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1.
Hum Mol Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600786

RESUMO

We previously identified five SNPs at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5,662 cases and 9,237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF]=0.40) was associated with DLBCL risk (OR=0.83, P=3.62x10-13). rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5,510 cases and 12,817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF=0.45) was also associated with DLBCL risk (OR=1.20, P=2.31x10-12). This SNP is 29,426 bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

2.
Am J Gastroenterol ; 114(9): 1478-1487, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31425154

RESUMO

OBJECTIVES: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 2 commonly ordered liver function tests, and ALT has long been considered more liver-specific than AST. Between the 2, the one which is better in predicting liver or non-liver-related mortality remains unsettled. METHODS: The cohort, 416,122 adults, came from a self-paying comprehensive health surveillance program during 1994-2008 and was followed up till 2008. Mortality came from National Death Index, with 10,412 deaths identified. Hazard ratios (HRs), computed by Cox model, and life expectancy, by life table method, were presented for 5 levels of AST and ALT with elevated AST or ALT defined as ≥40 IU/L. Liver disease included liver cancer and other liver conditions. RESULTS: There were 3 times more elevated ALT (15.4%) than AST (5.7%). However, those with elevated AST had higher mortality for all-cause (HR = 2.44), for liver disease (HR = 27.2), and for liver cancer (HR = 47.6) than its ALT counterparts (HR = 1.69, 10.8, and 20.2, respectively). Elevated AST also lost more years of life expectancy (10.2) than those lost by ALT (5.2) and larger than most common risks. Elevated AST had increased mortality from all cancers (HR = 3.57), stroke (HR = 1.36), respiratory diseases (HR = 1.34), and injuries (HR = 1.82), other than just liver disease. All-cause mortality remained significantly increased, when high risk groups were excluded, such as frequent drinkers, hepatitis carriers, those died from nonmedical conditions, those died in the first 3 years, or advanced fibrosis index based on 4 factors or aspartate transaminase-to-platelet ratio index. Results were consistent between those returned for second visits and those analyzed in initial visits. DISCUSSION: Those with elevated AST (≥40 IU/L) had life expectancy cut short by 10.2 years, doubled the number of years lost with elevated ALT. For all-cause and for liver-related mortality, AST was an important predictor, better than ALT.

3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1143-1148, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418370

RESUMO

OBJECTIVE: To investigate the clinical efficacy and Safety of R-CDOP regimen for treatment of newly diagnosed DLBCL patients with adverse prognostic factors. METHODS: The clinical data of 94 patients who suffered from DLBCL and received treatment with R-CDOP regimen, from October 2013 to February 2018 were collected and analyzed retrospectively. The clinical efficacy, survival benifits and safety, as well as the OS and PFS were compared according to clinical features. RESULTS: After treatment of 94 cases with R-CDOP regimen, 73 cases reachived CR, 14 cases reachived PR, 2 cases were in SD and 4 cases were in PD, the ORR was 92.55% (87/94). The OS rate and PFS rate in followed-up 1 year were 94.68%(89/94) and 85.11%(80/94) separately, However, the median OS and PFS were not reached. There was no significant difference in the followed-up cumulative OS rate and PFS rate between patients with different Age, Ann-Arbor stage, IPI score, number of extranodal tumors, tumor diameter, expression of Ki-67 and LDH level and tissue involvement status(P>0.05). There was no significant difference in the 1 years PFS rate and OS rate between patients with number of extranodal tumors for 0-1 and ≥2(P>0.05). There was no significant difference in the 1 years PFS rate and OS rate between patients with tumor diameter for <7.5 cm and ≥7.5 cm(P>0.05). CONCLUSION: The R-CDOP regimen in the treatment of newly diagnosed DLBCL patients with poor prognostic factors can efficiently improve the early clinical efficacy, prolong the survival time and possess good safety, but the clinical prognosis for long-term remains to be observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfoma Difuso de Grandes Células B , Ciclofosfamida , Intervalo Livre de Doença , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
4.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1228-1237, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263055

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

5.
Sci Rep ; 9(1): 9989, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292496

RESUMO

C-peptide, insulin, leptin, and other metabolic hormones are assumed to play roles in breast cancer development; though, results are inconsistent. In this prospective case-control study nested within the Mano a Mano Cohort Study, we assessed the risk of breast cancer with regard to plasma levels of c-peptide, gastric inhibitory polypeptide, insulin, leptin, monocyte chemoattractant protein-1, pancreatic polypeptide, and peptide YY. Among women followed for a median of 8.5 years, 109 breast cancer cases were identified and frequency-matched to 327 controls at a ratio of 1:3. Overall, only c-peptide was observed significantly associated with breast cancer risk. High c-peptide levels (≥ the median level of controls) were significantly associated with increased breast cancer risk (odds ratio [OR] = 1.39, 95% confidence interval [CI]: 1.01, 2.44). In an analysis of participants stratified by age, the significant association between c-peptide levels and breast cancer risk was evident in only women age ≥51 years (OR = 1.53, 95% CI: 1.02, 3.27). Among women age <51 years, high leptin levels were significantly associated with decreased breast cancer risk (OR = 0.49, 95% CI: 0.24, 0.82). Our findings suggest that selected metabolic hormones are associated with breast cancer development in Mexican American women.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31154579

RESUMO

In the original publication of the article, the sixth author name Krita A. Zanetti was mistakenly included as co-author. The corrected author group is given in the correction article. The original article has been corrected.

7.
J Thorac Oncol ; 14(9): 1594-1607, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163278

RESUMO

INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.

8.
Carcinogenesis ; 40(10): 1191-1197, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31001636

RESUMO

Obesity is one of modifiable risk factors for clear cell renal cell cancer (ccRCC). We aim to identify the association between obesity-driven biomarkers and ccRCC risk. This is a retrospective, two-phase, case-control study involving 682 cases and 733 controls. Obesity-driven biomarkers [gastric inhibitory polypeptide (GIP), C-peptide, insulin, resistin, adipsin, peptide YY, pancreatic polypeptide, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1, monocyte chemoattractant protein 1, lipocalin2, leptin, adiponectin] were measured using the Milliplex method. Multivariate logistic regression was used to assess the associations between biomarkers and ccRCC risk. Results revealed that GIP, C-peptide, IL-6 and TNF-α levels were consistently distinct between cases and controls. These markers were significantly associated with ccRCC risk in both phases (except C-peptide). In the combined population, compared with individuals with low levels of the biomarkers, individuals with high level of GIP [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.40-0.67] had lower risk, whereas individuals with high levels of C-peptide (OR = 1.46, 95% CI: 1.15-1.87), IL-6 (OR = 2.20, 95% CI: 1.50-3.22), TNF-α (OR = 1.90, 95% CI: 1.49-2.43) had significantly higher risk. Stratified analysis showed consistent associations with ccRCC risk in most subgroups (P < 0.05). The risk score based on the IL-6, TNF-α and GIP was positively associated with ccRCC risk in a dose-response manner (P for trend = 2.18E-13). Data from The Cancer Genome Atlas indicate that insulin signaling, IL-6 signaling and TNF-α signaling were enhanced in tumors. Collectively, our study demonstrates the integrative effect of insulin resistance and inflammation in ccRCC development, which may elucidate the basis of association between obesity and carcinogenesis. Further confirmation in prospective cohort studies are warranted for clinical applications in prevention and precision medicine of ccRCC.

9.
J Thorac Oncol ; 14(8): 1360-1369, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

10.
Cancer Epidemiol Biomarkers Prev ; 28(4): 715-723, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30894353

RESUMO

BACKGROUND: Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans. METHODS: We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status. RESULTS: We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72-0.90). CONCLUSIONS: We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans. IMPACT: Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

11.
Breast Cancer Res Treat ; 176(3): 687-696, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30771047

RESUMO

PURPOSE: The metabolic etiology of breast cancer has been explored in the past several years using metabolomics. However, most of these studies only included non-Hispanic White individuals. METHODS: To fill this gap, we performed a two-step (discovery and validation) metabolomics profiling in plasma samples from 358 breast cancer patients and 138 healthy controls. All study subjects were either Hispanics or non-Hispanic African Americans. RESULTS: A panel of 14 identified metabolites significantly differed between breast cancer cases and healthy controls in both the discovery and validation sets. Most of these identified metabolites were lipids. In the pathway analysis, citrate cycle (TCA cycle), arginine and proline metabolism, and linoleic acid metabolism pathways were observed, and they significantly differed between breast cancer cases and healthy controls in both sets. From those 14 metabolites, we selected 9 non-correlated metabolites to generate a metabolic risk score. Increased metabolites risk score was associated with a 1.87- and 1.63-fold increased risk of breast cancer in the discovery and validation sets, respectively (Odds ratio (OR) 1.87, 95% Confidence interval (CI) 1.50, 2.32; OR 1.63, 95% CI 1.36, 1.95). CONCLUSIONS: In summary, our study identified metabolic profiles and pathways that significantly differed between breast cancer cases and healthy controls in Hispanic or non-Hispanic African American women. The results from our study might provide new insights on the metabolic etiology of breast cancer.

12.
Cancer Epidemiol Biomarkers Prev ; 28(5): 935-942, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30700444

RESUMO

BACKGROUND: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. METHODS: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. RESULTS: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. CONCLUSIONS: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. IMPACT: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

13.
Sleep Health ; 5(1): 78-83, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30670171

RESUMO

BACKGROUND: To date, no study has investigated the association of sleep duration with cancer risk in Mexican Americans. ANALYSIS: Using data from the Mano-A-Mano Mexican American Cohort study, we analyzed the relationship between sleep duration and overall cancer risk among Mexican Americans. RESULTS: Of 10,802 subjects included in this study, 429 developed cancer during follow-up. Compared with study participants sleeping 8-9 hours per night, those sleeping less than 6 hours per night had significantly increased risk of overall cancer in both univariate and multivariate Cox regression analyses. After adjusting for social-demographic and lifestyle variables, sleeping less than 6 hours per night was associated with a 1.37-fold increased risk of overall cancer (hazard ratio = 1.37, 95% confidence interval: 1.01-1.97). In breast cancer alone, sleeping less than 6 hours per night was associated with a 1.86-fold increased risk of breast cancer (hazard ratio = 1.86, 95% confidence interval: 1.01-3.45) after adjustment for birthplace and language acculturation. In further stratified analysis, significant associations between sleeping less than 6 hours per night and overall cancer risk were evident among overweight participants, former drinkers, those with medium or high levels of physical activity, those married or living together, and those who had less than 2 hours of sitting time per day. In addition, increased cancer risk associated with long sleep duration (at least 9 hours per night) was observed among overweight participants and those with medium or high levels of physical activity. CONCLUSION: Our results provide evidence to link sleep duration with cancer risk among Mexican Americans.


Assuntos
Americanos Mexicanos/estatística & dados numéricos , Neoplasias/etnologia , Sono , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Adulto Jovem
14.
Carcinogenesis ; 40(3): 432-440, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-30590402

RESUMO

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

16.
Carcinogenesis ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30428030

RESUMO

Circulating microRNAs (miRNAs) are potential biomarkers for cancer diagnosis, screening, and prognosis. This study aimed to identify serum miRNAs as predictors of survival in patients with advanced non-small cell lung cancer (NSCLC). We profiled serum miRNAs in a pilot set of 4 patients with good survival (>24 months) and 4 patients with poor survival (<6 months). We selected 140 stably detectable miRNAs and 42 miRNAs reported in literature for further analysis. Expression of these 182 miRNAs was measured using high-throughput polymerase chain reaction assay, and their association with 3-year survival in the discovery (n=345) and validation (n=177) cohorts was assessed. Five serum miRNAs (miR-191, miR-28-3p, miR-145, miR-328, and miR-18a) were significantly associated with 3-year overall survival in both cohorts. A combined 5-miRNA risk score was created to assess the cumulative impact of these miRNAs on risk of death. Quartile analysis of the risk score showed significant association with 3-year death risk, with a 4.6-month, 6.8-month, and 9.3-month reduction in median survival time for the second, third, and fourth quartile, respectively. Survival tree analysis also identified distinct risk groups with different 3-year survival durations. Data from The Cancer Genome Atlas revealed all 5 miRNAs were differentially expressed (P<0.0001) in paired tumor and normal tissues. Pathway analysis indicated that target genes of these 5 miRNAs were mainly enriched in inflammatory/immune response pathways and pathways implicated in resistance to chemoradiotherapy and/or targeted therapy. Our results suggested that the 5-miRNA signature could serve as a prognostic predictor in advanced NSCLC patients.

17.
Cell Death Differ ; 25(11): 1885-1904, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30323273

RESUMO

The relative contribution of intrinsic genetic factors and extrinsic environmental ones to cancer aetiology and natural history is a lengthy and debated issue. Gene-environment interactions (G x E) arise when the combined presence of both a germline genetic variant and a known environmental factor modulates the risk of disease more than either one alone. A panel of experts discussed our current understanding of cancer aetiology, known examples of G × E interactions in cancer, and the expanded concept of G × E interactions to include somatic cancer mutations and iatrogenic environmental factors such as anti-cancer treatment. Specific genetic polymorphisms and genetic mutations increase susceptibility to certain carcinogens and may be targeted in the near future for prevention and treatment of cancer patients with novel molecularly based therapies. There was general consensus that a better understanding of the complexity and numerosity of G × E interactions, supported by adequate technological, epidemiological, modelling and statistical resources, will further promote our understanding of cancer and lead to novel preventive and therapeutic approaches.

18.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

19.
Am J Pathol ; 188(11): 2487-2496, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30201497

RESUMO

About 30% of patients undergoing nephrectomy for renal cell carcinoma (RCC) experience disease recurrence. We profiled miRNAs dysregulated in clear-cell (cc) RCC tumor tissues and predictive of recurrence. The expression levels of 800 miRNAs were assessed in paired tumor and normal tissues from a discovery cohort of 18 ccRCC patients. miRNAs found to be differentially expressed were examined in a validation set of 205 patients, using real-time quantitative PCR. Tumor-normal data from 64 patients in The Cancer Genome Atlas were used for external validation. Twenty-eight miRNAs were consistently dysregulated in tumor tissues. On dichotomized analysis, patients with high levels of miR-155-5p and miR-210-3p displayed an increased risk for ccRCC recurrence (hazard ratio, 2.64; 95% CI, 1.49 to 4.70; P = 0.0009; and hazard ratio, 1.80; 95% CI, 1.04 to 3.12; P = 0.036, respectively) and a shorter median recurrence-free survival time than did patients with low levels [P < 0.01 (log rank test)]. A risk score was generated based on the expression levels of miR-155-5p and miR-210-3p, and the trend test was significant (P = 0.005). On pathway analysis, target genes regulated by miR-155-5p and miR-210-3p were mainly enriched in inflammation-related pathways. We identified and validated multiple miRNAs dysregulated in ccRCC tissues; miR-155-5p and miR-210-3p were predictive of ccRCC recurrence, pointing to potential utility as biomarkers and underlying biological mechanisms.

20.
Sci Rep ; 8(1): 14006, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228315

RESUMO

MicroRNAs (miRNAs) may contribute to the initiation and progression of cancer. The role of circulating miRNAs as predictors of recurrence in esophageal adenocarcinoma (EAC) has not been extensively explored. Here we measured the expressions of 167 miRNAs in serum samples from a discovery cohort of 72 EAC patients (32 patients with recurrence and 40 patients without). A rank sum test was performed to identify differentially expressed miRNAs. Cox regression model was applied to estimate the effect of miRNA expression on recurrence-free survival. The eligible miRNAs were then validated in an independent cohort of 329 EAC patients (132 patients with recurrence and 197 patients without). miR-331-3p was identified and confirmed to be differentially expressed between EAC patients with and without recurrence and associated with recurrence-free survival. In both cohorts, the expression of miR-331-3p was consistently decreased in patients with recurrence compared to those without (P < 0.05). Using patients with low expression of miR-331-3p as reference, those with high expression had HRs for recurrence of 0.45 (95% CI, 0.21-0.96, P = 0.040) and 0.55 (95% CI, 0.38-0.78, P = 0.001) in the discovery and validation cohorts, respectively. Therefore, serum miR-331-3p may be a useful biomarker for identifying EAC patients at high risk of recurrence.

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