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1.
Cancers (Basel) ; 12(12)2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33266155

RESUMO

Women carriers of pathogenic variants (mutations) in the BRCA1/2 genes face a high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). However, metabolic factors may influence BRCA penetrance. We studied the association of metabolic factors with BRCA1/2 variants and the risk effect of metabolic exposures in relation to the position of the mutations within the BRCA1/2. Overall, 438 women carriers of BRCA1/2 mutations, aged 18-70, with or without a previous diagnosis of BC/OC and without metastases, who joined our randomized dietary trial, were included in the study. The pathogenic variants were divided, according to their predicted effect, into loss of function (LOF) and nonsynonymous variants. The association between metabolic exposures and variants were analyzed by a logistic regression model. LOF variant carriers showed higher levels of metabolic parameters compared to carriers of nonsynonymous variants. LOF variant carriers had significantly higher levels of plasma glucose and serum insulin than nonsynonymous variant carriers (p = 0.03 and p < 0.001, respectively). This study suggests that higher insulin levels are significantly associated with LOF variants. Further investigations are required to explore the association of metabolic factors with LOF variants and the mechanisms by which these factors may affect BRCA-related cancer risk.

2.
Clin Breast Cancer ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33357965

RESUMO

BACKGROUND: Women with deleterious mutations in BRCA1/2 have a high lifetime penetrance of developing breast cancer and/or ovarian cancer. Genetic and/or environmental factors may influence BRCA penetrance, and identifying modifiable exposures might be valuable for prevention. PATIENTS AND METHODS: We implemented a multicenter prospective 2-arm (1:1) randomized controlled trial to investigate whether a Mediterranean dietary intervention with moderate protein restriction would reduce potential modulators of BRCA penetrance such as insulin-like growth factor 1 (IGF-1), body weight, and metabolic risk factors. We studied the baseline characteristics of women with BRCA-positive disease who joined the trial cohort, focusing on the relationships between selected lifestyle exposures, metabolic/anthropometric parameters, and BRCA-related cancer. RESULTS: A total of 502 women (304 with a previous diagnosis of breast cancer and/or ovarian cancer and 198 unaffected) with deleterious BRCA mutations, with or without a previous cancer, aged 18 to 70 years and without metastases were included. Late age at menarche and pregnancy were negatively associated with BRCA-related cancer, especially in women with BRCA1-positive disease. Higher fat mass and the presence of 4 or 5 metabolic risk factors were significantly associated with BRCA-related cancer (hazard ratio, 1.87, 95% confidence interval, 1.21-2.88; and hazard ratio, 1.87, 95% confidence interval, 1.11-3.19, respectively), with greater effect in BRCA2-positive women. CONCLUSIONS: Our findings confirm previous observations about reproductive factors in women with BRCA disease and suggest a potential impact of metabolic factors in BRCA-related cancer. The prospective follow-up of the trial cohort will enable us to study the environmental modulators of BRCA penetrance and their impact in relation to the history of BRCA-related cancer. [ClinicalTrials.gov NCT03066856].

3.
Cancers (Basel) ; 12(4)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276467

RESUMO

Previous studies on breast and ovarian carcinoma (BC and OC) revealed constitutional BRCA1 and RAD51C promoter hypermethylation as epigenetic alterations leading to tumor predisposition. Nevertheless, the impact of epimutations at these genes is still debated. One hundred and eight women affected by BC, OC, or both and considered at very high risk of carrying BRCA1 germline mutations were studied. All samples were negative for pathogenic variants or variants of uncertain significance at BRCA testing. Quantitative BRCA1 and RAD51C promoter methylation analyses were performed by Epityper mass spectrometry on peripheral blood samples and results were compared with those in controls. All the 108 analyzed cases showed methylation levels at the BRCA1/RAD51C promoter comparable with controls. Mean methylation levels (± stdev) at the BRCA1 promoter were 4.3% (± 1.4%) and 4.4% (± 1.4%) in controls and patients, respectively (p > 0.05; t-test); mean methylation levels (± stdev) at the RAD51C promoter were 4.3% (± 0.9%) and 3.7% (± 0.9%) in controls and patients, respectively (p > 0.05; t-test). Based on these observations; the analysis of constitutional methylation at promoters of these genes does not seem to substantially improve the definition of cancer risks in patients. These data support the idea that epimutations represent a very rare event in high-risk BC/OC populations.

4.
Cancers (Basel) ; 12(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991861

RESUMO

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

5.
Psychooncology ; 28(9): 1871-1878, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31264307

RESUMO

OBJECTIVE: Female carriers of BRCA1/BRCA2 mutations (BRCAm) are at increased risk of developing breast and ovarian cancer. The main prevention options currently available consist in either clinical-radiological surveillance or risk-reducing surgery. This study investigated factors that might influence the choice of risk-reducing mastectomy (RRM) and/or salpingo-oophorectomy (RRSO) over surveillance in high-risk women. METHODS: One hundred twenty-eight BRCAm women, 75 (58.60%) cancer affected (C-A) and 53 (41.40%) cancer-unaffected (C-UN), completed a baseline questionnaire concerning socio-demographic factors, personal medical history, cancer family history, and psychological dimensions. Preferences about prevention strategies were evaluated after 15 months. Multivariate logistic regression was used to analyse the relationship between these factors and the choice of RRSO or RRM in the whole cohort and the choice of surgery (RRM and/or RRSO) in C-A and C-UN women. RESULTS: The analyses on the whole cohort highlighted factors associated with the choice of both RRM and RRSO ("cancer concern," "previous therapeutic mastectomy," and "number of cancer-affected family members"), but also a few specifically associated with either RRM (age) or RRSO ("health" and "energy" perception and "number of children"). Surgery was more likely to be chosen by C-A (76%) than C-UN women (34%). With the exception of "cancer concern," factors associated with the choice of surgery were different between C-A ("number of deaths for cancer in the family" and "feeling downhearted and blue") and C-UN ("number of children" and "health perception") women. CONCLUSION: This study highlights potential drivers underlying the choice of preventive surgery, which should be considered when supporting the decision-making process in these women.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/cirurgia , Neoplasias Ovarianas/cirurgia , Comportamento de Redução do Risco , Adulto , Neoplasias da Mama/genética , Comportamento de Escolha , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Mastectomia/psicologia , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Salpingectomia/psicologia , Inquéritos e Questionários , Conduta Expectante
6.
Gynecol Oncol Rep ; 28: 68-70, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957000

RESUMO

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a congenital disorder of yet unknown etiology, characterized by agenesis/hypoplasia of the müllerian duct system. The occurrence of ovarian cancer (OC) in MRKHS is rare, with <20 cases reported to date. Case: A woman affected with MRKHS, developed an abdominal mass at the age of 33 years. Surgical examination revealed a blind vagina, small rudimentary uterus, two fully developed tubes and large bilateral ovarian tumors. The histological diagnosis was a low-grade serous carcinoma (LGSOC) of both ovaries, staged IIB. The patient showed a normal female karyotype and resulted negative at the BRCA1/2 genetic testing. Conclusion: This is the first report of a LGSOC in a patient with MRKHS. Although the identification of familial cases with both MRKHS and OC raised the hypothesis of a common genetic origin, further data and reports of additional cases are needed in order to assess a possible association of the two conditions.

7.
Cancers (Basel) ; 11(1)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634417

RESUMO

Early age at onset of breast cancer (eoBC) is suggestive of an increased genetic risk. Although genetic testing is offered to all eoBC-affected women, in isolated cases the detection rate of pathogenic variants is <10%. This study aimed at assessing the role of constitutive promoter methylation at BC-associated loci as an underlying predisposing event in women with eoBC and negative family history. Promoter methylation at 12 loci was assessed by the MassARRAY technology in blood from 154 BRCA1/2 negative patients with eoBC and negative family history, and 60 healthy controls. Hypermethylation was determined, within each promoter, by comparing the patient's mean methylation value with thresholds based on one-sided 95% bootstrap confidence interval of the controls' mean. Three patients had hypermethylated results, two at BRCA1 and one at RAD51C. Analyses on tumor tissue from the patient exceeding the highest threshold at BRCA1 revealed a mean methylation >60% and loss of heterozygosity at chromosome 17q. The patient hypermethylated at RAD51C showed low methylation in the tumor sample, ruling out a role for methylation-induced silencing in tumor development. In isolated eoBC patients, BRCA1 constitutive promoter methylation may be a predisposing event. Further studies are required to define the impact of methylation changes occurring at BC-predisposing genes and their role in tumorigenesis.

8.
Cancers (Basel) ; 10(9)2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30181513

RESUMO

BACKGROUND: Insulin-like growth factor I (IGF-I) and other markers of insulin resistance (IRm) might influence the penetrance of BRCA gene mutation. In a demonstration project on BRCA mutation carriers we tested the effect of the 'Mediterranean diet', with moderate protein restriction, on serum levels of IGF-I and IRm. METHODS: BRCA mutation carriers, with or without breast cancer, aged 18⁻70 years and without metastases were eligible. After the baseline examinations, women were randomized to an active dietary intervention or to a control group. The intervention group attended six full days of life-style intervention activities (cookery classes followed by lunch, sessions of walking for 45 min and nutritional conferences) over the next six months. RESULTS: 213 BRCA mutation carriers completed the six-month study. Women in the intervention group (110) showed major changes in all the parameters under study. They significantly lost weight (p < 0.001), fat mass (p = 0.002), with reduced hip circumference (p = 0.01), triglycerides (p = 0.02) and IGF-I (p = 0.02) compared with controls. They also had a significantly higher levels of insulin-like growth factor-binding protein 3 (IGFI-BP3) (p = 0.03) and a lower IGF-I/IGFI-BP3 ratio (p = 0.04). The reduction of serum levels of IGF-I was significantly associated with the reduction in the consumption of animal products (p = 0.04). CONCLUSIONS: Women in the intervention group showed significant improvements in IGF-I and in other IRm that might influence the penetrance of BRCA mutations.

9.
Cancer Genet ; 221: 38-45, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29405995

RESUMO

Carcinosarcomas (CSs) are biphasic neoplasms composed of high grade, malignant, epithelial and mesenchymal elements. The incidence of gynecological CSs (GCSs) is 0.4/100,000 women per year. Patients affected with GCSs have been occasionally reported in Hereditary Breast Ovarian Cancer (HBOC) families, including a few cases with pathogenic variants in BRCA1/BRCA2 genes. The prevalence and the association of GCSs in HBOC families have not been systematically investigated. Thus, we searched for families with GCSs in the HBOC registry of the National Cancer Institute of Milan. Eleven families, including four BRCA1-positive and four BRCA2-positive, presented a case of GCS. In the three BRCA1-mutated patients for whom surgical specimens were available, DNA fragment and sequencing analyses revealed the loss of the constitutionally wild-type BRCA1 allele. All tumors presented also TP53 mutations and stained positive for the expression of the protein product by immunohistochemistry. Our results suggest that GCSs may be found not infrequently in HBOC families and assimilate the analyzed CSs to BRCA1-related breast/ovarian carcinomas, where the above findings are frequently observed. Exploring the role of BRCA genes in prospective unselected series of GCSs might improve the knowledge of the genesis of these malignancies and guide the proposition of prophylactic surgery and targeted therapy.


Assuntos
Neoplasias da Mama/genética , Neoplasias dos Genitais Femininos/genética , Neoplasias Ovarianas/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Neoplasias dos Genitais Femininos/patologia , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Inquéritos e Questionários
10.
Integr Cancer Ther ; 17(1): 153-160, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28741383

RESUMO

BACKGROUND: Insulin resistance is associated with higher breast cancer (BC) penetrance in BRCA mutation carriers. Metabolic syndrome (MetS), an insulin resistance syndrome, can be reversed by adhering to the Mediterranean diet (MedDiet). In a dietary intervention trial on BRCA mutation carriers, we evaluated adherence to the MedDiet, and the association with the MetS, by analyzing data from the Mediterranean Diet Adherence Screener (MEDAS). METHODS: BRCA mutation carriers, with or without BC, aged 18 to 70 years, were eligible for the trial. After the baseline examinations, women were randomized to a dietary intervention or to a control group. Both groups completed the MEDAS at baseline and at the end of the dietary intervention. RESULTS: A total of 163 women completed the 6 months of dietary intervention. Compared with controls, the women in the intervention group significantly reduced their consumption of red meat ( P < .01) and commercial sweets ( P < .01) and their MEDAS score rose significantly (+1.3 vs +0.55, P = .02). The number of MetS parameters decreased with increasing points of adherence to the MEDAS score ( P = .01). In the intervention group, there was a significant association with the greater reduction of MetS. CONCLUSION: BRCA mutation carriers in the intervention group experienced greater improvement in their MedDiet and MetS parameters.


Assuntos
Neoplasias da Mama/dietoterapia , Neoplasias da Mama/genética , Dieta Mediterrânea , Genes BRCA1 , Genes BRCA2 , Síndrome Metabólica/dietoterapia , Adulto , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Fatores de Risco
12.
Genet Med ; 20(4): 452-457, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28837162

RESUMO

PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.


Assuntos
Alelos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Fragilidade Cromossômica , DNA Helicases/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Predisposição Genética para Doença , Mutação , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Consanguinidade , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Estudos de Associação Genética , Genótipo , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Fenótipo , Medição de Risco , Fatores de Risco
13.
J Clin Oncol ; 35(20): 2240-2250, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28448241

RESUMO

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.


Assuntos
Neoplasias da Mama Masculina/genética , Genes BRCA1 , Genes BRCA2 , Herança Multifatorial , Mutação , Neoplasias da Próstata/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Predisposição Genética para Doença , Testes Genéticos , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos
14.
PLoS One ; 12(2): e0171663, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28199346

RESUMO

In BRCA1/2 families, early-onset breast cancer (BrCa) cases may be also observed among non-carrier relatives. These women are considered phenocopies and raise difficult counselling issues concerning the selection of the index case and the residual risks estimate in negative family members. Few studies investigated the presence of potential genetic susceptibility factors in phenocopies, mainly focussing on BrCa-associated single-nucleotide polymorphisms. We hypothesized that, as for other Mendelian diseases, a revertant somatic mosaicism, resulting from spontaneous correction of a pathogenic mutation, might occur also in BRCA pedigrees. A putative low-level mosaicism in phenocopies, which has never been investigated, might be the causal factor undetected by standard diagnostic testing. We selected 16 non-carriers BrCa-affected from 15 BRCA1/2 families, and investigated the presence of mosaicism through MALDI-TOF mass spectrometry. The analyses were performed on available tumour samples (7 cases), blood leukocytes, buccal mucosa and urine samples (2 cases) or on blood only (7 cases). In one family (n.8), real-time PCR was also performed to analyse the phenocopy and her healthy parents. On the 16 phenocopies we did not detect the family mutations neither in the tumour, expected to display the highest mutation frequency, nor in the other analysed tissues. In family 8, all the genotyping assays did not detect mosaicism in the phenocopy or her healthy parents, supporting the hypothesis of a de novo occurrence of the BRCA2 mutation identified in the proband. These results suggest that somatic mosaicism is not likely to be a common phenomenon in BRCA1/2 families. As our families fulfilled high-risk selection criteria, other genetic factors might be responsible for most of these cases and have a significant impact on risk assessment in BRCA1/2 families. Finally, we found a de novo BRCA2 mutation, suggesting that, although rare, this event should be taken into account in the evaluation of high-risk families.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Mosaicismo , Adulto , Neoplasias da Mama/diagnóstico , DNA/análise , DNA/isolamento & purificação , DNA/metabolismo , Tumor do Seio Endodérmico/diagnóstico , Tumor do Seio Endodérmico/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Pessoa de Meia-Idade , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Adulto Jovem
15.
Cancer ; 123(2): 210-218, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27648926

RESUMO

BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases. Cancer 2017;123:210-218. © 2016 American Cancer Society.


Assuntos
Neoplasias da Mama Masculina/genética , Exoma/genética , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Análise Mutacional de DNA/métodos , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Humanos , Itália , Masculino , Mutação/genética , Linhagem
17.
Eur J Intern Med ; 32: 65-71, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27062684

RESUMO

BACKGROUND: BRCA mutation screening is frequently offered on the basis of the fulfillment of empirical selection criteria, thought to be indicative of a genetic predisposition to breast/ovarian cancer (BrCa/OvCa). This study aimed to evaluate, in a large cohort of BrCa/OvCa families, the mutation detection rate (DR) associated with specific clinical features and the relative performance of the employed selection criteria. METHODS: BRCA gene analysis was performed on 1854 family probands. The Fisher exact test was used to compare the DRs associated with different clinical features. In a subset of families fulfilling only mutually exclusive criteria, odds ratios and 95% CI were estimated to test the relative effectiveness of each criterion. RESULTS: The overall DR was 29.3%. Among BrCa-only families, the DRs were significantly higher in the presence of early-onset compared with late-onset cases, and of bilateral compared with unilateral cases. In families with bilateral cases, ages at diagnosis of both the first and second tumour were significantly lower in mutation carriers. In families fulfilling mutually exclusive criteria, OvCa was the best predictor of BRCA mutations, with DRs (range: 31.8%-80.0%) significantly higher compared with the other criteria. Conversely, isolated early-onset BrCa and three or more late-onset BrCa displayed significantly lower predictive values (7.9% and 7.2%, respectively). CONCLUSIONS: The observed estimates, albeit confirming a DR above 10% for most of the considered criteria, highlighted some relevant differences among them. Such differences should be taken into account in the identification of patients who might benefit from genetic counselling and subsequent testing.


Assuntos
Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Adulto , Análise Mutacional de DNA , Feminino , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Medição de Risco
18.
Tumori ; 102(1): 45-50, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26357973

RESUMO

AIMS AND BACKGROUND: Patients with hereditary breast cancer (BC) may benefit from genetic counseling and testing for detection of causative mutations, definition of therapeutic and preventive strategies, and identification of at-risk relatives. Italy has few oncogenetic centers and genetic evaluation of all patients with BC is not feasible. Moreover, lack of uniformity in the selection of patients generates inappropriate referral to the geneticist. We designed a model that may represent a reproducible way to select patients at risk for hereditary BC, with the aims of rationalizing access to genetic centers and improving clinical management and surveillance. METHODS: The genetic unit of a Cancer Center and the Departments of Oncology from 2 public Hospitals in Milan were involved in the project. After training sessions at the genetic unit, operators from the 2 hospitals evaluated all patients with BC attending a first oncologic visit, through a specific interview. Patients considered at risk of hereditary BC attended counseling at the genetic unit. RESULTS: Of 419 patients, 61 (14.5%) were eligible for genetic counseling after the interview. Of these, 46 (10.9%) strictly met testing criteria. Overall, 52 (12.4%) patients underwent genetic counseling and 47 were tested for BRCA1/BRCA2 mutation. After genetic test results, the available options for treatment/surveillance were discussed by a multidisciplinary team, according to the level of genetic risk. CONCLUSIONS: It is possible to improve the process of referring patients with suspected hereditary BC for genetic risk assessment. The application of clinical screening reduced the genetics unit's workload and enabled optimization of time and resources.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Aconselhamento Diretivo , Mutação , Vigilância da População , Encaminhamento e Consulta , Adulto , Idoso , Neoplasias da Mama/prevenção & controle , Gerenciamento Clínico , Família , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Hospitais Públicos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Vigilância da População/métodos , Avaliação de Programas e Projetos de Saúde , Encaminhamento e Consulta/normas
19.
Sci Rep ; 5: 15454, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26482194

RESUMO

Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Deleção de Genes , Glomerulosclerose Segmentar e Focal/genética , Neoplasias Primárias Múltiplas/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Proteína 7 com Repetições F-Box-WD , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/metabolismo , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/metabolismo
20.
Hum Mol Genet ; 24(18): 5345-55, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26130695

RESUMO

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.


Assuntos
Processamento Alternativo , Códon sem Sentido , DNA Helicases/genética , Reparo do DNA , Éxons , Adulto , Idade de Início , Alelos , Sítios de Ligação , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , DNA Helicases/metabolismo , Análise Mutacional de DNA , Feminino , Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Humanos , Metanálise como Assunto , Pessoa de Meia-Idade , Motivos de Nucleotídeos , Matrizes de Pontuação de Posição Específica , Ligação Proteica , Fatores de Risco , Adulto Jovem
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