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1.
Am J Hum Genet ; 107(5): 837-848, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022221

RESUMO

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

2.
Int J Cancer ; 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32976626

RESUMO

Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear. We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings. In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk. Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC.

3.
NPJ Breast Cancer ; 6: 44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964118

RESUMO

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

4.
Am J Hum Genet ; 107(4): 778-787, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871102

RESUMO

Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression could potentially explain breast cancer risk phenotypes. Using data from the Breast Cancer Association Consortium (BCAC) and quantitative trait loci (QTL) from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Project (TCGA), we identify shared genetic relationships and reveal novel associations between cancer phenotypes and effector genes. Seventeen genes, including NTN4, were identified as potential mediators of breast cancer risk. For NTN4, we showed the rs61938093 CCV at this region was located within an enhancer element that physically interacts with the NTN4 promoter, and the risk allele reduced NTN4 promoter activity. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. These data provide evidence linking risk-associated variation to genes that may contribute to breast cancer predisposition.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Netrinas/genética , Alelos , Animais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genômica/métodos , Xenoenxertos , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Netrinas/metabolismo , Fenótipo , Locos de Características Quantitativas , Risco
5.
Front Genet ; 11: 550, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714364

RESUMO

Long non-coding RNAs (lncRNAs) play crucial roles in human physiology, and have been found to be associated with various cancers. Transcribed ultraconserved regions (T-UCRs) are a subgroup of lncRNAs conserved in several species, and are often located in cancer-related regions. Breast cancer is the most common cancer in women worldwide and the leading cause of female cancer deaths. We investigated the association of genetic variants in lncRNA and T-UCR regions with breast cancer risk to uncover candidate loci for further analysis. Our focus was on low-penetrance variants that can be discovered in a large dataset. We selected 565 regions of lncRNAs and T-UCRs that are expressed in breast or breast cancer tissue, or show expression correlation to major breast cancer associated genes. We studied the association of single nucleotide polymorphisms (SNPs) in these regions with breast cancer risk in the 122970 case samples and 105974 controls of the Breast Cancer Association Consortium's genome-wide data, and also by in silico functional analyses using Integrated Expression Quantitative trait and in silico prediction of GWAS targets (INQUISIT) and expression quantitative trait loci (eQTL) analysis. The eQTL analysis was carried out using the METABRIC dataset and analyses from GTEx and ncRNA eQTL databases. We found putative breast cancer risk variants (p < 1 × 10-5) targeting the lncRNA GABPB1-AS1 in INQUISIT and eQTL analysis. In addition, putative breast cancer risk associated SNPs (p < 1 × 10-5) in the region of two T-UCRs, uc.184 and uc.313, located in protein coding genes CPEB4 and TIAL1, respectively, targeted these genes in INQUISIT and in eQTL analysis. Other non-coding regions containing SNPs with the defined p-value and highly significant false discovery rate (FDR) for breast cancer risk association were discovered that may warrant further studies. These results suggest candidate lncRNA loci for further research on breast cancer risk and the molecular mechanisms.

6.
Gynecol Oncol ; 158(3): 702-709, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32641237

RESUMO

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

7.
Twin Res Hum Genet ; 23(2): 72-73, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32638674

RESUMO

We performed a candidate single-nucleotide polymorphism association study of cleft lip and palate in 1992 which earned more citations than it had subjects (N = 230).

8.
iScience ; 23(7): 101296, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32622267

RESUMO

Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk.

9.
J Med Genet ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546565

RESUMO

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

10.
11.
Cancers (Basel) ; 12(5)2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32438682

RESUMO

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. METHODS: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. RESULTS: No SNPs reached genome-wide significance (p < 5 × 10-8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10-6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10-7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10-7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. CONCLUSION: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.

12.
J Natl Cancer Inst ; 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359158

RESUMO

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history), and on average 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

13.
J Natl Cancer Inst ; 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32107557

RESUMO

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI:5.60-10.19, p = 5 × 10-40; RAD51D RR = 7.60, 95%CI:5.61-10.30, p = 5 × 10-39) and BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 × 10-4; RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI:6-21%) for RAD51C and 13% (95%CI:7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI:15-29%) for RAD51C and 20% (95%CI:14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

14.
Cancers (Basel) ; 12(1)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936698

RESUMO

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoural breast cell lines. We identified putative regulatory elements, containing CCVs, which looped to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumour suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

15.
Genome Biol ; 21(1): 8, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910858

RESUMO

BACKGROUND: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. RESULTS: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. CONCLUSIONS: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.


Assuntos
Neoplasias da Mama/genética , Cromatina/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos
16.
Genome Biol ; 21(1): 7, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910864

RESUMO

BACKGROUND: Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. RESULTS: Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. CONCLUSIONS: We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.


Assuntos
Neoplasias da Mama/genética , RNA não Traduzido/genética , Estudo de Associação Genômica Ampla , Humanos , Análise de Sequência de RNA
17.
J Natl Cancer Inst ; 112(3): 295-304, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31143935

RESUMO

BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women's Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10-7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Grupo com Ancestrais do Continente Europeu/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Ilhas de CpG , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Risco , Transcriptoma
18.
Int J Epidemiol ; 49(4): 1117-1131, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31872213

RESUMO

BACKGROUND: Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. METHODS: Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. RESULTS: Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08-1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. CONCLUSIONS: This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.

19.
Gynecol Oncol ; 155(3): 461-467, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31706666

RESUMO

OBJECTIVE: Although a high proportion of women with advanced stage ovarian cancer die within five years, approximately 30% will survive longer than this. The factors contributing to exceptional survival are currently poorly understood. The viewpoints of ovarian cancer survivors were qualitatively explored to determine the factors they felt have influenced their exceptional ovarian cancer survival. METHODS: Four focus groups, one each in Los Angeles (California), Ann Arbor (Michigan), New York (New York) and Edmonton (Alberta, Canada), were conducted with women who had survived at least five years. Physical activity, diet, meditation, prayer, treatment, complementary medicine, and side effects were explored in semi-structured discussions. The audiotaped sessions were transcribed and coded and then analyzed using Dedoose Version 8.0.35, a qualitative analysis software. RESULTS: Of the 26 women who participated, 23 had advanced stage disease. Three overarching themes emerged: (a) survivors had improved their 'lifestyles', including but not limited to fitness and diet; (b) survivors were able to draw on strong support systems, which included family, friends, support groups, faith communities, and healthcare workers; and (c) survivors had a strong life purpose, which manifested as positivity, taking charge of their lives, and advocating for themselves. CONCLUSIONS: Long-term survivors have varying experiences with their cancer, but identified lifestyle modification, motivation and persistence, strong life purpose, and strong support systems as key elements in their better survival. These preliminary findings indicate the need for further prospective studies to determine whether meaningful differences exist between short term and long term survivors on these characteristics.


Assuntos
Sobreviventes de Câncer/psicologia , Neoplasias Ovarianas/psicologia , Alberta/epidemiologia , California/epidemiologia , Feminino , Grupos Focais , Estilo de Vida Saudável , Humanos , Michigan/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , New York/epidemiologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Apoio Social
20.
Nat Commun ; 10(1): 3935, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477716

RESUMO

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.


Assuntos
Adenocarcinoma Mucinoso/genética , Carcinoma Epitelial do Ovário/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Ovarianas/genética , Adenocarcinoma Mucinoso/classificação , Adenocarcinoma Mucinoso/metabolismo , Carcinoma Epitelial do Ovário/classificação , Carcinoma Epitelial do Ovário/metabolismo , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/metabolismo , Análise de Sequência de DNA/métodos , Análise de Sobrevida
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