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1.
JAMA Netw Open ; 7(7): e2420034, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38958976

RESUMO

Importance: Prostate cancer, a leading cause of cancer death among men, urgently requires new prevention strategies, which may involve targeting men with an underlying genetic susceptibility. Objective: To explore differences in risk of early prostate cancer death among men with higher vs lower genetic risk to inform prevention efforts. Design, Setting, and Participants: This cohort study used a combined analysis of genotyped men without prostate cancer at inclusion and with lifestyle data in 2 prospective cohort studies in Sweden and the US, the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS), followed up from 1991 to 2019. Data were analyzed between April 2023 and April 2024. Exposures: Men were categorized according to modifiable lifestyle behaviors and genetic risk. A polygenic risk score above the median or a family history of cancer defined men at higher genetic risk (67% of the study population); the remaining men were categorized as being at lower genetic risk. Main Outcomes and Measures: Prostate cancer death analyzed using time-to-event analysis estimating hazard ratios (HR), absolute risks, and preventable deaths by age. Results: Among the 19 607 men included for analysis, the median (IQR) age at inclusion was 59.0 (53.0-64.7) years (MDCS) and 65.1 (58.0-71.8) years (HPFS). During follow-up, 107 early (by age 75 years) and 337 late (after age 75 years) prostate cancer deaths were observed. Compared with men at lower genetic risk, men at higher genetic risk had increased rates of both early (HR, 3.26; 95% CI, 1.82-5.84) and late (HR, 2.26; 95% CI, 1.70-3.01) prostate cancer death, and higher lifetime risks of prostate cancer death (3.1% vs 1.3% [MDCS] and 2.3% vs 0.6% [HPFS]). Men at higher genetic risk accounted for 94 of 107 early prostate cancer deaths (88%), of which 36% (95% CI, 12%-60%) were estimated to be preventable through adherence to behaviors associated with a healthy lifestyle (not smoking, healthy weight, high physical activity, and a healthy diet). Conclusions and Relevance: In this 20-year follow-up study, men with a genetic predisposition accounted for the vast majority of early prostate cancer deaths, of which one-third were estimated to be preventable. This suggests that men at increased genetic risk should be targeted in prostate cancer prevention strategies.


Assuntos
Predisposição Genética para Doença , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Pessoa de Meia-Idade , Idoso , Suécia/epidemiologia , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Estilo de Vida , Estudos de Coortes
2.
Eur J Cancer ; 162: 194-205, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35026490

RESUMO

BACKGROUND: The aggressive nature of breast cancers detected between planned mammographic screens, so-called interval cancers, remains elusive. Here, we aim to characterise underlying molecular features of interval cancer. METHODS: From 672 patients with invasive breast cancer, we analysed gene expression differences between 90 'true' interval cancer cases (i.e. women with low-dense breasts defined as per cent mammographic density <25%) and 310 screen-detected tumours while accounting for PAM50 subtypes and thus overall tumour aggressiveness. We computed an interval cancer gene expression profile (IC-Gx) in a total of 2270 breast tumours (regardless of interval cancer status) and tested for association with expression-based immune subtypes in breast cancer. In addition, we investigated the contribution of inherited and somatic genetic variants in distinct features of interval cancer. RESULTS: We identified 8331 genes nominally associated with interval cancer (P-value < 0.05, fold-change > 1.5). Gene set enrichment analysis showed immune-related pathways as key processes altered in interval cancer. Our IC-Gx, based on 47 genes with the strongest associations (false discovery rate < 0.05), was found to be associated mainly with immune subtypes involving interferon response. We isolated an interaction network of interval cancer and interferon genes for which a significant load of somatic and germline variants in class I interferon genes was observed. CONCLUSION: We identified novel molecular features of interval breast cancer highlighting interferon pathways as a potential target for prevention or treatment.


Assuntos
Neoplasias da Mama , Mama/patologia , Densidade da Mama , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Detecção Precoce de Câncer , Feminino , Humanos , Imunidade , Interferons/genética , Mamografia
3.
Int J Cancer ; 148(4): 884-894, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-32856720

RESUMO

The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P < .05) including Ki-67 proliferation status (P < 5 × 10-07 ). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P < 5 × 10-13 ), HER2-enriched subtype (P < 5 × 10-07 ) and worse 10-year breast cancer-specific survival (log-rank P < 5 × 10-04 ). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Coortes , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Risco
4.
Cancer Res ; 78(21): 6329-6338, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385609

RESUMO

Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes-or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer-specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16-2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12-3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64-0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329-38. ©2018 AACR.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Detecção Precoce de Câncer/métodos , Variação Genética , Adulto , Idoso , Proteína BRCA1/genética , Densidade da Mama , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Sobrevivência Celular , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Metástase Linfática , Mamografia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Risco , Resultado do Tratamento
5.
BMC Med ; 15(1): 154, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28797265

RESUMO

BACKGROUND: The risk of psoriasis in patients with breast cancer is largely unknown, as available evidence is limited to case findings. We systematically examined the incidence and risk factors of psoriasis in patients with breast cancer. METHODS: A Swedish nationwide cohort of 56,235 breast cancer patients (2001-2012) was compared to 280,854 matched reference individuals from the general population to estimate the incidence and hazard ratio (HR) of new-onset psoriasis. We also calculated HRs for psoriasis according to treatment, genetic, and lifestyle factors in a regional cohort of 8987 patients. RESULTS: In the nationwide cohort, 599 patients with breast cancer were diagnosed with psoriasis during a median follow-up of 5.1 years compared to 2795 cases in the matched reference individuals. This corresponded to an incidence rate of 1.9/1000 person-years in breast cancer patients vs. 1.7/1000 person-years in matched reference individuals. Breast cancer patients were at an increased risk of psoriasis (HR = 1.17; 95% confidence interval (CI) = 1.07-1.28), especially its most common subtype (psoriasis vulgaris; HR = 1.33; 95% CI = 1.17-1.52). The risk of psoriasis vulgaris was highest shortly after diagnosis but remained increased up to 12 years. Treatment-specific analyses indicated a higher risk of psoriasis in patients treated with radiotherapy (HR = 2.44; 95% CI = 1.44-4.12) and mastectomy (HR = 1.54, 95% CI = 1.03-2.31). Apart from treatment-specific effects, we identified genetic predisposition, obesity, and smoking as independent risk factors for psoriasis in breast cancer patients. CONCLUSIONS: The incidence of psoriasis is slightly elevated among patients with breast cancer, with treatment, lifestyle, and genetic factors defining the individual risk profile.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/epidemiologia , Psoríase/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Psoríase/complicações , Fatores de Risco , Suécia/epidemiologia , Adulto Jovem
6.
Sci Rep ; 7(1): 5942, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28725034

RESUMO

There is epidemiologic evidence showing that women with celiac disease have reduced risk of later developing breast cancer, however, the etiology of this association is unclear. Here, we assess the extent of genetic overlap between the two diseases. Through analyses of summary statistics on densely genotyped immunogenic regions, we show a significant genetic correlation (r = -0.17, s.e. 0.05, P < 0.001) and overlap (P permuted < 0.001) between celiac disease and breast cancer. Using individual-level genotype data from a Swedish cohort, we find higher genetic susceptibility to celiac disease summarized by polygenic risk scores to be associated with lower breast cancer risk (ORper-SD, 0.94, 95% CI 0.91 to 0.98). Common single nucleotide polymorphisms between the two diseases, with low P-values (P CD < 1.00E-05, P BC ≤ 0.05), mapped onto genes enriched for immunoregulatory and apoptotic processes. Our results suggest that the link between breast cancer and celiac disease is due to a shared polygenic variation of immune related regions, uncovering pathways which might be important for their development.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Doença Celíaca/complicações , Doença Celíaca/genética , Predisposição Genética para Doença , Variação Genética , Mapeamento Cromossômico , Feminino , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
7.
Br J Nutr ; 109(5): 894-7, 2013 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-22691288

RESUMO

Cancer patients receiving chemotherapy have a high risk of malnutrition secondary to the disease and treatment, and 40-80 % of cancer patients suffer from different degrees of malnutrition, depending on tumour subtype, location, staging and treatment strategy. Malnutrition in cancer patients affects the patient's overall condition, and it increases the number of complications, the adverse effects of chemotherapy and reduces the quality of life. The aim of the present study was to evaluate weight-loss prevalence depending on the tumour site and the gastrointestinal (GI) symptoms of oncology patients receiving chemotherapy. We included 191 cancer patients receiving chemotherapy. Files of all patients were reviewed to identify symptoms that might potentially influence weight loss. The nutritional status of all patients was also determined. The cancer sites in the patients were as follows: breast (31·9 %); non-colorectal GI (18·3 %); colorectal (10·4 %); lung (5·8 %); haematological (13·1 %); others (20·5 %). Of these patients, 58 % experienced some degree of weight loss, and its prevalence was higher among the non-colorectal GI and lung cancer patients. Common symptoms included nausea (59·6 %), anorexia (46 %) and constipation (31·9 %). A higher proportion of patients with ≥ 5 % weight loss experienced anorexia, nausea and vomiting (OR 9·5, 2·15 and 6·1, respectively). In conclusion, these results indicate that GI symptoms can influence weight loss in cancer patients, and they should be included in early nutritional evaluations.


Assuntos
Antineoplásicos/efeitos adversos , Gastroenteropatias/induzido quimicamente , Neoplasias/tratamento farmacológico , Redução de Peso , Adulto , Idoso , Anorexia/induzido quimicamente , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Feminino , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Desnutrição/epidemiologia , Desnutrição/etiologia , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/complicações , Estado Nutricional , Estudos Retrospectivos , Vômito/induzido quimicamente
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