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Diagnosed before age 50, early onset pancreatic malignancy (EOPM), is hypothesized to be a distinct subset of disease, although research is limited. To better characterize EOPM, and the effect of age at diagnosis on pancreatic cancer survival, we examined clinical characteristics and survival in EOPM and typical age-at-onset pancreatic malignancy (TOPM) cases. Vanderbilt University Medical Center (VUMC) Cancer Registry confirmed pancreatic adenocarcinomas (PDACs) and malignant pancreatic neuroendocrine tumors (PNETs) were evaluated. Clinical characteristics were compared using χ(2) tests. Overall survival was visualized with Kaplan-Meier functions; Cox proportional hazards regression was used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 1,697 pancreatic malignancies were diagnosed at the VUMC between 1988 and 2013. Of 1,407 PDACs, 118 (8.4%) were EOPM, which was associated with significantly better survival (adjusted HR: 0.82, 95% CI: 0.67-1.00). EOPM and TOPM PDACs significantly differed with regard to having multiple malignancies; survival associations significantly differed by race, stage of disease, treatment and multiple malignancies. Of 190 PNETs, 63 (33.1%) were EOPM, which was not significantly associated with survival (adjusted HR: 0.80, 95% CI: 0.46-1.40). Malignant neuroendocrine EOPM and TOPM cases significantly differed by stage of disease and tumor location; survival associations significantly differed by family history of pancreatic cancer, stage of disease and multiple malignancies. Differences in clinical characteristics and associations with survival were identified, indicating that EOPM is distinct from TOPM, and exists among both pancreatic adenocarcinomas and malignant pancreatic neuroendocrine tumors.
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Neoplasias Pancreáticas/epidemiologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estados Unidos/epidemiologiaRESUMO
MOTIVATION: The transition/transversion (Ti/Tv) ratio and heterozygous/nonreference-homozygous (het/nonref-hom) ratio have been commonly computed in genetic studies as a quality control (QC) measurement. Additionally, these two ratios are helpful in our understanding of the patterns of DNA sequence evolution. RESULTS: To thoroughly understand these two genomic measures, we performed a study using 1000 Genomes Project (1000G) released genotype data (N=1092). An additional two datasets (N=581 and N=6) were used to validate our findings from the 1000G dataset. We compared the two ratios among continental ancestry, genome regions and gene functionality. We found that the Ti/Tv ratio can be used as a quality indicator for single nucleotide polymorphisms inferred from high-throughput sequencing data. The Ti/Tv ratio varies greatly by genome region and functionality, but not by ancestry. The het/nonref-hom ratio varies greatly by ancestry, but not by genome regions and functionality. Furthermore, extreme guanine + cytosine content (either high or low) is negatively associated with the Ti/Tv ratio magnitude. Thus, when performing QC assessment using these two measures, care must be taken to apply the correct thresholds based on ancestry and genome region. Failure to take these considerations into account at the QC stage will bias any following analysis. CONTACT: yan.guo@vanderbilt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Evolução Molecular , Genoma Humano , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único/genética , Controle de Qualidade , Genótipo , Humanos , FenótipoRESUMO
The routine detection of large and medium copy number variants (CNVs) is well established. Hemizygotic deletions or duplications in the large Duchenne muscular dystrophy DMD gene responsible for Duchenne and Becker muscular dystrophies are routinely identified using multiple ligation probe amplification and array-based comparative genomic hybridization. These methods only map deleted or duplicated exons, without providing the exact location of breakpoints. Commonly used methods for the detection of CNV breakpoints include long-range PCR and primer walking, their success being limited by the deletion size, GC content and presence of DNA repeats. Here, we present a strategy for detecting the breakpoints of medium and large CNVs regardless of their size. The hemizygous deletion of exons 45-50 in the DMD gene and the large autosomal heterozygous PARK2 deletion were used to demonstrate the workflow that relies on real-time quantitative PCR to narrow down the deletion region and Sanger sequencing for breakpoint confirmation. The strategy is fast, reliable and cost-efficient, making it amenable to widespread use in genetic laboratories.
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Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.
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Carcinogênese , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 4/genética , Neoplasias Colorretais/patologia , Etnicidade , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Introduction: The COVID-19 pandemic has caused over 6 million deaths worldwide and is a significant cause of mortality. Mortality dynamics vary significantly by country due to pathogen, host, social and environmental factors, in addition to vaccination and treatments. However, there is limited data on the relative contribution of different explanatory variables, which may explain changes in mortality over time. We, therefore, created a predictive model using orthogonal machine learning techniques to attempt to quantify the contribution of static and dynamic variables over time. Methods: A model was created using Partial Least Squares Regression trained on data from 2020 to rank order the significance and effect size of static variables on mortality per country. This model enables the prediction of mortality levels for countries based on demographics alone. Partial Least Squares Regression was then used to quantify how dynamic variables, including weather and non-pharmaceutical interventions, contributed to the overall mortality in 2020. Finally, mortality levels for the first 60 days of 2021 were predicted using rolling-window Elastic Net regression. Results: This model allowed prediction of deaths per day and quantification of the degree of influence of included variables, accounting for timing of occurrence or implementation. We found that the most parsimonious model could be reduced to six variables; three policy-related variables - COVID-19 testing policy, canceled public events policy, workplace closing policy; in addition to three environmental variables - maximum temperature per day, minimum temperature per day, and the dewpoint temperature per day. Conclusion: Country and population-level static and dynamic variables can be used to predict COVID-19 mortality, providing an example of how broad temporal data can inform a preparation and mitigation strategy for both COVID-19 and future pandemics and assist decision-makers by identifying population-level contributors, including interventions, that have the greatest influence in mitigating mortality, and optimizing the health and safety of populations.
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COVID-19 , Humanos , COVID-19/epidemiologia , Teste para COVID-19 , Pandemias , Febre , Política PúblicaRESUMO
Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States and can be classified on the basis of various pathologic, molecular, and genetic features, including microsatellite instability (MSI). As MSI is generally associated with a more favorable outcome in colorectal cancers, it is feasible that microsatellite instability may also influence endometrial cancer survival. We examined MSI and survival in 45 African American and 31 white women diagnosed with endometrial cancer at a large, urban cancer center. Fifty-five tumors were classified as type I and 21 tumors were classified as type II. Unconditional logistic regression models found that microsatellite stable tumors were more frequently observed in white women compared with African American women (odds ratio, 8.61; 95% confidence interval, 1.01-73.69). Type I tumors with MSI were not found to be significantly associated with smoking status, tumor stage, or age. Only one type II tumor was classified as MSI. Neither race nor MSI status was a predictor of death from all causes or only endometrial cancer-related deaths were considered in univariate and multivariate survival models. The potential significance of a larger proportion of MSI tumors found in African American women with type I endometrial cancer should be assessed in a larger prospective study.
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DNA de Neoplasias/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/mortalidade , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , DNA de Neoplasias/isolamento & purificação , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Marcadores Genéticos/genética , Humanos , Histerectomia , Modelos Logísticos , Michigan/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , População BrancaRESUMO
The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non-small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy. SIGNIFICANCE: The complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage-specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Teorema de Bayes , Proteínas Proto-Oncogênicas p21(ras)/genética , Mutação , Genômica , Microambiente TumoralRESUMO
OBJECTIVE OF THE STUDY: Recent publications have reported an association between colon cancer and human papillomaviruses (HPV), suggesting that HPV infection of the colonic mucosa may contribute to the development of colorectal cancer. METHODS: The GP5+/GP6+ PCR reverse line blot method was used for detection of 37 types of human papillomavirus (HPV) in DNA from paraffin-embedded or frozen tissues from patients with colorectal cancer (n = 279) and normal adjacent tissue (n = 30) in three different study populations, including samples from the United States (n = 73), Israel (n = 106) and Spain (n = 100). Additionally, SPF10 PCR was run on all samples (n = 279) and the Innogenetics INNO-LiPA assay was performed on a subset of samples (n = 15). RESULTS: All samples were negative for all types of HPV using both the GP5+/GP6+ PCR reverse line blot method and the SPF10 INNO-LiPA method. CONCLUSIONS: We conclude that HPV types associated with malignant transformation do not meaningfully contribute to adenocarcinoma of the colon.
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Adenocarcinoma/virologia , Alphapapillomavirus/isolamento & purificação , Neoplasias Colorretais/virologia , DNA Viral/isolamento & purificação , Infecções por Papillomavirus/complicações , Alphapapillomavirus/genética , Estudos de Casos e Controles , Transformação Celular Viral , Feminino , Humanos , Israel , Masculino , Reação em Cadeia da Polimerase , Espanha , Estados UnidosRESUMO
PURPOSE: High-frequency microsatellite-instable (MSI-H) tumors account for approximately 15% of colorectal cancers. Therapeutic decisions for colorectal cancer are empirically based and currently do not emphasize molecular subclassification despite an increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI colorectal cancers using combined gene expression data sets. EXPERIMENTAL DESIGN: Three expression/query signatures (discovery data set) characterizing MSI-H colorectal cancer were matched with information derived from changes induced in cell lines by 164 compounds using the systems biology tool "Connectivity Map." A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle, and apoptosis effects of validated compounds were evaluated in a panel of cell lines. RESULTS: Fourteen of the 164 compounds were validated as targeting MSI-H cell lines using the bioinformatics approach; rapamycin, LY-294002, 17-(allylamino)-17-demethoxygeldanamycin, and trichostatin A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by rapamycin (18.3 versus 4.4 mumol/L; P = 0.0824) and LY-294002 (15.02 versus 10.37 mumol/L; P = 0.0385) when compared with microsatellite-stable cells. Preferential activity was also observed in MSH2 and MSH6 mutant cells. CONCLUSION: Our study shows that the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is of special relevance in mismatch repair-deficient colorectal cancer. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.
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Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Inibidores Enzimáticos/uso terapêutico , Perfilação da Expressão Gênica , Inibidores de Fosfoinositídeo-3 Quinase , Algoritmos , Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Cromonas/farmacologia , Cromonas/uso terapêutico , Neoplasias Colorretais/enzimologia , Biologia Computacional , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Instabilidade de Microssatélites , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/farmacologiaRESUMO
Background: Since 2011, the approval of several new agents has improved treatment options for malignant melanoma. We describe treatment patterns for malignant melanoma in the United States from the MarketScan database from 2011 to 2016.Methods: Treatments used for patients aged >18 years diagnosed with malignant melanoma after January 1, 2011 and enrolled in the Truven MarketScan database were analyzed. Patient data were collected for the 12-month period from the date of the first melanoma diagnosis to either death, the pre-specified study end date (August 31, 2016), or date of termination of health insurance. Treatment patterns from 2011-2013 and 2014-2016 were analyzed according to agent, year of drug administration, and line of therapy.Results: From 2011 to 2016, use of cytokines (63.8; 13.3%) and chemotherapy (19.6; 12.9%) decreased, and use of checkpoint inhibitors increased (2.0; 49.9%). Checkpoint inhibitor use also increased across all lines of therapy from 2011-2013 and 2014-2016. Use of BRAF/MEK inhibitors remained relatively stable from 2011 to 2016 (6.5-12.5%); however, the use of vemurafenib monotherapy decreased (6.5; 0.8%), and treatment with combination regimens increased (0; 10.9%) from 2011-2016. BRAF/MEK inhibitor use only increased in the first line setting from 2011-2013 (9.7%) to 2014-2016 (11.2%).Conclusion: With the approval of immune checkpoint inhibitors, BRAF/MEK inhibitors, and targeted therapies, the therapeutic landscape for the treatment of metastatic melanoma has shifted dramatically away from cytokines and chemotherapy. Treatment patterns will likely continue to evolve as scientific advances are made.
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Imunoterapia/métodos , Melanoma/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
Coffee consumption has been associated with the risk of cancer at several anatomical sites, but the findings, mostly from studies of non-Hispanic whites and Asians, are inconsistent. The association between coffee consumption and the incidence of cancer has not been thoroughly examined in African Americans. We conducted a nested case-control study including 1801 cancer cases and 3337 controls among African Americans from the Southern Community Cohort Study (SCCS) to examine the association between coffee drinking, as assessed by a semi-quantitative food frequency questionnaire, and the risk of four common cancers (lung, prostate, breast, colorectal). We used logistic regression adjusted for age, sex and cancer-specific risk factors. Overall, only ≤ 9.5% of African American cases and controls from the SCCS drank regular or decaffeinated coffee ≥ 2 times/day. After adjustment for major cancer-specific risk factors, coffee consumption was not statistically significantly associated with the risk of lung, breast, colorectal, or prostate cancers (OR range 0.78-1.10; P ≥ 0.27 for ≥ 2 versus < 1 times/day) or overall cancer risk (OR 0.93; 95% CI 0.75-1.16; P = 0.52 for ≥ 2 versus < 1 times/day). Coffee consumption was not associated with the risk of cancer among African Americans in our study.
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Negro ou Afro-Americano/estatística & dados numéricos , Café , Comportamento Alimentar/fisiologia , Resultados Negativos , Neoplasias/epidemiologia , Neoplasias/etiologia , Fatores Etários , Estudos de Casos e Controles , Café/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Masculino , Neoplasias/prevenção & controle , Prevalência , Risco , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários , Estados UnidosRESUMO
High mobility group A protein-2 (HMGA2) is an architectural transcription factor that binds to the A/T-rich DNA minor groove and is responsible for regulating transcriptional activity of multiple genes indirectly through chromatin change and assembling enhanceosome. HMGA2 is overexpressed in multiple tumor types, suggesting its involvement in cancer initiation and progression, thus, making it an ideal candidate for cancer diagnostic and prognostic. We performed a systematic review to examine the role of HMGA2 as a universal tumor cancer diagnostic and prognostic marker. We used Reporting Recommendations for Tumor Marker Prognostic Studies to systematically search OvidMedline, PubMed, and the Cochrane Library for English language studies, published between 1995 and June 2019. Meta-analysis provided pooled risk estimates and their 95% confidence intervals (CIs) for an association between overall survival and recurrence of cancers for studies with available estimates. We identified 42 eligible studies with a total of 5123 tumor samples in 15 types of cancer. The pooled percentage of HMGA2 gene expression in tumor samples was 65.14%. Meta-analysis showed that cancer patients with HMGA2 positive have significantly reduced survival, compared to patients without HMGA2 gene [pooled-hazard ratio (HR) = 1.85, 95% CI 1.48-2.22]. There was a positive association between cancer patients with HMGA2 overexpression and cancer recurrence though this association did not reach significance (pooled-HR = 1.44, 95% CI 0.80-2.07). Overexpression of HMGA2 was found in 15 types of cancer. There was an association between HMGA2 overexpression with reduced survival of cancer patients. HMGA2 is thus considered a promising universal tumor marker for prognostics.
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Biomarcadores Tumorais/metabolismo , Proteína HMGA2/metabolismo , Neoplasias/patologia , Terapia Combinada , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Prognóstico , Taxa de SobrevidaRESUMO
OBJECTIVE: To assess variations in hospitalizations, emergency department/observational (ED/OB) stays not resulting in hospitalization, reasons for hospitalization, and hospitalization discharge destinations after chemotherapy, information not provided as part of Oncology Care Model (OCM) baseline data. METHODS: OCM methodology was applied to the Medicare 20% sample data to identify 6-month patient episodes triggered by chemotherapy in 2012-2015. Proportions of episodes with hospitalization or ED/OB stays, reasons for hospitalization, and discharge destinations were summarized. RESULTS: Of 485,186 6-month episodes for 255,229 patients in 13,823 practices, 25% of episodes led to ≥1 hospitalization (from 14% in breast cancer to 56% in acute leukemia), and 23% to ED/OB stays (from 18% in breast cancer to 36% in liver cancer). In 2995 practices with ≥20 total episodes, practice-level proportions of episodes with hospitalization ranged from 14% to 31% (20th-80th percentile) and with ED/OB stays from 17% to 29%. For all cancers combined, the most frequent reasons for hospitalization were infection (13%), anemia (7%), dehydration (5%), and congestive heart failure (3%); the most common discharge destinations were home (71%) followed by a skilled nursing facility (13%), death (6%), and hospice (5%). Reasons for hospitalization and discharge destinations varied by cancer type; acute leukemia episodes led to the highest rates of infection and anemia, and central nervous system tumor episodes to the highest proportions of death or hospice discharge. CONCLUSION: The variations in frequency of and reasons for hospitalization, ED/OB stays, and hospitalization discharge destinations across cancer types should be considered when evaluating OCM practice performance.
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Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Medicare , Neoplasias/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Estudos Retrospectivos , Estados UnidosRESUMO
AIM: Talimogene laherparepvec (T-VEC) is an intralesional therapy for unresectable, metastatic melanoma. T-VEC real-world use in the context of anti-PD1-based therapy requires further characterization. MATERIALS & METHODS: A retrospective review of T-VEC use from 1 January 2017 and 31 March 2018 for melanoma patients was conducted at seven US institutions. RESULTS: Among 83 patients, three categories of T-VEC and anti-PD-1 therapy were identified: T-VEC used without anti-PD-1 (n = 29, 35%), T-VEC after anti-PD-1-based therapy (n = 22, 27%) and concurrent T-VEC and anti-PD-1-based therapy (n = 32, 39%). 25% of patients discontinued T-VEC therapy due to no remaining injectable lesions, 37% discontinued T-VEC due to progressive disease. Discontinuation of T-VEC did not differ by anti-PD-1-based therapy use or timing. CONCLUSION: In real-world settings, T-VEC may be used concurrently with or after anti-PD-1-based therapy.
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Exposure to sex hormones is a major risk factor for breast cancer and current treatments include hormone modifying drugs, among them aromatase inhibitors. We studied the association of CYP19 (Val(80) and [TTTA](n)) polymorphisms, the gene translated to aromatase, and the risk of breast cancer in BRCA carriers and noncarriers. The study consisted of 958 cancer cases and 931 healthy controls, including 474 carriers and 1,415 noncarriers. Cases and controls came from a population-based study of breast cancer in Israel, enriched with BRCA carriers from a clinical familial cancer service. Val(80) G/G genotype was associated with significantly increased risk of breast cancer compared with the Val(80) A/A genotype in BRCA1 carriers ages <50 years (odds ratio, 2.81; 95% confidence interval, 1.09-7.22; P = 0.032) but not in BRCA2 carriers or noncarriers of any age. A similar magnitude suggestive association, although nonstatistically significant, was found between Val(80) polymorphism and estrogen receptor-negative status of the breast tumors. A common haplotype composed of the Val(80) G allele and three haplotype-tagging single nucleotide polymorphisms (rs727479, rs10046, and rs4646) in the CYP19 coding region showed a trend to association with breast cancer risk in BRCA1 carriers ages <50 years. Published expression data show higher estrogen levels with higher repeats in [TTTA](n) found in linkage disequilibrium with Val(80). The present study suggests that the CYP19 Val(80) polymorphism and a haplotype that includes this polymorphism are associated with increased breast cancer risk in young women with BRCA1 mutations.
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Aromatase/genética , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Genes BRCA2 , Judeus , Adulto , Alelos , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Genótipo , Haplótipos , Humanos , Israel , Modelos Logísticos , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de RiscoRESUMO
Gastrointestinal malignancies are extremely rare in the pediatric population, and duodenal cancers represent an even more unusual entity. Intestinal cancers in young adults and children have been observed to be associated with functional deficiencies of the mismatch repair (MMR) system causing a cancer-predisposition syndrome. We report the case of a 16-year-old female with duodenal adenocarcinoma and past history of medulloblastoma found to have a novel germline bialleleic truncating mutation (c.[949C>T]+[949C>T]) of the PMS2 gene.
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Adenocarcinoma/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Duodenais/genética , Mutação em Linhagem Germinativa , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/secundário , Adenosina Trifosfatases/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Consanguinidade , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Metástase Linfática , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/secundário , Linhagem , Radioterapia AdjuvanteRESUMO
AIM: To describe treatment changes from 2011 to 2017 and demographic/clinical characteristics of patients with advanced melanoma who received systemic therapy by BRAF status. PATIENTS & METHODS: Treatment patterns were evaluated in adults from the Oncology Services Comprehensive Electronic Records database who received antimelanoma systemic therapy. RESULTS: Checkpoint inhibitors were prevailingly prescribed (66%); usage increased from 2011 (21%) to 2017 (84%). BRAF/MEK inhibitors were the second most common (21%); usage increased from 2011 (6%) to 2012 (18%) and stabilized until 2017 (22%). BRAF/MEK inhibitors (65%) and checkpoint inhibitors (57%) were predominantly used for BRAFMut melanoma. CONCLUSION: Overall, checkpoint inhibitors have supplanted other therapies for advanced melanoma. Treatment shifts have occurred for BRAFMut melanoma, notably increased use of checkpoint inhibitors and BRAF/MEK combinations compared with monotherapies.
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The oncofetal mRNA-binding protein, IMP1 or insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), promotes the overexpression of several oncogenic proteins by binding to and stabilizing their mRNAs. IMP1 is frequently overexpressed in melanoma and is associated with a poor prognosis, but the full spectrum of IMP1 target transcripts remains unknown. Here, we report the identification of protein kinase C-α (PKCα), as a novel molecular target of IMP1. Overexpression of IMP1 resulted in increased levels of PKCα, while RNAi knockdown of IMP1 resulted in decreased PKCα mRNA stability, PKCα protein levels, and MAPK/ERK activation. In addition to IMP1 acting as a positive regulator of PKCα mRNA, we also report the identification of miR-340 as a negative regulator of PKCα mRNA. In melanoma cancer cells, inhibition of miR-340 led to increased PKCα protein levels. PKCα plays important roles in numerous signaling pathways including the MAPK/ERK signaling pathway. PKCα activates RAF1, which in turn activates MEK1, and activates downstream transcriptional targets of MAPK through activation of JNK signaling. Together, these pathways provide a way to activate MAPK signaling downstream of BRAF and MEK1 inhibitors, which are commonly used to treat melanoma. Analysis of 117 melanoma tumors samples showed that overexpression of PKCα is associated with poorer overall survival. In patients harboring BRAF or NRAS mutations, PKCα overexpression is associated with an 11-fold increased risk of death. Thus, PKCα mRNA is a novel target of IMP1, which is commonly overexpressed in melanoma and is linked to poorer overall survival.
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Melanoma/genética , Proteína Quinase C-alfa/genética , Proteínas de Ligação a RNA/genética , Neoplasias Cutâneas/metabolismo , Linhagem Celular Tumoral , GTP Fosfo-Hidrolases/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases , Melanoma/mortalidade , Proteínas de Membrana/genética , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas B-raf/genética , Interferência de RNA , Risco , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Resultado do Tratamento , Regulação para CimaRESUMO
AIM: Talimogene laherparepvec (T-VEC) is an intralesional treatment for unresectable cutaneous, subcutaneous and nodal melanoma. COSMUS-1 was conducted to examine how T-VEC is used in US clinical practice. MATERIALS & METHODS: A chart review was conducted at seven centers, with 78 patients screened and 76 eligible. RESULTS: Patients began treatment with T-VEC between October 2015 and December 2016. Median follow-up was 9.4 months. Twenty percent of patients (n = 15) completed T-VEC treatment with no remaining injectable lesions or pathologic complete response. Flu-like symptoms were the most commonly reported adverse events (n = 8; 10.5%), followed by lesion ulceration (n = 4; 5.3%). No herpetic lesions or infections were reported. CONCLUSION: T-VEC was well tolerated and showed clinical utility.
RESUMO
Genetic variation in FGFR2 is a newly described risk factor for breast cancer. We estimated the relative risk and contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within Jewish and other Middle Eastern populations. We genotyped four FGFR2 single nucleotide polymorphisms (SNP) and tested for association of these SNPs and haplotypes with breast cancer risk in a population-based case-control study of 1,529 women with breast cancer and 1,528 controls. We found significant associations between breast cancer risk and all four studied SNPs in FGFR2 (P trend for all SNPs < 0.0001). In ethnicity-specific analysis, all four SNPs were significantly associated with breast cancer risk in Ashkenazi and Sephardi Jews, with a similar but not significant trend in Arabs. Haplotype analysis identified five common haplotypes (>1%). The previously described AAGT risk haplotype was significantly associated with breast cancer risk in Ashkenazi [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.07-1.45; P = 0.0059] and Sephardi Jews (OR, 1.46; 95% CI, 1.17-1.80; P = 0.0006) compared with the reference GGAC haplotype. The AAAC haplotype was significantly associated with breast cancer risk in Sephardi Jews (OR, 1.97; 95% CI, 1.16-3.35; P = 0.0125) but not in Ashkenazi Jews (OR, 0.83; 95% CI, 0.41-1.62; P = 0.5613) or in Arabs (OR, 1.31; 95% CI, 0.80-2.14; P = 0.2881). Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations. The identification of population-specific risk haplotypes in FGFR2 is likely to help identify causal variants for breast cancer.