RESUMO
Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-ß and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction.
Assuntos
Retículo Endoplasmático , MAP Quinase Quinase Quinases , Microtúbulos , Transdução de Sinais , Microtúbulos/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/genética , Acetilação , Animais , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Acetiltransferases/metabolismo , Acetiltransferases/genética , Estresse do Retículo Endoplasmático , Camundongos , Proteínas dos MicrotúbulosRESUMO
BACKGROUND: The United States is becoming increasingly diverse, but few molecular studies have assessed the progression of clear cell renal cell carcinoma (ccRCC) in diverse patient populations. This study examined ccRCC molecular variations in non-Hispanic White (NHW) and Hispanic patients and their effect on the association of gene expression with high-grade (Grade 3 or 4) ccRCC and overall mortality. METHODS: A total of 156 patients were included in VHL sequencing and/or TempO-Seq analysis. DESeq2 was used to identify the genes associated with high-grade ccRCC. Logistic regression analysis was performed to assess whether race and ethnicity was associated with high/moderate impact VHL somatic mutations and the ccA/ccB subtype. Cox regression analysis was performed to assess association of molecular subtype and gene expression with overall mortality. RESULTS: NHWs had moderate or high impact mutations in the VHL gene at a higher frequency than Hispanics (40.2% vs. 27.4%), while Hispanics had a higher frequency of the ccA subtype than NHWs (61.9% vs. 45.8%). ccA was more common in patients with BMI≥35 (65.2%) than in those with BMI < 25 (45.0%). There were 11 differentially expressed genes between high- and low-grade tumors. The Haptoglobin (HP) gene was most significantly overexpressed in high- compared to low-grade ccRCC in all samples (p-adj = 1.7 × 10-12 ). When stratified by subtype, the 11 genes were significantly differentially expressed in the ccB subtype, but none of them were significant after adjusting for multiple testing in ccA. Finally, patients with the ccB subtype had a significantly increased risk of overall mortality (HR 4.87; p = 0.01) compared to patients with ccA, and patients with high HP expression and ccB, had a significantly increased risk of mortality compared to those with low HP expression and ccA (HR 6.45, p = 0.04). CONCLUSION: This study reports ccRCC molecular variations in Hispanic patients who were previously underrepresented.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Brancos , Hispânico ou Latino/genética , EtnicidadeRESUMO
Defective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report ßIV-spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific ßIV-spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina. During sprouting, ßIV-spectrin expresses in stalk cells to inhibit their tip cell potential by enhancing VEGFR2 turnover in a manner independent of most cell-fate determining mechanisms. Rather, ßIV-spectrin recruits CaMKII to the plasma membrane to directly phosphorylate VEGFR2 at Ser984, a previously undefined phosphoregulatory site that strongly induces VEGFR2 internalization and degradation. These findings support a distinct spectrin-based mechanism of tip-stalk cell specification during vascular development.
Assuntos
Espectrina , Fator A de Crescimento do Endotélio Vascular , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Camundongos , Neovascularização Fisiológica , Proteômica , Transdução de Sinais , Espectrina/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Instabilidade de Microssatélites , Neoplasias Encefálicas , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Mutação , Síndromes Neoplásicas HereditáriasRESUMO
Oxylipins derived from arachidonic acid (ARA) have been implicated in the development of colorectal adenomas and colorectal cancer. The primary purpose of this work was to determine the relationship between plasma levels of oxylipins and colorectal adenoma characteristics at study entry, as well as with the development of a new adenoma during follow-up within a Phase III adenoma prevention clinical trial with selenium (Sel). Secondarily, we sought to determine whether the selenium intervention influenced plasma oxylipin levels. Four oxylipins were quantified in stored plasma samples from a subset of Sel study subjects (n = 256) at baseline and at 12-months. There were significantly lower odds of an advanced adenoma at baseline with higher prostaglandin E2 (PGE2), with an OR (95% CI) of 0.55 (0.33-0.92), and with 5-hydroxyeicosatetraenoic acid (5-HETE) ((0.53 (0.33-0.94)); and of a large adenoma with higher PGE2 ((0.52 (0.31-0.87)). In contrast, no associations were observed between any oxylipin and the development of a new adenoma during follow-up. Selenium supplementation was associated with a significantly smaller increase in 5-HETE after 12 months compared to the placebo, though no other results were statistically significant. The ARA-derived oxylipins may have a role in the progression of non-advanced adenoma to advanced, but not with the development of a new adenoma.
Assuntos
Adenoma/prevenção & controle , Ácido Araquidônico/sangue , Neoplasias Colorretais/prevenção & controle , Oxilipinas/sangue , Selênio/administração & dosagem , Adenoma/sangue , Idoso , Celecoxib/administração & dosagem , Neoplasias Colorretais/sangue , Suplementos Nutricionais , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Selenium (Se) is a trace element that has been linked to many health conditions. Genome-wide association studies (GWAS) have identified variants for blood and toenail Se levels, but no GWAS has been conducted to date on responses to Se supplementation. OBJECTIVES: A GWAS was performed to identify the single nucleotide polymorphisms (SNPs) associated with changes in Se concentrations after 1 year of supplementation. A GWAS of basal plasma Se concentrations at study entry was conducted to evaluate whether SNPs for Se responses overlap with SNPs for basal Se levels. METHODS: A total of 428 participants aged 40-80 years of European descent from the Selenium and Celecoxib Trial (Sel/Cel Trial) who received daily supplementation with 200 µg of selenized yeast were included for the GWAS of responses to supplementation. Plasma Se concentrations were measured from blood samples collected at the time of recruitment and after 1 year of supplementation. Linear regression analyses were performed to assess the relationship between each SNP and changes in Se concentrations. We further examined whether the identified SNPs overlapped with those related to basal Se concentrations. RESULTS: No SNP was significantly associated with changes in Se concentration at a genome-wide significance level. However, rs56856693, located upstream of the NEK6, was nominally associated with changes in Se concentrations after supplementation (P = 4.41 × 10-7), as were 2 additional SNPs, rs11960388 and rs6887869, located in the dimethylglycine dehydrogenase (DMGDH)/betaine-homocysteine S-methyltransferase (BHMT) region (P = 0.01). Alleles of 2 SNPs in the DMGDH/BHMT region associated with greater increases in Se concentrations after supplementation were also strongly associated with higher basal Se concentrations (P = 8.67 × 10-8). CONCLUSIONS: This first GWAS of responses to Se supplementation in participants of European descent from the Sel/Cel Trial suggests that SNPs in the NEK6 and DMGDH/BHMT regions influence responses to supplementation.
Assuntos
Suplementos Nutricionais , Estudo de Associação Genômica Ampla , Genótipo , Selênio/sangue , Selênio/farmacologia , População Branca , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Selênio/administração & dosagemRESUMO
Despite improvements over the past 20 years, African Americans continue to have the highest incidence and mortality rates of colorectal cancer (CRC) in the United States. While previous studies have found that copy number variations (CNVs) occur at similar frequency in African American and White CRCs, copy-neutral loss of heterozygosity (cnLOH) has not been investigated. In the present study, we used publicly available data from The Cancer Genome Atlas (TCGA) as well as data from an African American CRC cohort, the Chicago Colorectal Cancer Consortium (CCCC), to compare frequencies of CNVs and cnLOH events in CRCs in the two racial groups. Using genotype microarray data, we analyzed large-scale CNV and cnLOH events from 166 microsatellite stable CRCs-31 and 39 African American CRCs from TCGA and the CCCC, respectively, and 96 White CRCs from TCGA. As reported previously, the frequencies of CNVs were similar between African American and White CRCs; however, there was a significantly lower frequency of cnLOH events in African American CRCs compared to White CRCs, even after adjusting for demographic and clinical covariates. Although larger differences for chromosome 18 were observed, a lower frequency of cnLOH events in African American CRCs was observed for nearly all chromosomes. These results suggest that mechanistic differences, including differences in the frequency of cnLOH, could contribute to clinicopathological disparities between African Americans and Whites. Additionally, we observed a previously uncharacterized phenomenon we refer to as small interstitial cnLOH, in which segments of chromosomes from 1 to 5 Mb long were affected by cnLOH.
Assuntos
Negro ou Afro-Americano/genética , Neoplasias Colorretais/genética , Perda de Heterozigosidade , Idoso , Cromossomos Humanos Par 18/genética , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.
Assuntos
Distúrbios no Reparo do DNA/diagnóstico , Distúrbios no Reparo do DNA/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatologia , Síndrome de Bloom/diagnóstico , Síndrome de Bloom/genética , Síndrome de Bloom/fisiopatologia , Dano ao DNA/genética , Distúrbios no Reparo do DNA/fisiopatologia , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Anemia de Fanconi/fisiopatologia , Humanos , Síndrome de Quebra de Nijmegen/diagnóstico , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/fisiopatologiaRESUMO
Many colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MSI and absence of MLH1 methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified five cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Mutação em Linhagem Germinativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Heterozigoto , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Análise de Sequência de DNARESUMO
Firefighters are exposed to carcinogens and have elevated cancer rates. We hypothesized that occupational exposures in firefighters would lead to DNA methylation changes associated with activation of cancer pathways and increased cancer risk. To address this hypothesis, we collected peripheral blood samples from 45 incumbent and 41 new recruit non-smoking male firefighters and analyzed the samples for DNA methylation using an Illumina Methylation EPIC 850k chip. Adjusting for age and ethnicity, we performed: 1) genome-wide differential methylation analysis; 2) genome-wide prediction for firefighter status (incumbent or new recruit) and years of service; and 3) Ingenuity Pathway Analysis (IPA). Four CpGs, including three in the YIPF6, MPST, and PCED1B genes, demonstrated above 1.5-fold statistically significant differential methylation after Bonferroni correction. Genome-wide methylation predicted with high accuracy incumbent and new recruit status as well as years of service among incumbent firefighters. Using IPA, the top pathways with more than 5 gene members annotated from differentially methylated probes included Sirtuin signaling pathway, p53 signaling, and 5' AMP-activated protein kinase (AMPK) signaling. These DNA methylation findings suggest potential cellular mechanisms associated with increased cancer risk in firefighters.
Assuntos
Metilação de DNA , Bombeiros , Adulto , Ilhas de CpG , Redes Reguladoras de Genes/genética , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , não Fumantes , Exposição Ocupacional , Transdução de Sinais/genéticaRESUMO
Objective: While controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic ß-cell function and insulin sensitivity. Research design and methods: In a subset of 400 individuals participating in a randomized, placebo-controlled trial of Se at 200 µg/day for colorectal adenomatous polyps, fasting plasma glucose and insulin were measured before randomization and within 6 months of completing intervention. Change in the homeostasis model assessment-ß cell function (HOMA2-%ß) and insulin sensitivity (HOMA2-%S) were compared between arms. A subgroup of 175 (79 Se and 96 placebo) participants underwent a modified oral glucose tolerance test (mOGTT) at the end of intervention and change in glucose values was assessed. Results: No statistically significant differences were observed for changes in HOMA2-%ß or HOMA2-%S between those who received Se compared with placebo. After a mean of 2.9 years on study, mean HOMA2-%ß values were 3.1±24.0 and 3.1±29.8 for the Se and placebo groups, respectively (p=0.99). For HOMA2-%S, the values were -0.5±223.2 and 80.9±1530.9 for the Se and placebo groups, respectively (p=1.00). Stratification by sex or age did not reveal any statistically significant effects on insulin sensitivity by treatment group. For mOGTT, mean baseline fasting blood glucose concentrations were significantly higher among participants in the placebo group compared with the Se group (96.6±14.6 and 92.3±12.0, respectively; p=0.04), a trend which remained through the 20 min assessment. Conclusions: These findings do not support a significant adverse effect of daily Se supplementation with 200 µg/day of selenized yeast on ß-cell function or insulin sensitivity as an explanation for previously reported associations between Se and T2D. Further clarification of longer term effects of Se is needed. Clinical trial registry: NIH Clinical Trials.gov number NCT00078897.
Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , Selênio/efeitos adversos , Adenoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/tratamento farmacológico , Suplementos Nutricionais/efeitos adversos , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Pólipos/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Selênio/farmacologiaRESUMO
African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Negro ou Afro-Americano/genética , Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Metilação de DNA/genética , Repetições de Microssatélites/genética , Caderinas/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Fator de Transcrição GATA6/genética , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Oxigenases de Função Mista/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição SOX9/genética , Fatores de Transcrição/genética , Sequenciamento do Exoma , Via de Sinalização Wnt/genéticaRESUMO
INTRODUCTION: Pseudogenes are paralogues of functional genes historically viewed as defunct due to either the lack of regulatory elements or the presence of frameshift mutations. Recent evidence, however, suggests that pseudogenes may regulate gene expression, although the functional role of pseudogenes remains largely unknown. We previously reported that MYLKP1, the pseudogene of MYLK that encodes myosin light chain kinase (MLCK), is highly expressed in lung and colon cancer cell lines and tissues but not in normal lung or colon. The MYLKP1 promoter is minimally active in normal bronchial epithelial cells but highly active in lung adenocarcinoma cells. In this study, we further validate MYLKP1 as an oncogene via elucidation of the functional role of MYLKP1 genetic variants in colon cancer risk. METHODS: Proliferation and migration assays were performed in MYLKP1-transfected colon and lung cancer cell lines (H441, A549) and commercially-available normal lung and colon cells. Fourteen MYLKP1 SNPs (MAFs >0.01) residing within the 4 kb MYLKP1 promoter region, the core 1.4 kb of MYLKP1 gene, and a 4 kb enhancer region were selected and genotyped in a colorectal cancer cohort. MYLKP1 SNP influences on activity of MYLKP1 promoter (2kb) was assessed by dual luciferase reporter assay. RESULTS: Cancer cell lines, H441 and A549, exhibited increased MYLKP1 expression, increased MYLKP1 luciferase promoter activity, increased proliferation and migration. Genotyping studies identified two MYLKP1 SNPs (rs12490683; rs12497343) that significantly increase risk of colon cancer in African Americans compared to African American controls. Rs12490683 and rs12497343 further increase MYLKP1 promoter activity compared to the wild type MYLKP1 promoter. CONCLUSION: MYLKP1 is a cancer-promoting pseudogene whose genetic variants differentially enhance cancer risk in African American populations.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Neoplasias do Colo/genética , Quinase de Cadeia Leve de Miosina/genética , Pseudogenes , Negro ou Afro-Americano/genética , Proteínas de Ligação ao Cálcio/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Expressão Gênica , Humanos , Quinase de Cadeia Leve de Miosina/metabolismo , Oncogenes , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fatores de Risco , População Branca/genéticaRESUMO
BACKGROUND: Screening in the average risk population for colorectal cancer (CRC) is expected to reduce the incidence of distant (i.e., metastatic) CRCs at least as much as less advanced CRCs. Indeed, since 2000, during which time colonoscopy became widely used as a screening tool, the overall incidence of CRC has been reduced by 29%. OBJECTIVE: The purpose of the current study was to determine whether the reduction of incidence rates is the same for all stages of disease. METHODS: We evaluated incidence data from the Surveillance, Epidemiology, and End Results (SEER) program from 2000-2014 for Localized, Regional, and Distant disease. Joinpoint models were compared to assess parallelism of trends. Data were stratified by race, age, tumor location, and sex to determine whether these subgroupings could explain overall trends. RESULTS: Inconsistent with the expectations of a successful screening program, the reduction in incidence rates of distant CRCs from 2000-2014 has been slower than the reductions in incidence rates of both regional and localized CRCs. This trend is evident even when the data are stratified by age at diagnosis, sex, race, or tumor location. CONCLUSIONS: The slower decrease in the incidence rate of distant disease is not consistent with a screening effect, that is, CRC screening may not be effective in preventing many distant CRCs. As a consequence, distant CRCs represent an increasing fraction of all CRCs, accounting for 21% of all CRCs in 2014. The analysis indicates that inadequate screening does not explain the slower decrease in incidence of distant CRCs. Consequently, we suggest that a subtype of CRC exists that advances rapidly, evading detection because screening intervals are too long to prevent it. Microsatellite unstable tumors represent a known subtype that advances more rapidly, and we suggest that another rapidly advancing subtype very likely exists that is microsatellite stable.
Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/prevenção & controle , Detecção Precoce de Câncer , Idoso , Colonoscopia , Neoplasias Colorretais/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Programa de SEER , Estados UnidosRESUMO
Bloom Syndrome (BSyn) is an autosomal recessive disorder that causes growth deficiency, endocrine abnormalities, photosensitive skin rash, immune abnormalities, and predisposition to early-onset cancer. The available treatments for BSyn are symptomatic, and early identification of complications has the potential to improve outcomes. To accomplish this, standardized recommendations for health supervision are needed for early diagnosis and treatment. The purpose of this report is to use information from the BSyn Registry, published literature, and expertise from clinicians and researchers with experience in BSyn to develop recommendations for diagnosis, screening, and treatment of the clinical manifestations in people with BSyn. These health supervision recommendations can be incorporated into the routine clinical care of people with BSyn and can be revised as more knowledge is gained regarding their clinical utility.
Assuntos
Síndrome de Bloom/epidemiologia , Atenção à Saúde , Síndrome de Bloom/complicações , Síndrome de Bloom/diagnóstico , Síndrome de Bloom/terapia , Criança , Desenvolvimento Infantil , Pré-Escolar , Atenção à Saúde/história , Atenção à Saúde/organização & administração , Gerenciamento Clínico , Feminino , Diretrizes para o Planejamento em Saúde , História do Século XX , História do Século XXI , Humanos , Incidência , Inteligência , Masculino , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/etiologia , Neoplasias/terapia , Estado Nutricional , Fenótipo , Vigilância em Saúde Pública , Sistema de RegistrosRESUMO
Cancer disparities in Native Americans (NAs) and Hispanic Americans (HAs) vary significantly in terms of cancer incidence and mortality rates across geographic regions. This review reports that kidney and renal pelvis cancers are unevenly affecting HAs and NAs compared to European Americans of non-Hispanic origin, and that currently there is significant need for improved data and reporting to be able to advance toward genomic-based precision medicine for the assessment of such cancers in these medically underserved populations. More specifically, in states along the US-Mexico border, HAs and NAs have higher kidney cancer incidence rates as well as a higher prevalence of kidney cancer risk factors, including obesity and chronic kidney disease. They are also more likely to receive suboptimal care compared to European Americans. Furthermore, they are underrepresented in epidemiologic, clinical, and molecular genomic studies of kidney cancer. Therefore, we maintain that progress in precision medicine for kidney cancer care requires an understanding of various factors among HAs and NAs, including the real kidney cancer burden, variations in clinical care, issues related to access to care, and specific clinical and molecular characteristics.
Assuntos
Neoplasias Renais/etnologia , Pelve Renal/patologia , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Incidência , Indígenas Norte-Americanos/estatística & dados numéricos , Neoplasias Renais/patologia , Masculino , Medicina de Precisão , Prevalência , Estados Unidos/epidemiologiaRESUMO
Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer, yet molecular biomarkers have not been used for the prognosis of ccRCC to aide clinical decision making. This study aimed to identify genes associated with ccRCC aggressiveness and overall survival (OS). Samples of ccRCC tumor tissue were obtained from 33 patients who underwent nephrectomy. Gene expression was determined using whole-transcriptome sequencing. The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) RNA-seq data was used to test association with OS. 290 genes were differentially expressed between tumors with high and low stage, size, grade, and necrosis (SSIGN) score (≥7 vs. ≤3) with P ADJ<0.05. Four genes, G6PD, APLP1, GCNT3, and PLPP2, were also over-expressed in advanced stage (III and IV) and high grade (3 and 4) ccRCC and tumor with necrosis (P ADJ<0.05). Investigation stratifying by stage found that APLP1 and PLPP2 overexpression were significantly associated with poorer OS in the early stage (Quartile 1 vs. Quartile 4, HR = 3.87, 95% CI:1.25-11.97, P = 0.02 and HR = 4.77, 95% CI:1.37-16.57, P = 0.04 respectively). These genes are potential biomarkers of ccRCC aggressiveness and prognosis that direct clinical and surgical management.
RESUMO
African Americans have the highest incidence and mortality rates of colorectal cancer (CRC) of any ethnic group in the United States. Although some of these disparities can be explained by differences in access to care, cancer screening, and other socioeconomic factors, disparities remain after adjustment for these factors. Consequently, an examination of recent advances in the understanding of ethnicity-specific factors, including genetic and environmental factors relating to risk of CRC, the biology of CRC progression, and the changes in screening and mortality, is important for evaluating our progress toward eliminating the disparities. An overarching limitation in this field is the number and sample size of studies performed to characterize the etiological bases of CRC incidence and mortality in African Americans. Despite this limitation, significant differences in etiology are manifest in many studies. These differences need validation, and their impacts on disparities need more detailed investigation. Perhaps most heartening, improvements in CRC screening can be attributed to the smallest difference in CRC incidence between African Americans and whites since the late 1980s. Cancer mortality, however, remains a persistent difference.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias Colorretais/etnologia , Disparidades nos Níveis de Saúde , Transformação Celular Neoplásica , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Humanos , Incidência , Mutação , Fatores de Risco , Estados Unidos/epidemiologia , Vitamina D/sangueRESUMO
Bloom's syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, and a greatly increased risk of early onset of cancer and for the development of multiple cancers. Loss-of-function mutations of BLM, which codes for a RecQ helicase, cause Bloom's syndrome. The absence of a functional BLM protein causes chromosome instability, excessive homologous recombination, and a greatly increased number of sister chromatid exchanges that are pathognomonic of the syndrome. A common founder mutation designated blmAsh is present in about 1 in 100 persons of Eastern European Jewish ancestry, and there are additional recurrent founder mutations among other populations. Missense, nonsense, and frameshift mutations as well as multiexonic deletions have all been observed. Bloom's syndrome is a prototypical chromosomal instability syndrome, and the somatic mutations that occur as a result of that instability are responsible for the increased cancer risk. Although there is currently no treatment aimed at the underlying genetic abnormality, persons with Bloom's syndrome benefit from sun protection, aggressive treatment of infections, surveillance for insulin resistance, and early identification of cancer.
RESUMO
OBJECTIVE: Colorectal cancer (CRC) incidence is higher in African Americans (AAs) compared with non-Hispanic whites (NHWs). A diet high in animal protein and fat is an environmental risk factor for CRC development. The intestinal microbiota is postulated to modulate the effects of diet in promoting or preventing CRC. Hydrogen sulfide, produced by autochthonous sulfidogenic bacteria, triggers proinflammatory pathways and hyperproliferation, and is genotoxic. We hypothesised that sulfidogenic bacterial abundance in colonic mucosa may be an environmental CRC risk factor that distinguishes AA and NHW. DESIGN: Colonic biopsies from uninvolved or healthy mucosa from CRC cases and tumour-free controls were collected prospectively from five medical centres in Chicago for association studies. Sulfidogenic bacterial abundance in uninvolved colonic mucosa of AA and NHW CRC cases was compared with normal mucosa of AA and NHW controls. In addition, 16S rDNA sequencing was performed in AA cases and controls. Correlations were examined among bacterial targets, race, disease status and dietary intake. RESULTS: AAs harboured a greater abundance of sulfidogenic bacteria compared with NHWs regardless of disease status. Bilophila wadsworthia-specific dsrA was more abundant in AA cases than controls. Linear discriminant analysis of 16S rRNA gene sequences revealed five sulfidogenic genera that were more abundant in AA cases. Fat and protein intake and daily servings of meat were significantly higher in AAs compared with NHWs, and multiple dietary components correlated with a higher abundance of sulfidogenic bacteria. CONCLUSIONS: These results implicate sulfidogenic bacteria as a potential environmental risk factor contributing to CRC development in AAs.