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1.
Sci Rep ; 10(1): 7669, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376921

RESUMO

Current guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants - 185delAG (c.68_69delAG), 5382insC (c.5266dupC), and 6174delT (c.5946delT) - are common in the Ashkenazi Jewish population. We characterized a cohort of more than 2,800 research participants in the 23andMe database who carry one or more of the three Ashkenazi Jewish founder variants, evaluating two characteristics that are typically used to recommend individuals for BRCA testing: self-reported Jewish ancestry and family history of breast, ovarian, prostate, or pancreatic cancer. Of the 1,967 carriers who provided self-reported ancestry information, 21% did not self-report Jewish ancestry; of these individuals, more than half (62%) do have detectable Ashkenazi Jewish genetic ancestry. In addition, of the 343 carriers who provided both ancestry and family history information, 44% did not have a first-degree family history of a BRCA-related cancer and, in the absence of a personal history of cancer, would therefore be unlikely to qualify for clinical genetic testing. These findings may help inform the discussion around broader access to BRCA genetic testing.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Efeito Fundador , Variação Genética , Judeus/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Adulto Jovem
2.
BMJ Open ; 9(9): e029926, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551380

RESUMO

OBJECTIVES AND SETTING: Advances in multigene panel testing for cancer susceptibility has increased the complexity of counselling, requiring particular attention to counselees' psychosocial needs. Changes in psychosocial problems before and after genetic testing were prospectively compared between genetic test results in women tested for breast or ovarian cancer genetic susceptibility in French, German and Spanish clinics. PARTICIPANTS AND MEASURES: Among 752 counselees consecutively approached, 646 (86%) were assessed after the initial genetic consultation (T1), including 510 (68%) affected with breast cancer, of which 460 (61%) were assessed again after receiving the test result (T2), using questionnaires addressing genetic-specific psychosocial problems (Psychosocial Aspects of Hereditary Cancer (PAHC)-six scales). Sociodemographic and clinical data were also collected. RESULTS: Seventy-nine (17.2%), 19 (4.1%), 259 (56.3%), 44 (9.6%) and 59 (12.8%) women received a BRCA1/2, another high/moderate-risk pathogenic variant (PV), negative uninformative, true negative (TN) or variant of uncertain significance result (VUS), respectively. On multiple regression analyses, compared with women receiving another result, those with a VUS decreased more in psychosocial problems related to hereditary predisposition (eg, coping with the test result) (ß=-0.11, p<0.05) and familial/social issues (eg, risk communication) (ß=-0.13, p<0.05), almost independently from their problems before testing. Women with a PV presented no change in hereditary predisposition problems and, so as women with a TN result, a non-significant increase in familial/social issues. Other PAHC scales (ie, emotions, familial cancer, personal cancer and children-related issues) were not affected by genetic testing. CONCLUSIONS: In women tested for breast or ovarian cancer genetic risk in European genetics clinics, psychosocial problems were mostly unaffected by genetic testing. Apart from women receiving a VUS result, those with another test result presented unchanged needs in counselling in particular about hereditary predisposition and familial/social issues.


Assuntos
Adaptação Psicológica , Aconselhamento Genético , Predisposição Genética para Doença/psicologia , Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário , Comportamento Social , Adulto , Proteína BRCA1/genética , Feminino , França/epidemiologia , Aconselhamento Genético/métodos , Aconselhamento Genético/psicologia , Alemanha/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Humanos , Psicologia , Espanha/epidemiologia , Estresse Psicológico/diagnóstico , Estresse Psicológico/etiologia
3.
Cancer Med ; 8(15): 6789-6798, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31531966

RESUMO

BACKGROUND: Personal cancer diagnosis and family cancer history factor into which individuals should undergo genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome. Family history is often determined in the research setting through kindreds with disease clusters, or clinically from self-report. The population prevalence of individuals with diagnostic characteristics and/or family cancer history meeting criteria for HBOC testing is unknown. METHODS: Utilizing Surveillance, Epidemiology, and End Results (SEER) cancer registry data and a research resource linking registry records to genealogies, the Utah Population Database, the population-based prevalence of diagnostic and family history characteristics meeting National Comprehensive Cancer Network (NCCN) criteria for HBOC testing was objectively assessed. RESULTS: Among Utah residents with an incident breast cancer diagnosis 2010-2015 and evaluable for family history, 21.6% met criteria for testing based on diagnostic characteristics, but the proportion increased to 62.9% when family history was evaluated. The proportion of cases meeting testing criteria at diagnosis was 94% for ovarian cancer, 23% for prostate cancer, and 51.1% for pancreatic cancer. Among an unaffected Utah population of approximately 1.7 million evaluable for family history, 197,601 or 11.6% met testing criteria based on family history. CONCLUSIONS: This study quantifies the population-based prevalence of HBOC criteria using objectively determined genealogy and cancer incidence data. Sporadic breast cancer likely represents a portion of the high prevalence of family cancer history seen in this study. These results underline the importance of establishing presence of a deleterious mutation in an affected family member, per NCCN guidelines, before testing unaffected relatives.


Assuntos
Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias da Próstata/epidemiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Programa de SEER , Utah/epidemiologia
4.
J Hum Genet ; 64(8): 767-773, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31089269

RESUMO

PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2 c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2 variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.


Assuntos
Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Efeito Fundador , Mutação em Linhagem Germinativa , Deleção de Sequência , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Neoplasias da Mama/diagnóstico , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Grécia/epidemiologia , Haplótipos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Mutação com Perda de Função , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Linhagem , Medição de Risco , Fatores de Risco , Adulto Jovem
5.
Mol Genet Genomic Med ; 7(6): e677, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30968603

RESUMO

BACKGROUND: Breast cancer is the most common cancer among women worldwide. Here, we report the prevalence of BRCA1/2 mutations in patients with high-risk breast cancer from Inner Mongolia and Jilin, China, which was a part of a nationwide project on the detection of BRCA1/2 mutations in Chinese patients with hereditary breast cancer. METHODS: According to the criteria, index patients from a total of 245 independent families were initially recruited. All 49 exons of BRCA1 and BRCA2 and adjacent noncoding regions were screened for mutations based on next-generation sequencing from collected saliva. RESULTS: We detected 17 BRCA1/2 variants in 18 of 216 (8.3%) index patients with high-risk breast cancer. Among these, seven mutations were novel, including four BRCA1 mutations (c.123_124delCAinsAT, c.5093_5096delCTAA, c.5396-2A>G, and c.2054delinsGAAGAGTAACAAGTAAGAAGAGTAACAAGAAG), and three BRCA2 mutations (c.304A>T, c.7552_7553insT, and c.9548_9549insA). The BRCA1/2 variants were identified in 14% (8/57) of the patients with triple-negative breast cancer and in 6.3% (10/159) of the patients with non-triple-negative breast cancer. There was no significant difference between the two groups (p = 0.07). A higher frequency for BRCA1 mutations was observed in patients with triple-negative breast cancer than in those with non-triple-negative breast cancer (12.3% vs. 2.5%, p = 0.004). The frequencies of the BRCA2 mutations were not significantly different between patients with triple-negative breast cancer and those with non-triple-negative breast cancer (1.8% vs. 3.8%, p = 0.46). CONCLUSION: We found that patients with triple-negative breast cancer had a higher frequency of BRCA1 mutations than those with non-triple-negative breast cancer. In this study, no significant associations between the BRCA1/2 mutation status and age, family history of breast cancer, ovarian cancer, pancreatic cancer and prostate cancer, number of primary lesions, tumor size, or lymph node metastasis were observed.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Taxa de Mutação , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , China , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Humanos , Pessoa de Meia-Idade , Prevalência , Neoplasias de Mama Triplo Negativas/epidemiologia
6.
Breast Cancer Res Treat ; 175(1): 217-228, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30725383

RESUMO

PURPOSE: To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). METHODS: A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. RESULTS: A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. CONCLUSIONS: High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Imagem por Ressonância Magnética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Detecção Precoce de Câncer , Feminino , Genes BRCA1 , Genes BRCA2 , Alemanha/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico por imagem , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Programas de Rastreamento , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Vigilância em Saúde Pública , Reprodutibilidade dos Testes , Risco , Adulto Jovem
7.
Clin Genet ; 95(2): 293-301, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30417332

RESUMO

Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.


Assuntos
Comunicação , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Preferência do Paciente , Revelação da Verdade , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Aconselhamento Genético/ética , Aconselhamento Genético/métodos , Predisposição Genética para Doença , Testes Genéticos/ética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Avaliação de Resultados em Cuidados de Saúde , Cooperação do Paciente , Telefone
8.
Intern Med J ; 48(10): 1269-1272, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30288903

RESUMO

Federal funding for germline genetic testing in hereditary breast and ovarian cancer (HBOC) was recently introduced. Germline testing for HBOC under Medicare Benefits Schedule items 73296/73297 can be requested by any specialist, whereas the previous state- and territory-funded testing was limited to those operating within a familial cancer service. The impact of this decentralisation of HBOC testing on health and economic outcomes is uncertain, primarily as it has potential to significantly disrupt the clinical framework that generated the evidence used to justify clinical implementation of the Medicare Benefits Schedules.


Assuntos
Neoplasias da Mama/diagnóstico , Predisposição Genética para Doença/genética , Testes Genéticos/estatística & dados numéricos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Neoplasias Ovarianas/diagnóstico , Austrália , Neoplasias da Mama/economia , Neoplasias da Mama/genética , Feminino , Financiamento Governamental , Testes Genéticos/economia , Mutação em Linhagem Germinativa , Síndrome Hereditária de Câncer de Mama e Ovário/economia , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Neoplasias Ovarianas/economia , Neoplasias Ovarianas/genética , Fatores de Risco
9.
Genet Med ; 20(12): 1677-1686, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29988077

RESUMO

PURPOSE: Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing. METHODS: Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population. RESULTS: Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01-17.22], 8.61 [6.78-10.82], 8.22 [4.91-13.05], 4.54 [2.55-7.48], 5.23 [1.46-13.17], 3.20 [2.14-4.53], 2.49 [1.42-3.97], 1.67 [1.18-2.27], and 2.50 [1.12-4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78-19.59], 12.44 [2.94-33.30] and 3.82 [1.66-7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48-34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37-25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC. CONCLUSION: Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.


Assuntos
Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , França/epidemiologia , Predisposição Genética para Doença , Testes Genéticos , Variação Genética/genética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Fatores de Risco , Sequenciamento Completo do Exoma
10.
Cancer Med ; 7(4): 1349-1358, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29522266

RESUMO

The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67-4.94), CDH1 (OR: 17.04, 95%CI: 3.54-82), CHEK2 (OR: 2.93, 95%CI: 2.29-3.75), PALB2 (OR: 9.53, 95%CI: 6.25-14.51), and TP53 (OR: 7.30, 95%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.


Assuntos
Biomarcadores Tumorais , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Variação Genética , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Humanos , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Adulto Jovem
11.
Gynecol Oncol ; 148(3): 535-539, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29422346

RESUMO

OBJECTIVE: Estimate the prevalence and identify risk factors for bone loss in women with BRCA mutations. METHODS: Women, age 40 and older, with BRCA mutations identified from the Breast Cancer Surveillance database at Kaiser Permanente Northern California were invited to participate and undergo a dual-energy x-ray absorptiometry scan to assess for bone loss (osteopenia or osteoporosis). Multivariable logistic regression analysis was performed to assess clinical factors associated with bone loss. RESULTS: Of the 238 women in the final cohort, 20 women had intact ovaries (median age 54.5years) and 218 had undergone risk reducing salpingo-oophorectomy (RRSO) (median age 57). The prevalence of bone loss was 55% in the no RRSO group and 72.5% in the RRSO group (P=0.10). In multivariable analysis, only higher body mass index (OR 0.6 per 5kg/m2, 95% CI: 0.4-0.7) and nonwhite race compared to white (OR 0.5, 95% CI: 0.2-0.9) were protective for bone loss while older age (OR 1.5 per 10years, 95% CI: 1.1-2.1) and selective estrogen receptor modulator use (3.1, 95% CI: 1.2-10.1) were associated with increased odds of bone loss. Among women with RRSO, bone loss was more frequent in women who had postmenopausal (n=106) compared to women who had premenopausal RRSO (n=112), (82.1% and 63.4% respectively, P=0.002). In multivariable analysis, only BMI was protective of bone loss (OR 0.5, 95%, CI: 0.4-0.7) but neither age nor menopausal status at RRSO were associated with bone loss. CONCLUSION: Bone loss is common in women with BRCA mutations who undergo RRSO.


Assuntos
Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/cirurgia , Osteoporose/epidemiologia , Ovariectomia/estatística & dados numéricos , Procedimentos Cirúrgicos Profiláticos/estatística & dados numéricos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Absorciometria de Fóton , Fatores Etários , Idoso , Índice de Massa Corporal , Doenças Ósseas Metabólicas/epidemiologia , Grupo com Ancestrais do Continente Europeu , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prevalência , Fatores de Proteção , Comportamento de Redução do Risco , Salpingectomia/estatística & dados numéricos
12.
BMC Cancer ; 18(1): 83, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29338689

RESUMO

BACKGROUND: We evaluated the incidence and spectrum of pathogenic and likely pathogenic variants of cancer susceptibility genes in BRCA1/2 mutation-negative Korean patients with a high risk for hereditary breast cancer using a comprehensive multigene panel that included 35 cancer susceptibility genes. METHODS: Samples from 120 patients who were negative for BRCA1/2 mutations, but had been diagnosed with breast cancer that was likely hereditary, were prospectively evaluated for the prevalence of high-penetrance and moderate-penetrance germline mutations. RESULTS: Nine patients (7.5%) had at least one pathogenic or likely pathogenic variant. Ten variants were identified in these patients: TP53 in two patients, PALB2 in three patients, BARD1 in two patients, BRIP1 in two patients, and MRE11A in one patient. We also identified 30 types of 139 variants of unknown significance (VUS). High-penetrance germline mutations, including TP53 and PALB2, tended to occur with high frequency in young (< 35 years) breast cancer patients (4/19, 21.1%) than in those diagnosed with breast cancer at ≥35 years of age (1/101, 1.0%; p = 0.003). CONCLUSIONS: These combined results demonstrate that multigene panels offer an alternative strategy for identifying veiled pathogenic and likely pathogenic mutations in breast cancer susceptibility genes.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Proteína Homóloga a MRE11/genética , Pessoa de Meia-Idade , RNA Helicases/genética , Fatores de Risco , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética
13.
J Hum Genet ; 63(4): 447-457, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29176636

RESUMO

The hereditary breast and ovarian cancer (HBOC) registration system of Japan was established by the Japanese HBOC Consortium. The first trial was registered in 2015 in four institutions to which some registration committee members belonged. We analyzed the information of 830 Japanese pedigrees, who underwent BRCA1/2 genetic testing, including mutation carriers with BRCA1 (N = 127) and BRCA2 (N = 115), and their families. The mutation-positive rate was 19.7%. Variants of uncertain significance were found in 6.5% of all individuals subjected to genetic testing for BRCA1/2. Compared to the United States, Japan had a higher mutation-positive rate in most categories, except for the groups with male breast cancer. Among the intrinsic subtypes of BRCA1-associated breast cancers, 75.8% were triple-negative. The incidence rate of contralateral breast cancer in BRCA1/2 mutation carriers was 0.99%/year. Among 240 mutation carriers, 26 and 62 patients underwent risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), respectively; the respective frequencies of occult cancer were 7.1 and 3.2%. Metachronous breast cancer after RRM or peritoneal cancer after RRSO was not observed during the follow-up period. The nationwide registration system began last year and the system enables follow-up analysis in Japan.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Fenótipo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Genótipo , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/prevenção & controle , Humanos , Incidência , Japão/epidemiologia , Pessoa de Meia-Idade , Mutação , Linhagem , Prevalência , Sistema de Registros , Carga Tumoral , Adulto Jovem
14.
Horm Mol Biol Clin Investig ; 32(2)2017 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-29190211

RESUMO

Aim The aim of this study is to review the legal implications, the technology, the indications and the management of women with a familial background of breast and/or ovarian cancer. Methods We have reviewed the literature and national Austrian guidelines to describe the uptake of genetic counseling and the management options offered in Austria. Results Genetic testing for the BRCA1 and 2 mutations is free and readily available through a nation-wide program. Increased awareness and the availability of screening programs and prophylactic surgery have resulted in a profound increase in genetic counseling and testing in women with a familial background of breast and ovarian cancer in Austria. Conclusion While readily available country-wide counseling has led to an increase in counseling and testing, Austrian legislation mandates "non-directional counseling" resulting in a comparatively low uptake of prophylactic surgery.


Assuntos
Aconselhamento Genético/métodos , Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Áustria , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Aconselhamento Genético/normas , Testes Genéticos/normas , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/terapia , Humanos , Guias de Prática Clínica como Assunto
15.
Gynecol Oncol ; 145(1): 137-141, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28159408

RESUMO

OBJECTIVE: To evaluate the predictive efficacies including sensitivity and positive predictive value of the genetic risk prediction model BRCAPRO and the Myriad BRCA risk calculator in Korean ovarian cancer patients. METHODS: Individuals undergoing genetic testing for BRCA mutations from November 2010-August 2016 were recruited from the Department of Obstetrics and Gynecology at a single institute in Korea. The observed BRCA1 and BRCA2 mutation statuses were compared with the predicted carrier probabilities using BRCAPRO and the Myriad BRCA risk calculator. RESULTS: Two hundred thirty-two patients were recruited, of whom 99.1% (230/232) were of Korean ethnicity. Of the 232 individuals, 206 and 26 had ovarian and double primary breast/ovarian cancer, respectively. Thirty-six individuals had a family history of breast/ovarian cancer in first-degree relatives. Fifty-seven patients (24.6%) tested positive for BRCA mutation (41 BRCA1, 16 BRCA2). The mean BRCAPRO and Myriad scores for all patients were 6.4% and 7.7%, respectively. The scores were significantly higher for patients with positive BRCA mutation status (29.0% vs. 6.1%, P<0.001, 12.1% vs. 7.7%, P<0.001, respectively). For all patients, the respective areas under the receiver operating characteristics curves were 0.720 and 0.747 for the BRCAPRO and Myriad models to predict the risk of carrying a BRCA mutation. Both models overestimated the mutation probability in patients with a family history of breast/ovarian cancer (1.55-fold and 1.50-fold, respectively) and underestimated the probability in patients without a family history (both, 0.54-fold). CONCLUSION: BRCAPRO and Myriad seem to be acceptable risk assessment tools for determining the risk of carrying BRCA mutations in Korean ovarian cancer patients.


Assuntos
Adenocarcinoma de Células Claras/genética , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Endometrioide/genética , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Mutação , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Técnicas de Apoio para a Decisão , Feminino , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Humanos , Pessoa de Meia-Idade , Modelos Teóricos , Probabilidade , Curva ROC , República da Coreia , Medição de Risco
16.
PLoS One ; 12(1): e0169673, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28060958

RESUMO

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA1/2 mutation carriers. Premenopausal RRSO is hypothesized to increase fracture risk more than natural menopause. Elevated bone turnover markers (BTMs) might predict fracture risk. We investigated BTM levels after RRSO and aimed to identify clinical characteristics associated with elevated BTMs. METHODS: Osteocalcin (OC), procollagen type I N-terminal peptide (PINP) and serum C-telopeptide of type I collagen (sCTx) were measured in 210 women ≥ 2 years after RRSO before age 53. BTM Z-scores were calculated using an existing reference cohort of age-matched women. Clinical characteristics were assessed by questionnaire. RESULTS: BTMs after RRSO were higher than age-matched reference values: median Z-scores OC 0.11, p = 0.003; PINP 0.84, p < 0.001; sCTx 0.53, p < 0.001 (compared to Z = 0). After excluding women with recent fractures or BTM interfering medication, Z-scores increased to 0.34, 1.14 and 0.88, respectively. Z-scores for OC and PINP were inversely correlated to age at RRSO. No correlation was found with fracture incidence or history of breast cancer. CONCLUSIONS: Five years after RRSO, BTMs were higher than age-matched reference values. Since elevated BTMs might predict higher fracture risk, prospective studies are required to evaluate the clinical implications of this finding.


Assuntos
Osso e Ossos/metabolismo , Síndrome Hereditária de Câncer de Mama e Ovário/etiologia , Síndrome Hereditária de Câncer de Mama e Ovário/metabolismo , Ovariectomia , Salpingectomia , Adulto , Idoso , Biomarcadores , Reabsorção Óssea/metabolismo , Colágeno Tipo I/metabolismo , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Humanos , Pessoa de Meia-Idade , Osteocalcina/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Fatores de Risco , Comportamento de Redução do Risco
17.
Cancer Res Treat ; 49(4): 1012-1021, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28111427

RESUMO

PURPOSE: Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used to accurately calculate the odds ratio (OR) of genetic variants. MATERIALS AND METHODS: Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls. RESULTS: We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence interval to exceed 1.0 varied according to the frequency of the variant in each patient group, with more than 820 controls needed for a variant existing in 1% of cases. Using a sufficient number of relevant population data, we could efficiently classify variants and identified the BRCA1 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients. CONCLUSION: Our study suggests that BRCA1 p.Leu1780Pro is a novel pathogenic mutation found in Korean patients. We also determined the optimal number of relevant ethnic controls needed for accurate variant classification according to the ACMG guidelines.


Assuntos
Grupos Étnicos/genética , Genes BRCA1 , Genes BRCA2 , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Vigilância da População , Adulto , Biomarcadores Tumorais , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Efeito Fundador , Variação Genética , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Pessoa de Meia-Idade , Modelos Moleculares , Razão de Chances , Conformação Proteica , República da Coreia/epidemiologia , Relação Estrutura-Atividade , Sequenciamento Completo do Exoma
18.
Breast Cancer Res Treat ; 161(2): 191-201, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27826754

RESUMO

BACKGROUND: Germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers. Pakistan has one of the highest rates of breast cancer incidence in Asia, where BRCA1/2 small-range mutations account for 17% of early-onset and familial breast/ovarian cancer patients. We report the first study from Pakistan evaluating the prevalence of BRCA1/2 large genomic rearrangements (LGRs) in breast and/or ovarian cancer patients who do not harbor small-range BRCA1/2 mutations. MATERIALS AND METHODS: Both BRCA1/2 genes were comprehensively screened for LGRs using multiplex ligation-dependent probe amplification in 120 BRCA1/2 small-range mutations negative early-onset or familial breast/ovarian cancer patients from Pakistan (Group 1). The breakpoints were characterized by long-range PCR- and DNA-sequencing analyses. An additional cohort of 445 BRCA1/2 negative high-risk patients (Group 2) was analyzed for the presence of LGRs identified in Group 1. RESULTS: Three different BRCA1 LGRs were identified in Group 1 (4/120; 3.3%), two of these were novel. Exon 1-2 deletion was observed in two unrelated patients: an early-onset breast cancer patient and another bilateral breast cancer patient from a hereditary breast cancer (HBC) family. Novel exon 20-21 deletion was detected in a 29-year-old breast cancer patient from a HBC family. Another novel exon 21-24 deletion was identified in a breast-ovarian cancer patient from a hereditary breast and ovarian cancer family. The breakpoints of all deletions were characterized. Screening of the 445 patients in Group 2 for the three LGRs revealed ten additional patients harboring exon 1-2 deletion or exon 21-24 deletion (10/445; 2.2%). No BRCA2 LGRs were identified. CONCLUSIONS: LGRs in BRCA1 are found with a considerable frequency in Pakistani breast/ovarian cancer cases. Our findings suggest that BRCA1 exons 1-2 deletion and exons 21-24 deletion should be included in the recurrent BRCA1/2 mutations panel for genetic testing of high-risk Pakistani breast/ovarian cancer patients.


Assuntos
Rearranjo Gênico , Genes BRCA1 , Mutação em Linhagem Germinativa , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Idade de Início , Idoso , Sequência de Bases , Pontos de Quebra do Cromossomo , Éxons , Feminino , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Fenótipo , Vigilância da População , Deleção de Sequência , Adulto Jovem
19.
Curr Treat Options Oncol ; 17(8): 39, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27315065

RESUMO

OPINION STATEMENT: Ovarian cancer is an uncommon but deadly disease. There is no effective screening for the disease, and the majority of women with ovarian cancer present in advanced stage and eventually die from their disease. The majority of families with multiple cases of breast and ovarian cancer are found to carry germline mutations in BRCA1/2. Recent, more sensitive sequencing techniques have shown that nearly 20 % of ovarian cancer is associated with germline mutations in cancer susceptibility genes, with approximately 15 % accounted for by deleterious mutations in BRCA1/2. Women found to have mutations in BRCA1/2 can be empowered to make decisions on reproduction, cancer prevention, or treatment that may either avoid cancer or prolong survival. Though initial studies suggested that African American (AA) women were significantly less likely than White women to have mutations in BRCA1/2, this has been found to be untrue. Despite this revelation, and the clear importance of BRCA1/2 mutation status to appropriate clinical management, AA women still undergo genetic counseling and testing at much lower rates than do comparable White women. This disparity is not explained by factors such as calculated risk of a mutation, insurance coverage, or previous knowledge of the availability of testing. To date, no effective strategies have been identified that can overcome this disparity. Possible approaches include use of patient navigators, online social media, or EMR-based decision support aids. Funders should support research in this area, as it represents an actionable means to decrease the burden of ovarian and breast cancer in AA women.


Assuntos
Disparidades em Assistência à Saúde , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Populações Vulneráveis , Intervenção Médica Precoce , Feminino , Genes BRCA1 , Genes BRCA2 , Triagem de Portadores Genéticos , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/prevenção & controle , Humanos , Mutação
20.
J Hum Genet ; 61(6): 515-22, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26911350

RESUMO

Breast and/or ovarian cancer (BOC) are among the most frequently diagnosed forms of hereditary cancers and leading cause of death in India. This emphasizes on the need for a cost-effective method for early detection of these cancers. We sequenced 141 unrelated patients and families with BOC using the TruSight Cancer panel, which includes 13 genes strongly associated with risk of inherited BOC. Multi-gene sequencing was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations. When we considered familial breast cancer cases only, the detection rate increased to 52%. When cases were stratified based on age of diagnosis into three categories, ⩽40 years, 40-50 years and >50 years, the detection rates were higher in the first two categories (44.4% and 53.4%, respectively) as compared with the third category, in which it was 26.9%. Our study suggests that next-generation sequencing-based multi-gene panels increase the sensitivity of mutation detection and help in identifying patients with a high risk of developing cancer as compared with sequential tests of individual genes.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Adulto , Idade de Início , Idoso , Neoplasias da Mama/diagnóstico , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Duplicação Gênica , Genes BRCA1 , Genes BRCA2 , Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Índia/epidemiologia , Pessoa de Meia-Idade , Taxa de Mutação , Neoplasias Ovarianas/diagnóstico , Prevalência , Adulto Jovem
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