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1.
Int J Cancer ; 148(8): 1895-1909, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33368296

RESUMO

Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case-control" analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.

2.
Eur J Med Genet ; 63(12): 104080, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33039684

RESUMO

In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyze simultaneously several genes associated with an increased risk of developing these tumors. Thus, "Gastro Intestinal" (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in this context and established a list of genes for which the estimated risks associated with pathogenic variant seemed sufficiently reliable and high for clinical use. Pancreatic cancer susceptibility genes have been excluded. This expertise defined a panel of 14 genes of confirmed clinical interest and relevant for genetic counseling: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11. The reasons for the exclusion of the others 23 genes have been discussed. The paucity of estimates of the associated tumor risks led to the exclusion of genes, in particular CTNNA1, MSH3 and NTHL1, despite their implication in the molecular pathways involved in the pathophysiology of GI cancers. A regular update of the literature is planned to up-grade this panel of genes in case of new data on candidate genes. Genetic and epidemiological studies and international collaborations are needed to better estimate the risks associated with the pathogenic variants of these genes either selected or not in the current panel.

3.
Genet Med ; 22(10): 1653-1666, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32665703

RESUMO

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

4.
Ther Adv Med Oncol ; 12: 1758835919897530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32165926

RESUMO

Poly(ADP-ribose)polymerase (PARP) inhibitors are targeted therapy for cancers with homologous repair deficiency (HRD). They were first approved for ovarian cancer and have changed current treatment strategies. They have also demonstrated efficacy in HER2-negative metastatic breast cancer and advanced prostate cancer with BRCA1/2 or ATM mutations. Patients with somatic and/or germline BRCA1/2 mutations benefit more from these treatments than other patients. Nowadays, the diagnosis of HRD is largely based on germline genetic testing, which is performed after an in-person genetic counseling session, even for patients without any family history of cancer. However, with the increasing number of PARP inhibitor indications across different tumor types, rapid access to oncogenetic consultations will become a challenge. To meet this demand, tumor genomic testing could be offered at initial diagnosis. Telephone counseling and other referral systems could replace in-person consultations for certain subgroups of patients deemed to have a low risk of harboring a germline mutation. This article reviews international guidelines for genetic counseling testing. We herein propose new care pathways for breast, prostate and ovarian cancers, including tumor genomic testing at initial diagnosis in order to help triage genetic counseling referrals.

5.
Psychol Health Med ; 25(6): 756-766, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31505944

RESUMO

The disclosure of genetic information is an important issue in cancer prevention. This study based on a French national cohort of BRCA1/2 mutation carriers (GENEPSO-PS cohort, N=233) aimed to assess the prevalence of parental disclosure of genetic information to children 10 years after genetic testing, with a focus on gender differences. Most participants (n = 193, 131 women) reported having children. A total of 72.0% of offspring had received genetic information (88.8% for adult offspring, p < .001), with no differences according to the gender of the mutation-carrying parent. While female carriers disclosed genetic information more often than male carriers (54.1% versus 38.3%, p = .029), they did so irrespective of the gender of their offspring. Moreover, female carriers who had developed incident cancer after genetic testing disclosed genetic information more frequently than unaffected female carriers (70.7% versus 48.5%, p = .005). A multivariate analysis confirmed the effects of both gender and cancer on disclosure to offspring. The same results were obtained when the analysis was restricted to adult offspring. This study reveals high rates of disclosure of positive BRCA1/2 mutation status to children 10 years after genetic testing, irrespective of the gender of the carrier/offspring. However, female carriers disclosed genetic information more frequently than male carriers.

6.
Cancer Epidemiol Biomarkers Prev ; 29(2): 368-378, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792088

RESUMO

BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. CONCLUSIONS: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

7.
Psychooncology ; 28(9): 1894-1900, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31276266

RESUMO

OBJECTIVE: Genetic counseling in at-risk families is known to improve cancer prevention. Our study aimed to determine the rate of uptake of genetic counseling among adult children of BRCA1/2 mutation carriers and to identify the potential psychosocial factors associated with uptake of genetic counseling. METHODS: A self-reported questionnaire was mailed to 328 BRCA1/2 mutation carriers 10 years after BRCA1/2 test disclosure. Of the 233 carriers who returned the questionnaire (response rate = 71%), 135 reported having children over age 18 years and were therefore included in the analysis. Generalized estimating equations models were used to identify the factors associated with uptake of genetic counseling among adult children of mutation carriers. RESULTS: Data were gathered for a total of 296 children (46% male, 54% female). The vast majority were informed about the familial mutation (90.9%) and 113 (38%; 95% CI, 32%-44%) underwent genetic counseling. This percentage exceeded 80% in women over 40 years. In the multivariate model, female sex, advanced age, mutation in the father, diagnosis of cancer in the mutation-carrying parent after genetic testing, and good family relationships were all factors associated with higher uptake of genetic counseling. CONCLUSIONS: Adult children of BRCA1/2 mutation carriers in France do not undergo genetic counseling sufficiently often. Further studies should be conducted on the psychosocial factors that hinder the uptake of genetic counseling among adult children of BRCA1/2 mutation carriers.


Assuntos
Crianças Adultas/psicologia , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Adolescente , Adulto , Crianças Adultas/estatística & dados numéricos , Idoso , Feminino , França , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Autorrelato , Adulto Jovem
8.
Int J Cancer ; 144(8): 1962-1974, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30303537

RESUMO

Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost-effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious-predicted variants in DNA repair genes in familial breast cancer (BC) in a well-characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss-of-function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious-predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.


Assuntos
Neoplasias da Mama/genética , Reparo do DNA/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Medição de Risco/métodos , Irmãos
10.
Bull Cancer ; 105(10): 907-917, 2018 Oct.
Artigo em Francês | MEDLINE | ID: mdl-30268633

RESUMO

INTRODUCTION: Next generation sequencing allows the simultaneous analysis of large panel of genes for families or individuals with a strong suspicion of hereditary breast and/or ovarian cancer (HBOC). Because of lack of guidelines, several panels of genes potentially involved in HBOC were designed, with large disparities not only in their composition but also in medical care offered to mutation carriers. Then, homogenization in practices is needed. METHODS: The French Genetic and Cancer Group (GGC) - Unicancer conducted an exhaustive bibliographic work on 18 genes of interest. Only publications with unbiased risk estimates were retained. RESULTS: The expertise of each 18 genes was based on clinical utility criteria, i.e. a relative risk of cancer of 4 and more, available medical tools for screening and prevention of mutation carriers, and pre-symptomatic genetic tests for relatives. Finally, 13 genes were selected to be included in a HBOC diagnosis gene panel: BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, EPCAM. The reasons for excluding NBN, RAD51B, CHEK2, STK11, ATM, BARD1, BRIP1 from the HBOC diagnosis panel are presented. Screening, prevention and genetic counselling guidelines were detailed for each of the 18 genes. DISCUSSION: Due to the rapid increase in knowledge, the GGC has planned a yearly update of the bibliography to take into account new findings. Furthermore, genetic-epidemiological studies are being initiated to better estimate the cancer risk associated with genes which are not yet included in the HBOC diagnosis panel.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/genética , Antígenos CD , Caderinas , Proteínas de Ligação a DNA/genética , Molécula de Adesão da Célula Epitelial/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , França , Genes BRCA1 , Genes BRCA2 , Genes p53 , Marcadores Genéticos/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , PTEN Fosfo-Hidrolase/genética
11.
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
12.
Breast Cancer Res ; 20(1): 28, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665859

RESUMO

BACKGROUND: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. METHODS: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. RESULTS: We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies. CONCLUSIONS: Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/patologia , Proteína BRCA2/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/classificação , Neoplasias da Mama Masculina/complicações , Neoplasias da Mama Masculina/patologia , Dano ao DNA/genética , Reparo do DNA/genética , Feminino , Testes Genéticos , Genômica , Mutação em Linhagem Germinativa/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Deleção de Sequência/genética
13.
JNCI Cancer Spectr ; 2(2): pky023, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31360853

RESUMO

Background: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. Methods: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. Results: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). Conclusions: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.

14.
Fam Cancer ; 17(3): 451-457, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29080081

RESUMO

One of the main challenges in cancer genetics is responding to the exponential demand for genetic counseling, especially in patients with breast and/or ovarian cancer. To address this demand, we have set up a new procedure, based on pre-genetic counseling telephone interviews (PTI) followed by routing of patients: D1, a PTI is scheduled within 14 days; D7-D14, genetic counselors perform a 20 min PTI in order to establish a pre-genetic counseling file, by collecting personal and family medical history via a structured questionnaire and; D10-17, routing: pre-genetic counseling appointment files are analyzed by a cancer geneticist with 3 possible conclusions: (a) priority face-to-face genetic counseling (FTFGC) appointment with a cancer geneticist, if the genetic test results have an immediate therapeutic impact; (b) non-priority FTFGC with a genetic counselor, or (c) no FTFGC required or substitution by a more appropriate index case. In the context of breast and/or ovarian cancer, 1012 patients received PTIs, 39.1% of which did not lead to FTFGC. The mean delay for non-priority FTFGC was maintained at 18 weeks and priority FTFGC appointments were guaranteed within 8 weeks. The required resources for 1012 patients was estimated at 0.12 FTE secretaries, 0.62 FTE genetic counselors and 0.08 FTE cancer geneticists and the procedure was shown to be cost-effective. This new procedure allows the suppression of up to 1/3 of appointments, guarantees priority for appointments with therapeutic impact and optimizes the interaction and breakdown of tasks between genetic counselors and cancer geneticists.


Assuntos
Neoplasias da Mama/genética , Aconselhamento Genético/economia , Aconselhamento Genético/métodos , Neoplasias Ovarianas/genética , Análise Custo-Benefício , Feminino , Predisposição Genética para Doença , Humanos , Entrevistas como Assunto/métodos , Telefone
15.
Eur J Hum Genet ; 25(12): 1345-1353, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29255180

RESUMO

RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have recently been involved in breast and ovarian cancer predisposition: RAD51B, RAD51C, and RAD51D in ovarian cancer, RAD51B and XRCC2 in breast cancer. The aim of this study was to estimate the contribution of deleterious variants in the five RAD51 paralogs to breast and ovarian cancers. The five RAD51 paralog genes were analyzed by next-generation sequencing technologies in germline DNA from 2649 consecutive patients diagnosed with breast and/or ovarian cancer. Twenty-one different deleterious variants were identified in the RAD51 paralogs in 30 patients: RAD51B (n = 4), RAD51C (n = 12), RAD51D (n = 7), XRCC2 (n = 2), and XRCC3 (n = 5). The overall deleterious variant rate was 1.13% (95% confidence interval (CI): 0.72-1.55%) (30/2649), including 15 variants in breast cancer only cases (15/2063; 0.73% (95% CI: 0.34-1.11%)) and 15 variants in cases with at least one ovarian cancer (15/570; 2.63% (95% CI: 1.24-4.02%)). This study is the first evaluation of the five RAD51 paralogs in breast and ovarian cancer predisposition and it demonstrates that deleterious variants can be present in breast cancer only cases. Moreover, this is the first time that XRCC3 deleterious variants have been identified in breast and ovarian cancer cases.


Assuntos
Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Rad51 Recombinase/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia
16.
Carcinogenesis ; 38(10): 994-1003, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28981872

RESUMO

Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families.The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies.HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/complicações , Mutação , Neoplasias/genética , Telômero/genética , Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Encurtamento do Telômero/genética , Proteína bcl-X/genética
17.
JAMA ; 317(23): 2402-2416, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28632866

RESUMO

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação , Segunda Neoplasia Primária/genética , Neoplasias Ovarianas/genética , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Família , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Neoplasias Ovarianas/epidemiologia , Estudos Prospectivos , Medição de Risco , Fatores de Tempo
18.
Fam Cancer ; 16(2): 167-171, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27783335

RESUMO

Germline allele specific expression (ASE), resulting in a lowered expression of one of the BRCA1 alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer (HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case-control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without BRCA1 or BRCA2 deleterious mutation. BRCA1 ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing. The allelic ratios and the proportion of ASE were compared between controls and cases using a Student's t test and a Fisher exact test, respectively. The linearity and reproducibility of the ASE dosage was demonstrated with R2 > 0.99 and a coefficient of variation below 10 %, and ASE was detected in two positive controls harbouring BRCA1 truncated mutations. In the heterozygote population, composed of 99/264 controls (37.5 %) and 96/227 patients (42.3 %), we detected a 5 % ASE without truncated mutations, in each population. We failed to detect any significant difference of ASE between controls and patients. So far, BRCA1 Allelic specific expression is not usable in routine diagnosis as a possible predisposition marker in HBOC patients except for the detection of truncated mutations.


Assuntos
Desequilíbrio Alélico/genética , Proteína BRCA1/genética , Genes BRCA1 , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem
19.
Breast Cancer Res Treat ; 161(1): 117-134, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27796716

RESUMO

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.


Assuntos
Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Biomarcadores Tumorais , Cromossomos Humanos Par 11 , Feminino , Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Humanos , Locos de Características Quantitativas , Risco
20.
Breast Cancer Res ; 18(1): 112, 2016 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-27836010

RESUMO

BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Vigilância da População , Alelos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Éxons , Feminino , Heterozigoto , Humanos , Perda de Heterozigosidade , Fenótipo , Regiões Promotoras Genéticas
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