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1.
Br J Cancer ; 121(2): 180-192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31213659

RESUMO

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

2.
BMJ ; 365: l1652, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088823

RESUMO

OBJECTIVE: To investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population. DESIGN: Retrospective, nationwide cohort study. SETTING: Specialised tertiary gender clinic in Amsterdam, the Netherlands. PARTICIPANTS: 2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment. MAIN OUTCOME MEASURES: Incidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people. RESULTS: The total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5). CONCLUSIONS: This study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.


Assuntos
Neoplasias da Mama/epidemiologia , Estrogênios/efeitos adversos , Transexualismo/tratamento farmacológico , Adulto , Antagonistas de Androgênios/uso terapêutico , Neoplasias da Mama Masculina/epidemiologia , Estrogênios/uso terapêutico , Feminino , Humanos , Incidência , Masculino , Países Baixos/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Testosterona/uso terapêutico , Adulto Jovem
3.
Am J Hum Genet ; 104(1): 21-34, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554720

RESUMO

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

4.
J Natl Cancer Inst ; 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

5.
J Med Genet ; 55(1): 15-20, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28490613

RESUMO

BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação/genética , Neoplasias Ovarianas/genética , Segregação de Cromossomos , Feminino , Humanos , Fatores de Risco
6.
J Clin Endocrinol Metab ; 102(12): 4534-4540, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040582

RESUMO

Context: Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series. Objective: To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT. Design: Nationwide retrospective Dutch cohort study. Setting: Tertiary referral center. Patients: We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers. Investigation: Germline CDC73 mutation analysis. Mean Outcome: CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance. Results: Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism-jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers. Conclusions: Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.


Assuntos
Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/fisiopatologia , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Hiperparatireoidismo Primário/patologia , Neoplasias Maxilomandibulares/genética , Neoplasias Maxilomandibulares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Países Baixos , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/patologia , Penetrância , Estudos Retrospectivos , Adulto Jovem
7.
Nature ; 551(7678): 92-94, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29059683

RESUMO

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.


Assuntos
Neoplasias da Mama/genética , Loci Gênicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Ásia/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Sítios de Ligação/genética , Neoplasias da Mama/diagnóstico , Simulação por Computador , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico , Medição de Risco , Fatores de Transcrição/metabolismo
8.
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
9.
Br J Cancer ; 115(10): 1174-1178, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27755534

RESUMO

BACKGROUND: It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis. METHODS: We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC. RESULTS: BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31). CONCLUSIONS: Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Mutação/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Prognóstico , Adulto Jovem
10.
Menopause ; 23(8): 903-10, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27326821

RESUMO

OBJECTIVE: It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature. METHODS: Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families. Information was obtained by a standardized questionnaire. Kaplan-Meier curves were constructed, and Cox regression was used to assess the association between BRCA1/2 mutation status and ANM. Adjustments were made for birth cohort, family, smoking, use of hormonal contraceptives, and parity. RESULTS: A total of 1,208 BRCA1/2 mutation carriers and 2,211 proven noncarriers were included. Overall, no association was found between BRCA1/2 mutation status and ANM (adjusted hazard ratio [HR] = 1.06 [95% CI, 0.87-1.30]). We examined if the null finding was due to informative censoring by uptake of risk-reducing salpingo-oophorectomy. Indeed, within the oldest birth cohort, in which the percentage of surgical menopause events was lowest and comparable between carriers and noncarriers, the HR for earlier natural menopause in carriers was 1.45 (95% CI, 1.09-1.94). The second oldest birth cohort, however, demonstrated a decreased HR (0.67 [95% CI, 0.46-0.98]), and thus no trend over birth cohorts was found. CONCLUSIONS: Various types of selection bias hamper the comparison of ANM between BRCA1/2 mutation carriers and noncarriers, genetically tested in the clinic.


Assuntos
Envelhecimento/genética , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Menopausa/genética , Mutação , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Regressão , Adulto Jovem
11.
J Clin Oncol ; 34(23): 2750-60, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27269948

RESUMO

PURPOSE: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. PATIENTS AND METHODS: CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. RESULTS: Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. CONCLUSION: These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Estudos de Casos e Controles , Feminino , Heterozigoto , Homozigoto , Humanos , Pessoa de Meia-Idade , Razão de Chances , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Medição de Risco , Deleção de Sequência
12.
Cancer Epidemiol Biomarkers Prev ; 25(8): 1251-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27277847

RESUMO

BACKGROUND: Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1/2 mutation on the breast cancer lifetime risk, when adjusted for referral bias. METHODS: A Dutch national cohort including 1,314 proven BRCA1/2 mutation carriers and covering 54,752 person years. Data were collected by family cancer clinics, via questionnaires and from the national Dutch Cancer Registry. The parent-of-origin effect was assessed using Cox regression analyses, both unadjusted and adjusted for referral bias. Referral bias was operationalized by number of relatives with cancer and by personal cancer history. RESULTS: The mutation was of paternal origin in 330 (42%, P < 0.001) BRCA1 and 222 (42%, P < 0.001) BRCA2 carriers. Paternal origin increased the risk of prevalent breast cancer for BRCA1 [HR, 1.54; 95% confidence interval (CI), 1.19-2.00] and BRCA2 carriers (HR, 1.40; 95% CI, 0.95-2.06). Adjusted for referral bias by several family history factors, these HRs ranged from 1.41 to 1.83 in BRCA1 carriers and 1.27 to 1.62 in BRCA2 carriers. Adjusted for referral bias by personal history, these HRs were 0.66 (95% CI, 0.25-1.71) and 1.14 (95% CI, 0.42-3.15), respectively. CONCLUSION: A parent-of-origin effect is present after correction for referral bias by family history, but correction for the personal cancer history made the effect disappear. IMPACT: There is no conclusive evidence regarding incorporating a BRCA1/2 parent-of-origin effect in breast cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 25(8); 1251-8. ©2016 AACR.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Herança Paterna/genética , Adulto , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Encaminhamento e Consulta , Fatores de Risco
13.
Cancer Res ; 76(17): 5103-14, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27197191

RESUMO

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
14.
Ned Tijdschr Geneeskd ; 159: A8910, 2015.
Artigo em Holandês | MEDLINE | ID: mdl-26332814

RESUMO

In the majority of breast cancer families, DNA testing does not show BRCA1 or BRCA2 mutations and the genetic cause of breast cancer remains unexplained. Routine testing for the CHEK2*1100delC mutation has recently been introduced in breast cancer families in the Netherlands. The 1100delC mutation in the CHEK2-gene may explain the occurrence of breast cancer in about 5% of non-BRCA1/2 families in the Netherlands. In the general population the CHEK2*1100delC mutation confers a slightly increased breast cancer risk, but in a familial breast cancer setting this risk is between 35-55% for first degree female carriers. Female breast cancer patients with the CHEK2*1100delC mutation are at increased risk of contralateral breast cancer and may have a less favourable prognosis. Female heterozygous CHEK2*1100delC mutation carriers are offered annual mammography and specialist breast surveillance between the ages of 35-60 years. Prospective research in CHEK2-positive families is essential in order to develop more specific treatment and screening strategies.


Assuntos
Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Feminino , Testes Genéticos , Genótipo , Humanos , Mamografia , Mutação , Países Baixos , Prognóstico , Fatores de Risco , Deleção de Sequência
15.
PLoS One ; 9(11): e109973, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25390939

RESUMO

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Sítios de Ligação , Estudos de Casos e Controles , Mapeamento Cromossômico , Biologia Computacional , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Receptores Estrogênicos/metabolismo
16.
Hum Mutat ; 35(4): 442-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24395671

RESUMO

Fanconi anemia (FA) is a rare recessive disorder with chromosomal instability, congenital abnormalities, and a high cancer risk. The breast cancer susceptibility gene BRCA2 (FANCD1) is one of the 16 genes involved in this recessive disease. We have identified a novel mutation of the splice donor site of intron 1 in the noncoding region of BRCA2 in a Japanese FA family. This mutation may account for the FA phenotype in a patient originally reported to have biallelic mutations in BRCA2. Subsequent functional studies revealed that one of the mutations, K2729N, was a neutral change. As reported here, a more careful analysis resulted in the identification of a novel splice site mutation. Functional analysis using a mouse embryonic stem cell-based assay revealed that it causes aberrant splicing, reduced transcript levels and hypersensitivity to DNA damaging agents, suggesting that it is likely to be pathogenic. Although similar pathogenic variants in the noncoding region of BRCA1 and 2 were not identified in a cohort of 752 familial breast cancer cases, we still think this finding is relevant for mutation analysis in Hereditary Breast and Ovarian Cancer Syndrome families in a diagnostic setting.


Assuntos
Proteína BRCA2/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Animais , Proteína BRCA1/genética , Sequência de Bases , Células Cultivadas , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Íntrons , Camundongos , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Sítios de Splice de RNA
17.
Eur J Cancer ; 49(8): 1993-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23415889

RESUMO

AIM: The CHEK2∗1100delC mutation confers a relative risk of two for breast cancer (BC) in the general population. This study aims to explore the excess cancer risk due to the CHEK2∗1100delC mutation within a familial non-BRCA1/2 breast cancer setting. PATIENTS AND METHODS: Cancer incidences were compared between first degree relatives of 107 familial breast cancer patients positive for the CHEK2∗1100delC mutation (CHEK2 positive families) and first degree relatives of 314 familial breast cancer patients without the CHEK2∗1100delC mutation (CHEK2 negative families). All families were derived from the same pool of familial non-BRCA1/2 breast cancer families (n=2554). Medical information of 2188 first degree relatives of these families was analysed for cancer risk. CHEK2∗1100delC status of relatives was unknown. RESULTS: Increased breast cancer risk (hazard ratio (HR) 2.0 (95% confidence interval (CI): 1.4-2.7), p<0.001) was observed in sisters of CHEK2∗1100delC positive index cases compared to sisters of CHEK2∗1100delC negative index cases. HR was 1.6 (95% CI: 1.0-2.4) for mothers of CHEK2 positive versus negative index cases (p=0.041). For second primary breast cancers HR was increased in CHEK2∗1100delC positive index cases (HR 2.1, 95% CI: 1.3-3.3, p=0.003) and their sisters (HR 2.6, 95% CI: 1.1-6.1, p=0.025). CONCLUSION: There is an excess breast cancer risk in first degree relatives of CHEK2∗1100delC positive non-BRCA1/2 familial breast cancer patients compared to non-CHEK2∗1100delC familial breast cancer relatives. Genotyping for the CHEK2∗1100delC mutation in a familial breast cancer setting contributes to optimal clinical surveillance in countries in which this mutation is prevalent. Carriers and female relatives are eligible for stringent breast surveillance programs.


Assuntos
Neoplasias da Mama/genética , Família , Predisposição Genética para Doença/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Ponto de Checagem 2 , Saúde da Família , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Risco , Deleção de Sequência , Irmãos
18.
J Med Genet ; 48(12): 860-3, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22058428

RESUMO

BACKGROUND: Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk. METHODS AND RESULTS: Homozygosity for the CHEK2*1100delC allele was identified in 8/2554 Dutch independent familial non-BRCA1/2 breast cancer cases. The genotype relative risk for breast cancer of homozygous and heterozygous familial breast cancer cases was 101.34 (95% CI 4.47 to 121 000) and 4.04 (95% CI 0.88 to 21.0), respectively. Female homozygotes appeared to have a greater than twofold increased breast cancer risk compared to familial CHEK2*1100delC heterozygotes (p=0.044). These results and the occurrence of multiple primary tumours in 7/10 homozygotes indicate a high cancer risk in homozygous women from non-BRCA1/2 families. CONCLUSIONS: Intensive breast surveillance is therefore justified in these homozygous women. It is concluded that diagnostic testing for biallelic mutations in CHEK2 is indicated in non-BRCA1/2 breast cancer families, especially in populations with a relatively high prevalence of deleterious mutations in CHEK2.


Assuntos
Neoplasias da Mama/genética , Mutação da Fase de Leitura , Homozigoto , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Alelos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Quinase do Ponto de Checagem 2 , Feminino , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Risco
19.
Pediatr Blood Cancer ; 55(4): 742-4, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20589654

RESUMO

Bi-allelic germline mutations of the Fanconi anemia (FA) genes, PALB2/FANCN and BRCA2/FANCD1, have been reported in a few Wilms tumor (WT) patients with an atypical FA phenotype. Therefore, we screened a random cohort of 47 Dutch WT cases for germline mutations in these two FA-genes by DNA sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Although several cases appeared to carry missense variants, no bi-allelic pathogenic mutations were identified, indicating that bi-allelic mutations in these FA-genes do not contribute significantly to the occurrence of WT.


Assuntos
Anemia de Fanconi/genética , Genes BRCA2 , Neoplasias Renais/genética , Mutação , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Tumor de Wilms/genética , Criança , Pré-Escolar , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Humanos , Lactente , Masculino
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