BRCA mutations: Implications of genetic testing in ovarian Cancer

Ovarian cancer (OC) is one of the most lethal gynecological cancers with a 5?year survival rate that ranges from 30% to 40%. Breast cancer genes (BRCA1 and BRCA2) play a key role in maintaining genomic stability. Mutations in BRCA1/2 genes lead to the accumulation of double?strand breaks, resulting in tumorigenesis. The risk of developing OC in women with BRCA1 and BRCA2 mutations is 39% and 11%, respectively, by 70 years of age. BRCA1/2 mutation testing is thus important to identify women at greatest risk of developing OC in addition to its impact on diagnosis, prognosis, and targeted therapy. Genetic testing is required to identify the BRCA mutations and thus select patients who can benefit from polyadenosine diphosphate (ADP)杛ibose polymerase (PARP) inhibitor therapy. Tumor BRCA mutation testing can detect both germline and somatic mutations allowing implementation of preventive strategies on a broader population. Various international guidelines recommend BRCA1/2 mutation genetic testing in all OC patients irrespective of age and family history. This review focuses on the role of BRCA mutation testing in OC

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)

Prevalence and oncologic outcomes of BRCA1/2 mutation and variant of unknown significance in epithelial ovarian carcinoma patients in Korea

OBJECTIVE: BRCA mutational status is important in the management of ovarian cancer, but there is a lack of evidence supporting genetic testing in Asian populations. This study was performed to investigate the prevalence and prognostic outcomes of BRCA1/2 mutation and variant of unknown significance (VUS) in Korean patients diagnosed with epithelial ovarian cancer (EOC). METHODS: Among patients newly diagnosed with EOC between January 2007 and January 2017, those tested for germline BRCA1/2 mutation were studied, regardless of family history. Overall survival (OS) and progression-free survival (PFS) were compared between the patients with and without BRCA1/2 mutation and VUS. RESULTS: A total of 313 patients underwent BRCA testing: 88 patients had a BRCA1/2 mutation and 48 patients had a BRCA1/2 VUS (28.1% and 15.3%, respectively). There were no significant associations between BRCA1/2 mutation, BRCA1/2 wild-type, or BRCA1/2 VUS with age at diagnosis, histologic distribution, or residual disease status after primary cytoreductive surgery. BRCA1 mutation, including BRCA1 VUS, showed no difference in PFS or OS compared to BRCA1 wild-type. In contrast, BRCA2 mutation showed longer PFS than that of BRCA2 wild-type (P=0.04) or BRCA2 VUS (P=0.02). BRCA2 mutation, including BRCA2 VUS, did not show any difference in OS compared to BRCA2 wild-type. CONCLUSION: BRCA mutation and BRCA VUS had similar clinical characteristics and survival outcomes, except that BRCA2 mutation showed better PFS. The results of this study will help to understand the prognostic significance of BRCA mutation and VUS in Korean patients.

Genes de predisposición al cáncer de mama / Breast Cancer Predisposition Genes

Resumen El cáncer de mama es una enfermedad con una importante incidencia y mortalidad entre las mujeres. Los factores genéticos en su génesis aún no han sido reconocidos completamente, pero se admite el importante papel que juegan los genes de predisposición como el BRCA1 y BRCA2, y otros genes de reciente aparición, en las formas hereditarias y principalmente en el fenotipo triple negativo. El cáncer de mama hereditario representa entre un 5-10 % del total de casos de esta patología. BRCA1 y BRCA2 son genes de gran tamaño, y su principal función es mantener la integridad cromosómica, reparando rupturas de doble cadena del ADN por medio de recombinación homóloga. Los otros genes de predisposición en su mayoría cumplen una función en el mantenimiento y reparación del DNA. Actualmente existen pruebas para detección de mutaciones de estos genes en pacientes en riesgo, las cuales permiten implementar intervenciones médicas tempranas, el respaldo psicológico a la persona y la obtención de un diagnóstico más confiable; lo cual a largo plazo podría reducir los altos costos del cáncer. Entre las terapias disponibles para estos pacientes se encuentran desde cirugías preventivas como la mastectomía bilateral y la salpingo-ooforectomía hasta tratamientos farmacológicos como el uso de tamoxifeno, anticonceptivos orales o los recientes inhibidores de la PARP (Poly ADP Ribose Poymerase). Esta revisión pretende hacer énfasis en las características biológicas, genéticas, diagnósticas y terapéuticas del cáncer de mama hereditario para todo el personal de salud.

Abstract Breast cancer is a disease with a significant incidence and mortality among women. Genetic factors in its genesis have not yet been fully recognized, but the important role of predisposing genes such as BRCA1 and BRCA2, and other newly discovered genes in hereditary forms and mainly in the triple negative phenotype are recognized. Hereditary breast cancer represents between 5-10 % of the total cases of this pathology. BRCA1 and BRCA2 are large genes, and their main function is to maintain chromosomal integrity, repairing double strand breaks of DNA by means of homologous recombination. The other predisposing genes, for the most part, play a role in the maintenance and repair of DNA. Currently, there are tests to detect mutations of these genes in patients at risk, implementing early medical interventions, psychological support to the person and obtaining a more reliable diagnosis; which in the long run could reduce the high costs of cancer. Among the available therapies for these patients are preventive surgeries such as bilateral mastectomy and salpingo-oophorectomy, pharmacological treatments such as the use of tamoxifen, oral contraceptives or the recent PARP inhibitors (Poly ADP Ribose Poymerase). The objective of this review is to emphasize the biological, genetic, diagnostic and therapeutic aspects of hereditary breast cancer for all health workers.

GENETIC AND DEMOGRAPHIC FACTORS OF A BRAZILIAN POPULATION SAMPLE AT-RISK OF HEREDITARY BREAST AND OVARIAN CANCER / Fatores genéticos e demográficos de uma amostra da população brasileira sob risco de síndrome de câncer de mama e ovário hereditários

Objective: Genetic-related breast cancer has a tendency to manifest earlier and to be more aggressive than sporadic cancer. There are few studies evaluating the prevalence and incidence of hereditary breast and ovarian cancer (HBOC) among Brazilians. In order to improve assistance, efforts to characterize the population at risk of HBOC could help to formulate locally designed guidelines. Methodology: Descriptive retrospective study in Hospital Erasto Gaertner's service of Oncogenetics, in Curitiba, state of Paraná, Brazil. We included individuals at-risk for HBOC, according to the National Comprehensive Cancer Network (NCCN) criteria, who had performed genetic tests for HBOC. We collected complete family history, presented as heredograms. We excluded families with inappropriate family history. Results: Of the 27 patients analyzed (total of 25 families), 7% were asymptomatic, 8% had ovarian cancer and 85% had breast cancer. Mutations were found in 29.6%, 6 cases of BRCA1, 1 of BRCA2 and 1 of TP53. Triple negative was the most common reported subtype, representing 60% of breast cancers; among patients with identified pathogenic variants, 2 were BRCA2 mutated and 1 TP53 mutated. The mean age of diagnosis was 40 years for those identified as probands on heredograms; in the generation above, it was 52,5, and in the below, 33, suggesting the antecipation phenomena Two new mutations were identified in Brazilian population, both in BRCA1: c.4258 G>A and c.5345 G>A. The most frequent NCCN criteria were number 2, 9, 8 and 4. Estimated penetrance was 22%. Conclusion: This is the first descriptive study in the population at-risk for HBOC in the state of Paraná. We could identify two new pathogenic variants of BRCA1 in Brazilian population. A comprehensive family history was included in the study, depicted as heredograms of each family. Despite the low number of patients, the main results are in agreement with previous studies

Objetivo: Os carcinomas de mama hereditários têm a tendência de se manifestar precocemente e serem mais agressivos do que os esporádicos. São poucos os estudos que avaliam a prevalência e a incidência da síndrome de câncer de mama e ovário hereditário (SCMOH) na população brasileira. No intuito de melhorar a assistência prestada, a análise das características encontradas na população em risco para SCMOH ajudaria a formulação de protocolos regionais para a abordagem desses pacientes. Metodologia: Estudo descritivo retrospectivo realizado no serviço de Oncogenética do Hospital Erasto Gaertner em Curitiba, Paraná. Incluímos indivíduos em risco para SCMOH pelos critérios estabelecidos pela National Comprehensive Cancer Network (NCCN) e que realizaram testes genéticos para SCMOH. Coletamos o histórico familiar completo, apresentado na forma de heredograma. Foram excluídas famílias com histórico familiar inapropriado. Resultados: Das 27 pacientes analisadas (total de 25 famílias), 7% eram assintomáticas, 8% tiveram câncer de ovário e 85%, câncer de mama. Mutações foram encontradas em 29,6%, sendo 6 casos de BRCA1, 1 de BRCA2 e 1 de TP53. Tumores triplo negativos foram os mais encontrados entre os subtipos, representando 60% dos carcinomas de mama; dentre os pacientes com variantes patogênicas, 2 eram de mutações em BRCA2 e 1 em TP53. A média de idade entre as pacientes foi de 40 anos entre probandas dos heredogramas; na geração superior, foi de 52,5 anos e na inferior, de 33, sugerindo o fenômeno de antecipação. Duas novas mutações foram descritas na população brasileira, as duas sendo em BRCA1: c.4258 G>A e c.5345 G>A. Os critérios NCCN mais encontrados foram os de número 2, 9, 8 e 4. A penetrância estimada foi de 22%. Conclusão: Este foi o primeiro estudo descritivo de uma população em risco para SCMOH no estado do Paraná. Encontramos duas novas mutações que não haviam sido descritas na população brasileira até então. Foi realizada a análise detalhada do histórico familiar das pacientes, sendo descrita e detalhada em heredogramas para cada família. Apesar do baixo número de indivíduos analisados, os resultados principais foram de acordo com o encontrado em estudos prévios

Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube / 부인종양

OBJECTIVE: The aim of the present study was to assess the frequency of germline mutations in patients with peritoneal carcinoma (PC) or the fallopian tube carcinoma (FTC), using a multi-gene panel. METHODS: Twenty-six patients diagnosed with either PC or FTC between January 2013 and December 2016 were recruited consecutively. Germline DNA was sequenced using a 6-gene next generation sequencing (NGS) panel following genetic counseling. Surgico-medical information was obtained from hospital records. Genetic variations were detected using the panel and were cross-validated by Sanger direct sequencing. RESULTS: Germline BRCA1/2 mutations were identified in 6 patients (23.1%). Four were detected in patients with PC and 2 were in FTC patients. No mutations were detected in TP53, PTEN, CDH1, or PALB2. We identified 11 variant of uncertain significance (VUS) in 9 patients; 2 in BRCA1, 3 in BRCA2, 2 in TP53, and 4 in CDH1. We also detected a CDH1 c.2164+16->A VUS in 3 patients. CONCLUSION: The prevalence of germline BRCA1/2 mutations in patients with PC or FTC is comparable to that of BRCA1/2 mutations in epithelial ovarian cancer patients.

Polymorphism analysis of rs16941 and rs16942 loci of BRCA1 gene Uighur and Han sporadic breast cancer / 临床与实验病理学杂志

Purpose To investigate whether there is a difference in BRCA1 gene single nucleotide polymorphisms (SNPs) in Uighurs and Han Chinese sporadic breast cancer,and to analyze the relationship between SNPs locus and tumor susceptibility.Methods 100 cases of sporadic breast cancer (Uighur and Han 50 cases each) and 100 cases of mammary gland disease (Uighur and Han 50 cases each) were collected as the research object,the BRCA1 gene rs16941 and rs16942 were sequenced.Results The distribution of AA,AG and GG genotypes of rs16941 and rs16942 between Uygur and Han breast cancer groups were statistically significant (P =0.009,P =0.017).Compared with AA genotype of rs16941,AG genotype of rs16941 could reduce the risk of breast cancer in Uighurs (OR =0.964,95％ CI:0.260-3.583,P =0.009).Compared with AA genotype of rs16942,AG genotype of rs16942 could increase the risk of breast cancer in Uighurs (OR =1.017,95％ CI:0.293-3.916,P =0.017).Compared with AA genotype of rs16941,AG genotype could reduce the risk of breast cancer in Han nationality (OR=0.824,95％ CI:0.210-3.234,P =0.044).Conclusion The distribution of AA,AG and GG genotypes of rs16941 and rs16942 in Uygur and Han breast cancer groups are statistically significant,and SNPs is correlated with tumor susceptibility.

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

OBJETIVO:Reunir evidencias de la variación en la frecuencia de las mutaciones de BRCA1 y BRCA2 y la historia familiar en pacientes con cáncer de glándula mamaria (CGM) y cáncer de ovario (CO) de diferentes orígenes geográficos.MÉTODO:En este trabajo se realizó una revisión sistemática, siguiendo los parámetros del protocolo PRISMA, para estimar la prevalencia de mutaciones en los genes BRCA 1/2 en pacientes con CGM y CO, la incidencia de la historia familiar y la prevalencia observada en casos esporádicos en este tipo de cáncer.RESULTADOS:Se observa una heterogeneidad en la frecuencia de las mutaciones de estos genes en los estudios de historia familiar, con una variación entre 0.0 y 0.48 en pacientes y familiares con CGM y CO similares a los previamente reportados.DISCUSIÓN: Este amplio rango de la frecuencia se debe al origen de la población estudiada, el número de individuos analizados y la metodología de genotipificación utilizada. La revisión revela que el CGM y CO familiar es dos veces más frecuente, en comparación con los casos de esta misma patología con origen esporádico.CONCLUSIONES:Este tipo de estudios moleculares les permite a las personas que presentan historia familiar con CGM y CO realizarse análisis precoces y chequeos para prevenir en un futuro el desarrollo de alguna de estas neoplasias.

OBJECTIVE:Collect evidence about the frequency variation of BRCA1 and BRCA2 mutations and family history in patients with mammary gland cancer (MGC) and ovarian cancer (OC) from different geographical backgrounds.METHOD: This paper presents a systematic review using the PRISMA protocol parameters to estimate the prevalence of mutations in BRCA 1/2 genes in patients with MGC and OC, the incidence of family history and the observed prevalence in sporadic cases with this type of cancer.RESULTS:Heterogeneity is observed in the frequency of mutations of these genes in studies of family history ranging between 0.0 and 0.48 in patients and families with MGC and OC similar to those previously reported.DISCUSSION:This wide range of frequency is due to the origin of the studied population, the number of individuals analyzed and genotyping methodology used. The review reveals that the family MGC and OC is twice as common compared with cases of the same disease of a sporadic origin.CONCLUSIONS: This type of molecular studies allows other people who have family history of MGC and OC to perform early analysis and tests to prevent the future development of this neoplasia.

Association between single nucleotide polymorphisms of BRCA1-A complex genes and susceptibility ;of triple-negative breast cancer / 中国癌症杂志

Background and purpose:The mutation of BRCA1 gene is widely acknowledged to be related to the incidence of triple-negative breast cancer (TNBC). The aim of this study was to investigate the association between TNBC and single nucleotide polymorphisms (SNPs) of BRCA1-associated genes. Methods:This study investigated the associations between the BRCA1-A complex genes and risk of developing TNBC in a case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls diagnosed in the Fudan University Shanghai Cancer Center during 2008-2011. This study also detected 37 common variants in Abraxas, BRE, Rap80, NBA1 and BRCC36 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls were used to investigate the associations between TNBC-speciifc SNPs genotype and non-TNBCs susceptibility. Results:This study found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC (P<0.01). Compared with CC genotype, women with the GC genotype (OR=0.70, 95%CI:0.51-0.97) and GG genotype (OR=0.48, 95%CI:0.21-1.07) had a lower risk of developing TNBC (P=0.03). In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 were associated with a lower chance of TNBC development. In the second part of the study, the result showed that there was no difference in rs7250266 expression between non-TNBC and normal people (0.19 vs 0.18, P=0.85).Conclusion:Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility in Chinese women.

Novel Germline Mutation of BRCA1 Gene in a 56-Year-Old Woman with Breast Cancer, Ovarian Cancer, and Diffuse Large B-Cell Lymphoma / Journal of the Korean Cancer Association, 대한암학회지

We report a case of a 56-year-old woman with breast cancer, ovarian cancer, and diffuse large B-cell lymphoma with a BRCA1 gene mutation. Evidence is mounting that there is a large increase in the risk for hematologic malignancies among patients with genetic changes in the BRCA pathways. The genomic analysis demonstrated a frameshift mutation in the BRCA1 gene: 277_279delinsCC (Phe93fs). It is a novel BRCA1 mutation that has never been reported, and caused malignant lymphoma as well as breast and ovarian cancer.

Relation between breast cancer related gene BRCA1 and the sensitivity to docetaxel chemotherapy / 中华内分泌外科杂志

Objective To investigate the relationship between the expression of BRCA1 in breast cancer tissues and the sensitivity to docetaxel chemotherapy.Methods The expression of BRCA1 was detected by immunohistochemical method and the new adjuvant chemotherapy containing docetaxel chemotherapy regimen (TEC)was given.The relationship between BRCA1 expression and efficacy of neoadjuvant chemotherapy with docetaxel was studied.Results The rate of complete response,partial response,stable disease and progress disease was 22.6％,71.7％,5.7％,and 0％ respectively in breast cancer patients with positive BRCA1 expression and 11.8％,58.9％,27.4％,and 2.0％ in breast cancer patients with negative BRCA1 expression.The difference between the 2 groups had statistical significance.Conclusion BRCA1 expression has a positive relationship with sensitivity to chemotherapy regimen containing docetaxel chemotherapy regimens (TEC),and can be used as a good marker for predicting efficacy of chemotherapy and screening agents.

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.

Risk Reducing Surgery in Carriers with Double Heterozygosity for BRCA1 and BRCA2 Mutations

Among the treatment options for BRCA mutation carriers, risk reducing surgery is the most effective. However, this procedure has been rarely performed in Korea. Interestingly, our case showed double heterozygosity for BRCA1 and BRCA2 mutations. The patient was diagnosed with left renal cancer and left breast cancer at 45-years-of-age, 4 years before risk reducing surgery. The patient received left radical nephrectomy and left partial mastectomy with axillary lymph node dissection. After pretest counseling, the patient underwent genetic testing that identified BRCA1 and BRCA2 mutations. After post-test counseling, the patient decided on intensive surveillance. At 49-years-of-age, the patient was newly diagnosed with contralateral breast cancer. Treatment options were discussed once again. We performed bilateral total mastectomy with immediate reconstruction and prophylactic bilateral salpingo-oophorectomy after multidisciplinary discussion. The patient has been satisfied with the results of surgery. We think this procedure is a recommendable treatment option for BRCA mutation carriers.

Detection of BRCA1 gene promoter hypermethylation in plasma of sporadic breast cancer patients / 中国癌症杂志

0.05).Conclusions:Detection of hypermethylation change of BRCA1 promoter promises a definite value in histologic type,malignant metastases and early prognostic in sporadic breast cancer.