Lynch syndrome identification in a Brazilian cohort of endometrial cancer screened by a universal approach.

OBJECTIVE: To report the frequency of Lynch syndrome (LS) in a cohort of patients from Southeast Brazil bearing endometrial cancer (EC), using a tumor screening universal approach. METHODS: A total of 242 endometrial carcinomas were screened by immunohistochemistry (IHC) and microsatellite instability (MSI) for detection of DNA mismatch repair deficiency (dMMR). MLH1 methylation was assessed to identify sporadic cases. Patients with dMMR tumors were recruited for germline variant analysis by next-generation sequencing of the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. RESULTS: Ninety-three out of 242 tumors (38.5%) were classified as dMMR based on MSI and IHC results. Of these, 54 cases were selected for germline analysis, and 37/54 (68.5%) were available for sequencing. Ten patients (10/37, 27%) harbored germline pathogenic or likely pathogenic variants, most of them in the MSH6 gene (4/10, 40%). Seven variants of uncertain significance were found. Eight novel germline variants were identified. The LS prevalence in our cohort was of at least 4.1%. LS patients presented lower mean age at cancer diagnosis compared with patients diagnosed with sporadic EC. Individuals with dMMR tumors, without germline pathogenic variants detected in LS-genes ("Lynch-like" syndrome), had an intermediate mean age at cancer diagnosis between LS and sporadic cases. CONCLUSION: This is the first report of the LS prevalence in EC screened by a universal approach in Brazil. Our findings contribute to a better understanding of the mutational landscape of this syndrome in Brazil, which is relevant for improved identification, genetic counseling, prevention and control of cancer in LS.

BRCA1 Expression by Immunohistochemistry and Prognosis in Ovarian Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Homologous recombination deficiencies are associated with increased platinum sensitivity and potential response to poly (ADP-ribose) polymerase inhibitors in epithelial ovarian cancer. As an alternative to germline testing or somatic tumor sequencing, BRCA1 deficiency can be detected by immunohistochemistry and might predict homologous recombination deficiencies. OBJECTIVE: This study aimed to assess the association between BRCA1 expression by immunohistochemistry and the prognosis of patients with epithelial ovarian cancer. METHODS: We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We searched PubMed, EMBASE, Web of Science, and Scopus databases through July 2019. Reference lists of selected articles were screened for further studies. We conducted qualitative synthesis and meta-analyses of hazard ratios for overall survival and progression-free survival. RESULTS: Of 41 studies of BRCA1 expression using immunohistochemistry, 18 evaluated the association of BRCA1 expression with patient survival (2738 cases). The loss of BRCA1 expression was associated with improved overall survival (hazard ratio = 0.67, 95% confidence interval 0.57-0.77) and progression-free survival (hazard ratio = 0.70, 95% confidence interval 0.58-0.84). CONCLUSIONS: Negative BRCA1 expression assessed by immunohistochemistry was associated with a better prognosis in epithelial ovarian cancer.

Immunohistochemistry for the detection of BRCA1 and BRCA2 proteins in patients with ovarian cancer: a systematic review.

BACKGROUND: Loss of function in either breast cancer type 1 susceptibility protein (BRCA1) or breast cancer type 2 susceptibility protein (BRCA2) is a major risk factor for epithelial ovarian cancer (EOC) development. BRCA1 or BRCA2 deficiencies are associated with short-term prognosis and might have importance for the treatment of women with the disease. However, the screening of all possible mechanisms of dysfunction is expensive, time-consuming and difficult to apply in clinical practice. On the other hand, immunohistochemistry (IHC) is a simple and reliable method to access the expression of several proteins in tumour tissues. MATERIALS AND METHODS: This systematic review aims to evaluate the current usage of IHC to detect BRCA1 and BRCA2 deficiencies in EOC. We searched and evaluated all primary literature on the use of IHC for evaluating BRCA1 and BRCA2 proteins expression in EOC. The main concepts for the search were: ovarian neoplasms, IHC, BRCA1 and BRCA2. RESULTS: Forty-four studies from 925 unique titles were included. A total of 4206 tumour samples were evaluated for BRCA1 and 1041 for BRCA2 expression. Twelve BRCA1 primary antibodies were used in 41 studies, and the most common was the MS110 clone (75.6%). Seven BRCA2 primary antibodies were used in ten studies. Using the cut-off of 10%, 47.0% of EOCs are associated with loss of BRCA1 and 34.5% with the loss of BRCA2 expression. CONCLUSION: IHC was effective to detect loss of BRCA1 protein expression in EOC; however, data on BRCA2 expression were heterogeneous and difficult to interpret.

Molecular basis of familial adenomatous polyposis in the southeast of Brazil: identification of six novel mutations.

BACKGROUND: The goal of this study was to screen point mutations and deletions in APC and MUTYH genes in patients suspected of familial adenomatous polyposis (FAP) in a Brazilian cohort. METHODS: We used high-resolution melting, Sanger direct sequencing and multiplex ligation-dependent probe association (MLPA) assays to identify point mutations, and large genomic variations within the coding regions of APC and MUTYH genes. RESULTS: We identified 19 causative mutations in 40 Brazilian patients from 20 different families. Four novel mutations were identified in the APC gene and two in the MUTYH gene. We also found a high intra- and inter-familial diversity regarding extracolonic manifestations, and gastric polyps were the most common manifestation found in our cohort. CONCLUSION: We believe that the FAP mutational spectrum can be population-specific and screening FAP patients in different populations can improve pre-clinical diagnosis and improve clinical conduct.