</i>-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 <i>BRCA1</i> germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.</p> </div

Differentially expressed genes between BRCA1/BRCA2-negative and -positive mutation-driven tumors.

<p>(*)Concordant results in gene expression and array-CGH analysis.</p

Hierarchical clustering based on 34 differentially expressed genes in <i>BRCA1/BRCA2</i>-associated and -negative tumors.

<p>Each row represents a gene, and each column represents a tumor sample. Red indicates strong expression; green indicates weak expression; and black indicates moderate expression. Red squares represent <i>BRCA1</i> or <i>BRCA2</i> pathogenic-associated tumors, and green squares represent tumors from <i>BRCA1/2</i> WT (non mutated). The colored lines of the dendrogram represent the support for each clustering: black and gray lines indicate greater reliability; yellow and red lines indicate lesser reliability.</p

Deleterious mutations detected in the <i>BRCA1</i>, <i>BRCA2</i> and <i>TP53</i> genes.

<p>BIC, Breast Cancer Information Core; IARC, International Agency for Research on Cancer; HR, hormonal receptor status; (a), mutation identified in Brazilian patients reported by others; ND: not determined – (ID_2032 patient is adopted).</p

Distribution of <i>BRCA1/2</i> status according to immunohistochemical characteristics and familial history.

<p>WT, wild type; UV, unclassifed variant; MUT, mutated; FH, cancer family history; HR, hormonal receptor tumor; TN, triple negative; NTN, non-triple negative; (+), positive; (−), negative; p, Pearson chi-square.</p><p>(*) Statistically significant with a 95% confidence interval; for familial history distribution the 54 unrelated young patients were considered; for distribution of HR, TN/NTN and HER2 status the 55 young patients (54 unrelated and one sister) were considered.</p

Unclassified Variants (UVs) identified in <i>BRCA1</i> and <i>BRCA2</i> genes.

<p>N, number of probands who harbor the UV; Exon: where the UV is mapped; BIC, Breast Cancer Information Core (not described in BIC database; unkown: with unknown clinical relevance); LOVD-IARC (no result: not classified in LOVD-IARC database); Align GVGD, C0, less likely to interfere in protein function; C15, C45, C55, C65, more likely to interfere in protein function.</p