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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.
Nat Commun ; 9(1): 4568, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30410027

RESUMO

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, rg = 0.77 (P = 2.6 × 10-11), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10-55). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.

3.
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.

4.
Br J Cancer ; 115(7): 776-83, 2016 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-27537391

RESUMO

BACKGROUND: The impact of an inherited BRCA2 mutation on the prognosis of women with breast cancer has not been well documented. We studied the effects of oestrogen receptor (ER) status, other prognostic factors and treatments on survival in a large cohort of BRCA2 mutation carriers. METHODS: We identified 285 breast cancer patients with a 999del5 BRCA2 mutation and matched them with 570 non-carrier patients. Clinical information was abstracted from patient charts and pathology records and supplemented by evaluation of tumour grade and ER status using archived tissue specimens. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. The effects of various therapies were studied in patients treated from 1980 to 2012. RESULTS: Among mutation carriers, positive ER status was associated with higher risk of death than negative ER status (HR=1.94; 95% CI=1.22-3.07, P=0.005). The reverse association was seen for non-carriers (HR=0.71; 95% CI: 0.51-0.97; P=0.03). CONCLUSIONS: Among BRCA2 carriers, ER-positive status is an adverse prognostic factor. BRCA2 carrier status should be known at the time when treatment decisions are made.


Assuntos
Neoplasias da Mama/genética , Estrogênios , Genes BRCA2 , Mutação , Neoplasias Hormônio-Dependentes/genética , Síndromes Neoplásicas Hereditárias/genética , Receptores Estrogênicos/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Feminino , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/química , Neoplasias Hormônio-Dependentes/mortalidade , Neoplasias Hormônio-Dependentes/terapia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/genética , Síndromes Neoplásicas Hereditárias/mortalidade , Síndromes Neoplásicas Hereditárias/terapia , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
5.
PLoS One ; 11(7): e0158801, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27463617

RESUMO

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.


Assuntos
Cromossomos Humanos Par 9 , Genes BRCA1 , Genes BRCA2 , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Mapeamento Cromossômico , Feminino , Humanos , Polimorfismo de Nucleotídeo Único
6.
Eur J Cardiothorac Surg ; 50(6): 1111-1117, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27334108

RESUMO

OBJECTIVES: Acute thoracic aortic dissection (ATAD) is a devastating condition associated with a high mortality rate. Recent reports suggest that its incidence is rising. Utilizing nationwide data comprising the whole Icelandic population, we aimed to determine the incidence, mortality rate and time-dependent mortality risk of ATAD. METHODS: Data were retrospectively collected using centralized hospital discharge registries, autopsy records and Cause of Death Registry in Iceland from 1992 to 2013. RESULTS: Age- and gender-adjusted incidence of ATAD was 2.53/100 000/year, and no significant change in incidence was observed during the study period. The mean age was 66.9 ± 13.6 years and 66.0% (101/153) were Stanford type A. Of the whole group, 17.6% (27/153) died prior to hospital arrival, whereas the risk of death for patients who arrived alive to a hospital was 21.4% (27/126) within 24 h and 45.2% (57/126) at 30 days. During the course of the study, patients with type A dissection were more likely to undergo an operation and the management of type B dissection changed from open to endovascular repair. The 30-day mortality rate declined every year and the 5-year survival rate improved in the last third of the study. CONCLUSIONS: The incidence of ATAD was 2.53/100 000/year and remained constant throughout the study, contradicting recent perceptions of a rising incidence. ATAD, type A in particular, remains a highly lethal condition: Over half of all patients die within 30 days of the index event. A reduced 30-day mortality rate and an increased long-term survival rate indicate improved overall outcomes in patients with this complex condition.


Assuntos
Aneurisma Dissecante/epidemiologia , Aneurisma da Aorta Torácica/epidemiologia , Fatores Etários , Idoso , Aneurisma Dissecante/mortalidade , Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/cirurgia , Feminino , Humanos , Incidência , Irlanda/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida
7.
Hum Mol Genet ; 25(5): 1008-18, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26740556

RESUMO

Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).


Assuntos
Neoplasias da Mama/genética , Carcinoma Basocelular/genética , Caspase 8/genética , Neoplasias da Próstata/genética , Processamento de RNA , Retroelementos , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Bases , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Caspase 8/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , Fatores de Proteção , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
8.
Gynecol Oncol ; 141(2): 386-401, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-25940428

RESUMO

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias Epiteliais e Glandulares/enzimologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Epitelial do Ovário , Feminino , Humanos
9.
J Ocul Pharmacol Ther ; 30(6): 464-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24734973

RESUMO

PURPOSE: Dorzolamide nanoparticle γ-cyclodextrin eye drops may prolong the effect of dorzolamide on intraocular pressure. We test whether the nanoparticle drops have an irritating or toxic effect on the eye in an in vivo rabbit model. METHODS: Eighteen pigmented rabbits were divided into 4 groups receiving dorzolamide nanoparticle γ-cyclodextrin eye drops×1/day or×2/day, Trusopt® (dorzolamide HCl)×3/day, and untreated controls that received no drops. The rabbits received treatment for 1 month. After sacrifice, 33 eyes and 25 Harderian glands were evaluated for histopathology in a masked way. RESULTS: Mild inflammation was seen in 19/31 eyes and 13/23 Harderian glands. The difference in inflammation (n=eyes/n=glands)between the γ-cyclodextrin nanoparticle eye drops×1/day (n=5/5),×2/day (n=5/3), Trusopt (n=7/4), or untreated control (n=2/0) groups was nonsignificant in both eyes and glands (P=0.87 and P=0.92) Acute inflammation was seen in 1 Harderian gland that received γ-cyclodextrin nanoparticle eye drops×2/day. The difference in conjunctival injection between the groups was nonsignificant (P=0.30). CONCLUSIONS: Dorzolamide γ-cyclodextrin nanoparticle eye drops are no more locally toxic or irritating to the eye than Trusopt.


Assuntos
Inibidores da Anidrase Carbônica/toxicidade , Nanopartículas , Sulfonamidas/toxicidade , Tiofenos/toxicidade , gama-Ciclodextrinas/química , Animais , Inibidores da Anidrase Carbônica/administração & dosagem , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Glândula de Harder/efeitos dos fármacos , Glândula de Harder/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Soluções Oftálmicas , Coelhos , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem
10.
Acta Ophthalmol ; 92(2): 121-5, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23164069

RESUMO

PURPOSE: To determine the incidence rate as well as causative diagnoses and surgical indications of enucleation in Iceland during the years 1992-2004. METHODS: A retrospective population-based incidence study involving the entire population of Iceland. Medical records of all patients who underwent enucleation in Iceland from January 1992 through December 2004 were reviewed. The annually updated Icelandic census was used as a denominator data. RESULTS: Fifty-six eyes were enucleated during 1992-2004. No eviscerations were done, and the three exenterations performed were not included in the study. The mean annual age-adjusted incidence rate of enucleation in Iceland was 1.48 enucleations per 100 000 population in comparison with 2.66 enucleations per 100 000 for the time period 1964-1991. With advancing age, a significant increasing linear trend existed (p < 0.001). The median age at enucleation was 51 years (SD 22; mean 55 years; 16-91 years). The three most common surgical indications for enucleation were blind painful eye, suspected ocular malignancy and acute trauma. The most common causative diagnosis for enucleation was traumatic lesion (39%). The annual incidence was 2.00 enucleations per 100 000 for men and 0.95 for women. There were significantly more men in the traumatic lesion group (p < 0.001), but no gender predominance was found in the other groups of causative diagnoses (p = 0.8). CONCLUSION: The overall mean annual incidence of enucleation in Iceland is continually decreasing, although the incidence of severe ocular trauma and ocular malignancy is fairly stable.


Assuntos
Oftalmopatias/epidemiologia , Enucleação Ocular/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Oftalmopatias/cirurgia , Traumatismos Oculares/epidemiologia , Traumatismos Oculares/cirurgia , Neoplasias Oculares/epidemiologia , Neoplasias Oculares/cirurgia , Dor Ocular/epidemiologia , Dor Ocular/cirurgia , Feminino , Humanos , Islândia/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Implantes Orbitários , Implantação de Prótese , Estudos Retrospectivos , Distribuição por Sexo , Adulto Jovem
11.
Photodermatol Photoimmunol Photomed ; 30(1): 25-34, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24255991

RESUMO

BACKGROUND: The combination of seawater baths and narrowband ultraviolet B (NB-UVB) is a known treatment for psoriasis. This study evaluates two treatment regimens that combine bathing in geothermal seawater and NB-UVB therapy in comparison with NB-UVB monotherapy. METHODS: Sixty-eight psoriasis patients were randomly assigned to outpatient bathing in geothermal seawater combined with NB-UVB therapy three times a week, intensive daily treatment involving bathing in geothermal seawater combined with NB-UVB therapy, or NB-UVB therapy alone three times a week; treatment period was 6 weeks. Disease severity [Psoriasis Area Severity Index (PASI) and Lattice System Physician's Global Assessment scores], quality of life (Dermatology Life Quality Index) and histological changes were evaluated before, during and after treatment. The primary end point was the proportion of patients who achieved PASI 75 at 6 weeks. RESULTS: At 6 weeks, the percentage of patients who achieved PASI 75 and PASI 90 was significantly greater for both regimens, bathing in geothermal seawater three times a week (68.1% and 18.2%, respectively) and intensive treatment with geothermal seawater (73.1% and 42.3%, respectively) than for NB-UVB monotherapy (16.7% and 0%, respectively) (P < 0.05 in all comparisons). Clinical improvement was paralleled by improvement in quality of life and histological score and a reduction in NB-UVB doses. CONCLUSION: Bathing in geothermal seawater combined with NB-UVB therapy in psoriasis induces faster clinical and histological improvement, produces longer remission time and permits lower NB-UVB doses than UVB therapy alone.


Assuntos
Balneologia , Fontes Termais , Fototerapia , Psoríase/terapia , Água do Mar , Adulto , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Cancer Med ; 2(4): 437-46, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24156016

RESUMO

Amplification of 8p12-p11 is relatively common in breast cancer and several genes within the region have been suggested to affect breast tumor progression. The aim of the study was to map the amplified 8p12-p11 region in a large set of breast tumors in an effort to identify the genetic driver and to explore its impact on tumor progression and prognosis. Copy number alterations (CNAs) were mapped in 359 tumors, and gene expression data from 577 tumors (359 tumors included) were correlated with CNA, clinical-pathological factors, and protein expression (39 tumors). 8p12-p11 was amplified in 11.4% of tumors. The smallest region of amplification harbored one full-length gene, ZNF703. ZNF703 mRNA expression was significantly higher in estrogen receptor (ER)-positive than ER-negative tumors (P = 2 × 10(-16)), a reflection of high expression in luminal tumors. Forty-eight percent of tumors with ZNF703 amplification were luminal B tumors in which the best correlation between DNA copy number and mRNA was seen (P = 1.2 × 10(-7)) as well as correlation between mRNA and protein expression (P = 0.02). High ZNF703 mRNA correlated with poor survival in patients with ER-positive luminal B tumors (log rank P = 0.04). Furthermore, high ZNF703 mRNA expression correlated with poor outcome in patients with ZNF703 copy number neutral, ER-positive, luminal B tumors (log rank P = 0.004). The results support ZNF703 as the driver gene of the 8p12 amplification and suggest that independent of amplification, high expression of the gene affects prognosis in luminal B tumors.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Amplificação de Genes , Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Proteínas de Transporte/metabolismo , Mapeamento Cromossômico , Cromossomos Humanos Par 8 , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Breast Cancer Res Treat ; 140(2): 375-84, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23857704

RESUMO

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24-2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91-4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41-1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Diploide , Análise de Sobrevida , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Prognóstico
15.
BMC Cancer ; 12: 621, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23270421

RESUMO

BACKGROUND: The minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression of TOX3. The SNP is closely located to TOX3 residing within an uncharacterised gene LOC643714. The aim of the study was to examine the association of the risk allele with expression of TOX3 and LOC643714, and of mRNA levels and genotype with clinical and pathological characteristics. METHODS: The SNP was genotyped in DNA isolated from blood and normal tissue from 160 breast cancer patients and mRNA levels were measured by microarrays and quantitative real-time (qRT)-PCR in breast tumours. Association with clinical and pathological characteristics was analysed by parametric tests. RESULTS: An association of the risk allele of rs3803662 with lower TOX3 expression was confirmed in oestrogen receptor (ER) positive tumours. It was more often observed in lobular tumours (p = 0.04), and carriers of the risk allele who had been diagnosed with luminal A tumours had shorter overall survival (OS) than carriers of the non-risk allele (p = 0.01). Positive correlation between the mRNA levels of TOX3 and LOC643714 was observed (r = 0.44 and p < 0.001). Association analysis with tumour pathology showed that low TOX3 and LOC643714 expression correlated with high Ki67 levels (p = 0.026 and p = 0.002) and the basal subtype (p < 0.001 and p < 0.001), whereas high expression correlated with ER (p = 0.004 and p < 0.001) and progesterone receptor (PgR) (p = 0.005 and p < 0.001) expression. Furthermore, high TOX3 and LOC643714 correlated with positive lymph nodes (p < 0.001 and p = 0.01). Patients with ER positive tumours and high levels of TOX3 mRNA had shorter overall- and distant metastasis free-survival (p = 0.017 and p = 0.021), an effect mostly attributable to patients with luminal B tumours. CONCLUSIONS: The results suggest that the effect of the risk allele of rs3803662 is strongest in luminal A tumours and that the expression levels of TOX3 and/or LOC643714 affect the progression of breast cancer. The effect may vary depending on the subtype and developmental stage of the tumour.


Assuntos
Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Receptores de Progesterona/genética , Alelos , Análise de Variância , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Feminino , Estudos de Associação Genética , Genótipo , Humanos , RNA Mensageiro/metabolismo , Receptores de Progesterona/metabolismo , Análise de Sobrevida
16.
Nat Genet ; 44(12): 1326-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23104005

RESUMO

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.


Assuntos
Adenocarcinoma/genética , Mutação , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Linhagem Celular , Cromossomos Humanos Par 8 , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Risco , Análise de Sequência de DNA
17.
Cancer Res ; 72(16): 4028-36, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22706203

RESUMO

Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we used gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated, and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter methylation but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1-deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1 hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer but rarely in BRCA2 hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings show the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1 status.


Assuntos
Proteína BRCA1/deficiência , Neoplasias da Mama/genética , Genes do Retinoblastoma , Neoplasia de Células Basais/genética , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Hibridização Genômica Comparativa , Feminino , Dosagem de Genes , Rearranjo Gênico , Genes BRCA1 , Mutação em Linhagem Germinativa , Humanos , Hibridização in Situ Fluorescente , Neoplasia de Células Basais/metabolismo , Neoplasia de Células Basais/patologia , Proteína do Retinoblastoma/biossíntese , Proteína do Retinoblastoma/genética , Transcriptoma
18.
PLoS One ; 6(9): e23833, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21915264

RESUMO

Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high)/CD24(low) ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.


Assuntos
Células Epiteliais/citologia , Células Epiteliais/metabolismo , Apoptose/fisiologia , Western Blotting , Desdiferenciação Celular , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Fator de Crescimento Epidérmico/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Citometria de Fluxo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Imunoquímica , Técnicas In Vitro , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
19.
Laeknabladid ; 97(3): 143-8, 2011 Mar.
Artigo em Islandês | MEDLINE | ID: mdl-21451193

RESUMO

INTRODUCTION: Survival of patients with testicular germ cell tumours has improved in recent years, mainly due to new modes of chemotherapy. We analyzed incidence, staging and survival of patients diagnosed during the last ten years in Iceland and compared the results to previous studies. MATERIALS AND METHODS: A retrospective study including all Icelandic males diagnosed during 2000-2009. Pathology reports were reviewed and the tumours staged (Boden-Gibb). Overall survival was estimated and seminomas (ST) and non-seminomas (N-ST) compared. RESULTS: 97 males were diagnosed, age-adjusted incidence being 5.9/100.000 males per year. The number of ST and N-ST was almost equal, and the mean age was 35.6 (range; 15-36), but patients with ST were 11.5 years older compared to N-ST. Symptoms were similar in both groups, also tumor size (4.0 cm), which did not change during the study period. Most of the tumours were in stage I, or 78.4%, 13.4% were in stage II og 8.2% in stage III-IV. ST were diagnosed at a significantly lower stage compared to N-ST (91.7 versus 65.3% in stage I; p=0.003). No distant metastases were diagnosed in patients with ST but in 8 patients with N-ST. Four patients died during the study period, two due to N-ST but no patient died because of ST. Five-year survival for the whole patient group was 95.1%. CONCLUSION: The incidence of testicular carcinoma in Iceland is similar to neighbouring countries and has remained fairly constant for the last two decades. At the same time the number of patients with localized disease (stage I) as well as the size of the tumours has not changed significantly. Survival in Iceland is comparable to the best results reported elsewhere.


Assuntos
Seminoma/epidemiologia , Neoplasias Testiculares/epidemiologia , Adulto , Idoso , Humanos , Islândia/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Estudos Retrospectivos , Seminoma/mortalidade , Seminoma/patologia , Seminoma/terapia , Análise de Sobrevida , Taxa de Sobrevida , Neoplasias Testiculares/mortalidade , Neoplasias Testiculares/patologia , Neoplasias Testiculares/terapia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
20.
Sci Transl Med ; 2(62): 62ra92, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21160077

RESUMO

Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.


Assuntos
Biomarcadores Tumorais/genética , Detecção Precoce de Câncer/métodos , Marcadores Genéticos/genética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Biomarcadores Tumorais/sangue , Humanos , Calicreínas/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Proteínas Secretadas pela Próstata/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteínas com Domínio T/genética , Telomerase/genética
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