Presença da mutação do gene BRCA1 em cadelas com tumores mamários malignos / Presence of BRCA1 gene mutation in bitches with malignant mammary tumors

Mammary tumors (MTs) in bitches are similar to breast cancers in women. Thus, they can be used as a model for human breast cancer and findings can be extrapolated for use in human medicine. BRCA1 is a tumor suppressor gene. When the gene has a mutation, it cannot repair damaged DNA, which causes genetic instability and tumorigenesis. Therefore, we aimed to study the frequency of single nucleotide polymorphisms (SNPs) in the BRCA1 gene that are associated with distinct histological types of malignant MT in bitches. The study population consisted of 91 bitches, including a control group of 6 animals with healthy mammary glands and 85 animals with MTs. All animals underwent a presurgery evaluation consisting of a questionnaire administered to the person responsible for the animal, a physical examination, collection of peripheral blood for hematological and serum biochemistry evaluations, an electrocardiogram, and a preanesthesia evaluation. In addition, distant metastasis was studied via chest radiography and abdominal ultrasound. After evaluations were complete, the animals that could undergo surgery were administered general anesthesia and underwent a mastectomy or mammary gland sample collection. Histopathological examination and molecular analysis were performed to identify mutations in the BRCA1 gene. Histopathological examinations found 10 different types of malignant tumors in 36 sick animals. Tumor samples plus samples from the 6 control animals were subjected to DNA extraction, polymerase chain reaction (PCR) analysis, and genetic sequencing. The tumor with the highest incidence (33.33%) was a complex carcinoma, followed by carcinoma in mixed tumor (13.88), tubular carcinoma (13.88) and carcinosarcoma (13.88). Molecular analysis revealed 3 different SNP points in 5 samples (4006G>A, 3619A>G, and 3761C>T). The allelic variant 4006G>A (1/36) resulted in the alteration of the amino acid valine by isoleucine (V1336 I). The mutation 3619A>G (2/36) inserted the amino acid alanine instead of threonine (T1207 A). The mutation 3761C>T (2/36) led to the alteration of the amino acid serine by phenylalanine (S1254 F), a mutation for which there are no published reports. The histological types that showed BRCA1 mutations were complex carcinoma (1/5), carcinoma in mixed tumor (1/5), papillary carcinoma (1/5) and tubular carcinoma (2/5). Software analysis identified the new SNP (nucleotide 3761) in BRCA1 and 2 point mutations in nucleotides 4006 and 3619 and responsible for genetic instability. The development of breast cancer is caused by many endogenous and exogenous factors. The results of our study show that these factors have a greater presence in female, mixed breed, uncastrated, and older dogs, confirming the data in the veterinary literature. In the present study, we found different histological types of malignant breast tumors with mutations in the BRCA1 gene, as other authors have reported. However, we also found the mutation 3761C>T, which, to the best of our knowledge, has not been reported in the literature. This shows the need for studies in veterinary medicine that assess mutations in the BRCA1 gene and the most common histological types. In conclusion, SNPs in the BRCA1 gene cause genetic instability, resulting in additional mutations that lead to the development of breast tumors. They are point mutations that affect transcription, resulting in truncated proteins. These proteins may have a loss of function, leading to carcinogenesis.(AU)

Association between single nucleotide polymorphism of BARD1 gene and BRCA1 gene mutation in epithelial ovarian cancer / 中华妇产科杂志

Objective To investigate the relationship between single nucleotide polymorphism (SNP) of BARD 1 gene and BRCA1 gene in epithelial ovarian cancer (EOC).Methods Nineteen EOC patients with BRCA1 gene mutation and 50 EOC cases without BRCA1 gene mutation between January 2016 and October 2016 were collected,and all EOC were diagnosed by pathological method.BARD1 gene variants were detected by next generation sequencing (NGS).The SNP of BARD1 gene was analyzed by Pearson linear correlation.Logistic regression analysis was used to research the clinicopathologic features and BRCA1 gene mutation associated with BARD1 gene SNP.Pearson's chi-square test was used to analyze the association between BARD1 gene Val507Met,Arg378Ser and Pro24Ser with different clinicopathologic features and BRCA1 gene mutation risk.Results (1) Eight BARD1 gene variants were found in 69 ovarian cancer patients,in which Val507Met,Arg378Ser and Pro24Ser were common variants,and the rate of mutation were all 54％ (37/69).(2) There was a significant linear correlation among Val507Met,Arg378Ser and Pro24Ser (all P＜0.01).(3) Obvious differences were found in Val507Met,Arg378Ser and Pro24Ser of BARD1 gene between BRCA1+ and BRCA1 (all P＜0.05).(4) No differences were found between BARD1 gene Val507Met,Arg378Ser and Pro24Ser and the clinicopathologic features (all P＞0.05),while obvious differences were found in BRCA1 gene mutation compared to the controls group.The risk of BRCA1 mutation in Val507Met and Arg378Ser were more evident in subjects with negative family history,positive menopause history,negative tubal ligation,onset age (≤60 years old) and sensitivity to platinum-based chemotherapy in EOC (all P＜0.05),while Pro24Ser was only more evident in positive menopause history of EOC (P＜0.05).Conclusions BARD1 Val507Met,Arg378Ser and Pro24Ser are the common genotypes,which are associated with BRCA1 mutation in EOC.The family history,menopause history,tubal ligation,onset age and sensitivity to platinum-based chemotherapy have effects on BARD1 SNP in the risk of BRCA1 gene mutation.

Câncer de mama hereditário: rastreamento de mutações nos genes BRCA1 e BRCA2 e busca de novos genes de susceptibilidade / Hereditary breast cancer: screening for mutations in the BRCA1 and BRCA2 genes and search for new susceptibility genes

O Câncer de Mama Hereditário (HBC) é uma doença autossômica dominante caracterizada, principalmente, por mutações germinativas nos genes BRCA1 e BRCA2 que conferem alto risco em desenvolver câncer de mama e ovário. A identificação da causa genética responsável pelo aumento de risco em mulheres com critérios clínicos para HBC é extremamente importante para o manejo das mesmas. Dessa forma, o objetivo do presente estudo foi avaliar mutações pontuais germinativas e alterações no número de cópias (CNV) nos genes BRCA1 e BRCA2 em 128 famílias brasileiras, as quais preencheram os seguintes critérios para HBC: 108 para Câncer de Mama e Ovário Hereditário (HBOC), 20 para Câncer de Mama e Colón Hereditário (HBCC), sendo que 32 preencheram critérios clínicos para ambos. Amostras de DNA de sangue periférico foram utilizadas para avaliar a presença de mutações germinativas através do sequenciamento completo dos genes BRCA1 e BRCA2 nas sequências codificadoras e limites éxon-íntron e também verificar as mutações pontuais nos genes TP53 (R337H) e CHEK2 (1100delC). Os pacientes não portadores de mutações nos genes BRCA1/2 foram selecionados para análise de MLPA (multiplex ligation-dependent probe amplification) para avaliar as CNVs nestes genes. A prevalência de mutações patogênicas neste estudo foi de 25% (32/128), incluindo 21 no BRCA1 (2 splice site, 2 missense, 9 frameshift, 6 nonsense e 2 CNVs), 7 no BRCA2 (3 frameshift e 4 nonsense), 3 no TP53 (3 missense) e uma no gene CHEK2 (1100delC). Sete (25% - 7/28) das mutações patogênicas identificadas nos genes BRCA1 e BRCA2 foram descritas pela primeira vez neste estudo, cinco no gene BRCA1, incluindo uma nova mutação no sítio de splice no BRCA1, cuja patogenicidade foi confirmada através da análise do transcrito; e duas no gene BRCA2...

Hereditary Breast Cancer (HBC) is an autosomal dominant disease mainly characterized by germline mutations in BRCA1 and BRCA2 genes that confer high risk for developing breast and ovarian cancer. The identification of high-risk women carrying mutations responsible for the disease is extremely important for their management. Thus, the aim of this study was to evaluate germline mutations and copy number variations (CNVs), in BRCA1 and BRCA2 in 128 Brazilian families, who met the following criteria for HBC: 108 for Hereditary Breast and Ovarian Cancer (HBOC) and 20 for Hereditary Breast and Colon Cancer (HBCC). Thirty two patients met clinical criteria for both syndromes. DNA samples from peripheral blood were used to assess the presence of germline mutations by capillary sequencing of the entire coding sequence of BRCA1 and BRCA2 genes, exon - intron boundaries, as well as TP53 (R337H) and CHEK2 (1100delC) variants. Patients who did not carry mutations in the BRCA1/2 genes were selected for MLPA analysis (multiplex ligation-dependent probe amplification) to assess CNVs in these genes. The prevalence of pathogenic mutations in this study were 25 % (32 /128) , including 21 in BRCA1 (2 splice site, 2 missense, 9 frameshift, 6 nonsense and 2 CNVs), 7 BRCA2 (3 nonsense and 4 frameshift ), 3 in TP53 (3 missense) and one in CHEK2 gene. Seven (25 % - 7/28) out of 28 pathogenic mutations in BRCA1 and BRCA2 genes were first described in this study, of which five were in the BRCA1, including a novel splice site mutation, whose pathogenicity was confirmed by transcript analysis and two in the BRCA2 gene. Among the VUS carriers 18 different were found variants, where two of them were described for the first time. The analysis of the three algorithms for protein prediction of VUS ( Polyphen, SIFT and AlignGVGD) showed that seven variants have been classified as probably pathogenic in at least one of them (four in one algorithm , two in two algorithms and one...

Fenocópia: nem tudo é o que parece / Fenocopy: not everything is what seems to be

O câncer de mama e de ovário são apresentações fenótipas altamente prevalentes da síndrome de câncer de mama e ovário hereditário (HBOC) associada com mutações germinativas nos genes BRCA1, BRCA2, RAD51C, PALB2, entre outros. Fenocópia é o indivíduo cujo fenótipo, originado por influências principalmente ambientais, é idêntico ao fenótipo produzido por um determinado genótipo, de certo modo mimetizando um fenótipo produzido por um gene. Neste artigo apresentamos um caso clínico de uma mulher com carcinoma ductal in situ (CDIS) após ooforectomia bilateral redutora de risco, pertencente a uma família com HBOC e cujo teste genético BRCA1 foi inconclusivo. Insistimos no rastreamento genético em outro membro da família afetado. A investigação genética feita em sua sobrinha com câncer de ovário foi conclusiva, com a identificação da mutação c.5083del19 no gene BRCA1. Concluímos que a mulher com CDIS era de fato uma fenocópia, tendo desenvolvimento um CDIS esporádico (não hereditário).

Breast and ovary cancers are highly prevalent phenotypes of the hereditary breast and ovary cancer syndrome (HBOC) associated with germline mutations in one of the susceptible genes BRCA1, BRCA2, RAD51C, PALB2, among others. A phenocopy is an individual whose phenotype, under a particular environmental condition, is identical to the one of another individual whose phenotype is determined by the genotype, someway mimicking the phenotype produced by a gene. In this article we described a woman with breast ductal carcinoma in situ (DCIS) after profilactic bilateral oophorectomy belonging to a family with HBOC whose genetic testing BRCA1 was inconclusive. We insisted with the genetic screening of another affected family member. The genetic testing of her nephew with ovary cancer was clarifying, with the identification of deleterious mutation c.5083del19 in the BRCA1 gene. We concluded that the woman with CDIS was in fact a phenocopy, and developed a sporadic (not hereditary) CDIS.

ERCC1 and BRCA1 mRNAs expression levels in malignant pleural and peritoneal effusions are associated with chemosensitivity to cisplatin in vitro / 肿瘤

Objective:The aim of this study was to investigate the association of mRNA expressions of ERCC1 (excision repair cross-complementing group 1) and BRCA1 (breast cancer 1) with chemosensitivity to cisplatin in malignant pleural and peritoneal effusions.Methods:Malignant pleural and peritoneal effusions were collected from 46 patients diagnosed with stage Ⅳ malignant tumor, prospectively. The tumor cells were isolated and the sensitivity of tumor cells to cisplatin was detected by adenosine triphosphate-bioluminescence assay (ATP-TCA). Real-time quantitative PCR was used to determine the mRNA expressions of ERCC1 and BRCA1. Results:The expression level of ERCC1 mRNA was negatively correlated with sensitivity of non-small cell lung cancer (NSCLC) to cisplatin (P= 0.001, r=0.685). BRCA1 mRNA expression level had negative correlation with sensitivity to cisplatin in both NSCLC (P=0.014, r=0.541) and gastric cancer (P=0.002, r=0.625). A significant interaction was found between the effects of ERCC1 and BRCA1 mRNA expressions on sensitivity to cisplatin (P=0.010 for all patients;P=0.027 for gastric cancer patients).Conclusion:ERCC1 and BRCA1 mRNA expression levels correlated with ex vivo chemosensitivity of tumor cells to cisplatin in malignant pleural and peritoneal effusions. Detection of both ERCC1 and BRCA1 may have a higher reliability in predicting the sensitivity of tumor cells to cisplatin than detection of single ERCC1 or BRCA1 expression.

Effects of early exposure of new born rats to octylphenol on breast cancer incidence and BRCA1 expression / 肿瘤

Objective: To investigate the effects of early exposure of new born rats to octylphenol (OP) on breast cancer incidence and breast cancer susceptibility gene 1 (BRCA1) expression. Methods: Female Sprague-Dawley rats were randomly divided into control (Con) group, model (Mod) group, OP 20, OP 40, OP 80 groups. OP was subcutaneously injected into rats from d 21 to d 27. The rats were given dimethylbenz[a]anthracene (DMBA) intragastrically on d 42 and were sacrificed on 180 d. The incidence of breast cancer, the changes in serum levels of estradiol and progesterone, the alteration of estrogen receptor (ER) expression and BRCA1 mRNA and protein expression in breast cancer tissues were observed. Results: No breast cancer occurred in Con group. The incidence rate of breast cancer in the Mod group, OP 20 group, OP 40 group, and OP 80 group were 70% (14/20), 60% (12/20), 25% (5/20), and 50% (10/20), respectively. The fluorescence intensities of BRCA1 expression were 31.54 ± 6.15, 36.27 ± 7.57, 61.69 ± 9.96 and 47.38 ± 10.45, respectively; the logarithm value of BRCA1 mRNA expressions were 3.46 ± 6.52, 4.12 ± 0.86, 5.53 ± 0.75, and 4.35 ± 0.58, respectively. The ER expression in breast cancer tissues decreased after the rats were exposed to OP. Conclusion: OP decreased the occurrence of DMBA-induced breast cancers, which may be related with up-regulation of BRCA1 expression and down-regulation of ER expression in breast cancers.