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1.
JAMA Oncol ; 6(8): 1218-1230, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32614418

RESUMO

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

2.
Breast Cancer Res ; 22(1): 79, 2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711554

RESUMO

BACKGROUND: We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking. METHODS: A digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed. RESULTS: The digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04-0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37-2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance. CONCLUSIONS: The digitalMLPA is a reliable method to detect a BRCA1- and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Feminino , Seguimentos , Humanos , Técnicas de Amplificação de Ácido Nucleico , Compostos Organoplatínicos/administração & dosagem , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
3.
Int J Cancer ; 147(10): 2708-2716, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32383162

RESUMO

Breast cancer risk is approximately twice as high in first-degree relatives of female breast cancer cases than in women in the general population. Less than half of this risk can be attributed to the currently known genetic risk factors. Recessive risk alleles represent a relatively underexplored explanation for the remainder of familial risk. To address this, we selected 19 non-BRCA1/2 breast cancer families in which at least three siblings were affected, while no first-degree relatives of the previous or following generation had breast cancer. Germline DNA from one of the siblings was subjected to exome sequencing, while all affected siblings were genotyped using SNP arrays to assess haplotype sharing and to calculate a polygenic risk score (PRS) based on 160 low-risk variants. We found no convincing candidate recessive alleles among exome sequencing variants in genomic regions for which all three siblings shared two haplotypes. However, we found two families in which all affected siblings carried the CHEK2*1100delC. In addition, the average normalized PRS of the "recessive" family probands (0.81) was significantly higher than that in both general population cases (0.35, P = .026) and controls (P = .0004). These findings suggest that the familial aggregation is, at least in part, explained by a polygenic effect of common low-risk variants and rarer intermediate-risk variants, while we did not find evidence of a role for novel recessive risk alleles.

4.
Eur J Hum Genet ; 28(8): 1020-1027, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32300191

RESUMO

When hereditary breast and ovarian cancer (HBOC) due to a BRCA1/BRCA2 germline pathogenic variant is diagnosed, the proband will be asked to inform other at-risk family members. In the Netherlands, a guideline was introduced in 2012 which provided detailed recommendations regarding this proband-mediated procedure. We now evaluated the uptake of predictive BRCA1/BRCA2 testing in 40 consecutive HBOC families diagnosed in our centre in 2014. We performed a retrospective observational study of all 40 families in which a pathogenic BRCA1/BRCA2 germline variant was identified during 2014. We scored the uptake of predictive and confirmatory testing by the end of 2018 and explored factors associated with the level of uptake. Two families were excluded. In the remaining 38 families, among 239 family members ≥18 years at 50% risk of being a mutation carrier or at 25% risk if the family member at 50% risk was deceased, 102 (43%) were tested. Among 108 females 25-75 years of age at 50% risk, 59 (55%) underwent predictive or confirmatory testing, and among 43 males at 50% risk with daughters ≥18 years, 22 (51%) were tested. Factors which complicated cascade screening included family members living abroad, probands not wanting to share information and limited pedigree information. In conclusion, the standard proband-mediated procedure of informing relatives seems to be far from optimal. We suggest a tailored approach for each family, including the option of a direct approach to at-risk family members by the geneticist. In addition, we suggest detailed monitoring and follow-up of families.

6.
NPJ Genom Med ; 3: 7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29479477

RESUMO

Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1/BRCA2. We employed an online survey of 65 questions covering four areas: laboratory characteristics, details on technological methods, variant classification, and client-support information. Eight United States (US) laboratories and 78 non-US laboratories completed the survey. Most laboratories (93%; 80/86) used MPS platforms to identify variants. Laboratories differed widely on: (1) technologies used for large rearrangement detection; (2) criteria for minimum read depths; (3) non-coding regions sequenced; (4) variant classification criteria and approaches; (5) testing volume ranging from 2 to 2.5 × 105 tests annually; and (6) deposition of variants into public databases. These data may be useful for national and international agencies to set recommendations for quality standards for BRCA1/BRCA2 clinical testing. These standards could also be applied to testing of other disease genes.

7.
Fam Cancer ; 16(2): 271-277, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27826806

RESUMO

Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (<0.2%). For VHL (6.5%) and LFS (4.9%) the difference was not statistically significant. PND for Rb started 3 years after introduction of diagnostic DNA testing and remained stable over the years. For the other cancer syndromes PND started 10-15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences.


Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Genes do Retinoblastoma/genética , Testes Genéticos/estatística & dados numéricos , Síndromes Neoplásicas Hereditárias/diagnóstico , Diagnóstico Pré-Natal/estatística & dados numéricos , Retinoblastoma/diagnóstico , Análise Mutacional de DNA , Detecção Precoce de Câncer/métodos , Feminino , Aconselhamento Genético , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/genética , Países Baixos , Gravidez , Diagnóstico Pré-Natal/métodos , Retinoblastoma/genética , Estudos Retrospectivos , Inquéritos e Questionários
8.
Clin Cancer Res ; 23(5): 1236-1241, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27620280

RESUMO

Purpose: As estrogen receptor-positive (ER+) breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER-negative (ER-) BRCA1-mutated breast cancer, it has been suggested that these tumors are "sporadic" and not BRCA1 driven. With the introduction of targeted treatments specific for tumors with a nonfunctioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors.Experimental Design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER- tumors, 36 BRCA2-mutated ER+-associated tumors, and 182 sporadic ER+ tumors.Results: The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER- breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wild-type BRCA1 allele was observed. In addition, clinicopathologic variables in BRCA1-mutated ER+ cancer were also more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1-mutated ER- cancers.Conclusions: As BRCA1-mutated ER+ tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER+ breast cancer. Clin Cancer Res; 23(5); 1236-41. ©2016 AACR.


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Receptores Estrogênicos/genética , Adulto , Idoso , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Variações do Número de Cópias de DNA/genética , Feminino , Recombinação Homóloga/genética , Humanos , Perda de Heterozigosidade/genética , Pessoa de Meia-Idade , Mutação
9.
Sci Rep ; 6: 30026, 2016 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-27424772

RESUMO

The HOXB13 p.G84E mutation has been firmly established as a prostate cancer susceptibility allele. Although HOXB13 also plays a role in breast tumor progression, the association of HOXB13 p.G84E with breast cancer risk is less evident. Therefore, we comprehensively interrogated the entire HOXB13 coding sequence for mutations in 1,250 non-BRCA1/2 familial breast cancer cases and 800 controls. We identified two predicted deleterious missense mutations, p.G84E and p.R217C, that were recurrent among breast cancer cases and further evaluated their association with breast cancer risk in a larger study. Taken together, 4,520 familial non-BRCA1/2 breast cancer cases and 3,127 controls were genotyped including the cases and controls of the whole gene screen. The concordance rate for the genotyping assays compared with Sanger sequencing was 100%. The prostate cancer risk allele p.G84E was identified in 18 (0.56%) of 3,187 cases and 16 (0.70%) of 2,300 controls (OR = 0.81, 95% CI = 0.41-1.59, P = 0.54). Additionally, p.R217C was identified in 10 (0.31%) of 3,208 cases and 2 (0.087%) of 2,288 controls (OR = 3.57, 95% CI = 0.76-33.57, P = 0.14). These results imply that none of the recurrent HOXB13 mutations in the Dutch population are associated with breast cancer risk, although it may be worthwhile to evaluate p.R217C in a larger study.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Países Baixos/epidemiologia , Risco
10.
Hum Mutat ; 37(7): 627-39, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26913838

RESUMO

Clinical mutation screening of the cancer susceptibility genes BRCA1 and BRCA2 generates many unclassified variants (UVs). Most of these UVs are either rare missense substitutions or nucleotide substitutions near the splice junctions of the protein coding exons. Previously, we developed a quantitative method for evaluation of BRCA gene UVs-the "integrated evaluation"-that combines a sequence analysis-based prior probability of pathogenicity with patient and/or tumor observational data to arrive at a posterior probability of pathogenicity. One limitation of the sequence analysis-based prior has been that it evaluates UVs from the perspective of missense substitution severity but not probability to disrupt normal mRNA splicing. Here, we calibrated output from the splice-site fitness program MaxEntScan to generate spliceogenicity-based prior probabilities of pathogenicity for BRCA gene variants; these range from 0.97 for variants with high probability to damage a donor or acceptor to 0.02 for exonic variants that do not impact a splice junction and are unlikely to create a de novo donor. We created a database http://priors.hci.utah.edu/PRIORS/ that provides the combined missense substitution severity and spliceogenicity-based probability of pathogenicity for BRCA gene single-nucleotide substitutions. We also updated the BRCA gene Ex-UV LOVD, available at http://hci-exlovd.hci.utah.edu, with 77 re-evaluable variants.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Biologia Computacional/métodos , Substituição de Aminoácidos , Simulação por Computador , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Humanos , Mutação de Sentido Incorreto , Processamento de RNA
11.
Genet Med ; 18(2): 137-44, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25905441

RESUMO

PURPOSE: Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast cancer. Rapid genetic counseling and testing (RGCT) before surgery may influence choice of primary surgical treatment. In this article, we report on the psychosocial impact of RGCT. METHODS: Newly diagnosed breast cancer patients at risk for carrying a BRCA1/2 mutation were randomized to an intervention group (offer of RGCT) or a usual care control group (ratio 2:1). Psychosocial impact and quality of life were assessed with the Impact of Events Scale, Hospital Anxiety and Depression Scale, Cancer Worry Scale, and the EORTC QLQ-C30 and QLQ-BR23. Assessments took place at study entry and at 6- and 12-month follow-up visits. RESULTS: Between 2008 and 2010, 265 patients were recruited into the study. Completeness of follow-up data was more than 90%. Of the 178 women in the intervention group, 177 had genetic counseling, of whom 71 (40%) had rapid DNA testing and 59 (33%) received test results before surgery. Intention-to-treat and per-protocol analyses showed no statistically significant differences between groups over time in any of the psychosocial outcomes. CONCLUSIONS: In this study, RGCT in newly diagnosed breast cancer patients did not have any measurable adverse psychosocial effects.


Assuntos
Neoplasias da Mama/psicologia , Aconselhamento Genético/psicologia , Testes Genéticos , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
12.
J Natl Cancer Inst ; 108(2)2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26586665

RESUMO

BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Códon de Terminação , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Modelos Logísticos , Lisina/genética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Razão de Chances , Neoplasias Ovarianas/patologia , Medição de Risco , Fatores de Risco
13.
Carcinogenesis ; 36(2): 256-71, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25586992

RESUMO

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.


Assuntos
Proteínas Cromossômicas não Histona/genética , Predisposição Genética para Doença , Receptores Estrogênicos/metabolismo , Regiões 3' não Traduzidas/genética , Aurora Quinase B/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas Inibidoras de Apoptose/genética , Polimorfismo de Nucleotídeo Único , Risco , Survivina
14.
J Med Genet ; 51(2): 98-107, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24285858

RESUMO

BACKGROUND: BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. METHODS: We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model. RESULTS: The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (p heterogeneity = 0.0006) and stronger family histories of breast cancer (p heterogeneity < 0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location. CONCLUSIONS: BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.


Assuntos
Efeito Fundador , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Distribuição por Idade , Idade de Início , Idoso , Estudos de Coortes , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Humanos , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Linhagem , Risco , Adulto Jovem
15.
Cancer Discov ; 3(10): 1142-55, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23867111

RESUMO

UNLABELLED: Mutations in BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancers, and therefore sequence analysis of both genes is routinely conducted in patients with early-onset breast cancer. Besides mutations that clearly abolish protein function or are known to increase cancer risk, a large number of sequence variants of uncertain significance (VUS) have been identified. Although several functional assays for BRCA1 VUSs have been described, thus far it has not been possible to conduct a high-throughput analysis in the context of the full-length protein. We have developed a relatively fast and easy cDNA-based functional assay to classify BRCA1 VUSs based on their ability to functionally complement BRCA1-deficient mouse embryonic stem cells. Using this assay, we have analyzed 74 unclassified BRCA1 missense mutants for which all predicted pathogenic variants are confined to the BRCA1 RING and BRCT domains. SIGNIFICANCE: BRCA1 VUSs are frequently found in patients with hereditary breast or ovarian cancer and present a serious problem for clinical geneticists. This article describes the generation, validation, and application of a reliable high-throughput assay for the functional classification of BRCA1 sequence variants of uncertain significance.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Genes BRCA1 , Teste de Complementação Genética , Ensaios de Triagem em Larga Escala/métodos , Mutação de Sentido Incorreto , Neoplasias Ovarianas/genética , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Proteína BRCA1/química , Proliferação de Células , Cisplatino/farmacologia , Reparo do DNA , Ensaios de Seleção de Medicamentos Antitumorais , Células-Tronco Embrionárias/fisiologia , Feminino , Variação Genética , Recombinação Homóloga , Humanos , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Domínios RING Finger
16.
PLoS Genet ; 9(3): e1003173, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23544012

RESUMO

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , Alelos , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
PLoS Genet ; 9(3): e1003212, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23544013

RESUMO

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco
18.
J Pathol ; 229(4): 621-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23208944

RESUMO

Diffuse gastric cancers typically present as late-stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type; 30-40% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E-cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of α-E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since α-E-catenin functions in the same complex as E-cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23.


Assuntos
Caderinas/genética , Polimorfismo Genético/genética , Transdução de Sinais , Neoplasias Gástricas/genética , alfa Catenina/genética , Idoso , Alelos , Sequência de Aminoácidos , Antígenos CD , Caderinas/metabolismo , DNA de Neoplasias/genética , Exoma , Feminino , Biblioteca Gênica , Ligação Genética , Predisposição Genética para Doença , Genótipo , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise de Sequência de DNA , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , alfa Catenina/metabolismo
19.
J Med Genet ; 50(2): 74-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23231788

RESUMO

BACKGROUND: Nearly 15% of BRCA1 and BRCA2 DNA tests lead to the identification of Variants of Uncertain Significance (VUS). VUS are classified in the Netherlands according to the Bell system and it is current practice that class III VUS are communicated to counsellees, but not class II or lower VUS. Our aims were to investigate the utility of in silico characteristics in the classification of VUS and whether initial VUS classifications justify differences in communication protocols during counselling. METHODS: We classified 88 missense VUS in BRCA1 and BRCA2 on the basis of an in silico analysis and compared the classification of a subset of 60 VUS of which additional information including family, genetic and tumour data was available. RESULTS: VUS allocated to class III more frequently showed in silico indications of a deleterious effect than class II VUS. Of the 46 VUS assigned to class II by in silico analysis alone, nearly half were eventually recategorised as class I and 10% as class III when additional information was included. CONCLUSIONS: As in silico analysis alone is not always sufficient to unambiguously assign VUS to either class II or class III, we would argue that the prospect of obtaining additional information from a family should be given more weight during the decision process preceding the communication of a VUS test result. Research initiatives such as the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), which strive to combine diverse sources of information, will be valuable in aiding a definitive classification of a VUS.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Aconselhamento Genético , Algoritmos , Sequência de Aminoácidos , Substituição de Aminoácidos , Proteína BRCA1/química , Proteína BRCA1/metabolismo , Proteína BRCA2/química , Proteína BRCA2/metabolismo , Sequência de Bases , Neoplasias da Mama/genética , Simulação por Computador , Feminino , Testes Genéticos , Humanos , Mutação de Sentido Incorreto , Neoplasias Ovarianas/genética , Valor Preditivo dos Testes , Alinhamento de Sequência
20.
PLoS One ; 7(8): e42380, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22879957

RESUMO

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Ásia , Europa (Continente) , Feminino , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Receptores Estrogênicos/genética , Fatores de Risco
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