Detection of lung cancer at an early stage by sensitive screening tests could be an important strategy to improving prognosis. Our objective was to identify a panel of circulating microRNAs in plasma ...that will contribute to early detection of lung cancer.
Plasma samples from 100 early stage (I to IIIA) non-small-cell lung cancer (NSCLC) patients and 100 non-cancer controls were screened for 754 circulating microRNAs via qRT-PCR, using TaqMan MicroRNA Arrays. Logistic regression with a lasso penalty was used to select a panel of microRNAs that discriminate between cases and controls. Internal validation of model discrimination was conducted by calculating the bootstrap optimism-corrected AUC for the selected model.
We identified a panel of 24 microRNAs with optimum classification performance. The combination of these 24 microRNAs alone could discriminate lung cancer cases from non-cancer controls with an AUC of 0.92 (95% CI: 0.87-0.95). This classification improved to an AUC of 0.94 (95% CI: 0.90-0.97) following addition of sex, age and smoking status to the model. Internal validation of the model suggests that the discriminatory power of the panel will be high when applied to independent samples with a corrected AUC of 0.78 for the 24-miRNA panel alone.
Our 24-microRNA predictor improves lung cancer prediction beyond that of known risk factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau ( VHL ) gene in the cancer genome, unique to clear cell renal cancer ...(ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics.
Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination
of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter.
Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs
exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed
that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and
self-reported family history of RCC.
Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically
confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic,
prognostic, and translational studies.
Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung ...cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.
•CtDNA may play a crucial role in the detection of pre-clinical cancer.•TP53 mutations are detectable in the cfDNA of SCLC patients with early-stage tumors.•Detection of TP53 mutations in non-cancer controls poses serious challenges for the development of ctDNA screening tests.
Cell-free DNA (cfDNA) has potential for monitoring response to treatment and relapse, but also for early detection. This is the first study reporting the detection of circulating-tumor DNA (ctDNA) in cases diagnosed with small-cell lung cancer (SCLC). Our results show that TP53 mutations are detectable in the cfDNA of SCLC patients including those with early-stage tumors. Importantly, we also provide evidence that cancer-like TP53 mutations are present in non-cancer controls, which poses serious challenges for the development of ctDNA screening tests.
To examine the diversity of somatic alterations and clonal evolution according to aggressiveness of disease, nineteen tumor-blood pairs of 'formerly bronchiolo-alveolar carcinoma (BAC)' which had ...been reclassified into preinvasive lesion (adenocarcinoma in situ; AIS), focal invasive lesion (minimally invasive adenocarcinoma; MIA), and invasive lesion (lepidic predominant adenocarcinoma; LPA and non-lepidic predominant adenocarcinoma; non-LPA) according to IASLC/ATS/ERS 2011 classification were explored by whole exome sequencing. Several distinct somatic alterations were observed compare to the lung adenocarcinoma study from the Cancer Genome Atlas (TCGA). There were higher numbers of tumors with significant APOBEC mutation fold enrichment (73% vs. 58% TCGA). The frequency of KRAS mutations was lower in our study (5% vs. 32% TCGA), while a higher number of mutations of RNA-splicing genes, RBM10 and U2AF1, were found (37% vs. 11% TCGA). We found neither mutational pattern nor somatic copy number alterations that were specific to AIS/MIA. We demonstrated that clonal cell fraction was the only distinctive feature that discriminated LPA/non-LPA from AIS/MIA. The broad range of clonal frequency signified a more branched clonal evolution at the time of diagnosis. Assessment of tumor clonal cell fraction might provide critical information for individualized therapy as a prognostic factor, however this needs further study.
Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ...ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively.
TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) ...and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P(linear trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1 and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.
Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association ...study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10-10). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10-20 overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among ...patients with suspicious renal masses.
Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes.
In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 95% CI, 0.76 to 0.86). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 95% CI, 0.67 to 0.80) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 95% CI, 0.57 to 0.74
0.78 95% CI, 0.72 to 0.85). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio HR 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC.
Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.
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Background: For patients with suspicious renal masses, it is often unclear which should receive an intervention versus initial surveillance. Both clear cell and papillary renal cell carcinoma ...overexpress kidney injury molecule-1 (KIM-1) due to their proximal epithelial cell of origin. We investigated whether plasma KIM-1 improves risk stratification of patients with suspicious kidney masses. Methods: Pre-nephrectomy plasma KIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have ccRCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository. Multivariable models were used to assess the relationship between pre-nephrectomy plasma KIM-1, surgical pathology, and subsequent clinical outcomes. Results: In cohort 1, plasma KIM-1 distinguished RCC versus benign masses with AUC-ROC 0.81 (95% CI: 0.76-0.86). In cohort 2 (cT1a renal masses), plasma KIM-1 distinguished RCC versus benign masses with AUC-ROC 0.74 (95% CI: 0.67 to 0.80). Among patients in cohort 2, the prevalence of malignancy was 97% among patients with the highest quartile of KIM-1 compared to 55% among patients with the lowest quartile of KIM-1. Plasma KIM-1 was higher in clear cell RCC and papillary RCC compared to other histologies (p<0.001 in each cohort). Cohort 1 patients had prospective long-term follow-up, and higher pre-nephrectomy KIM-1 was associated with worse metastasis free survival (multivariable MFS HR 1.29 per unit increase in log KIM-1, 95% CI 1.10-1.53) and worse overall survival (multivariable OS HR 1.31 per unit increase in log KIM-1, 95% CI 1.10-1.54). Conclusions: In two independent cohorts of patients with renal masses, elevated baseline plasma KIM-1 is associated with higher risk of malignant pathology, worse metastasis free survival, and higher risk of death. Plasma KIM-1 may be a useful risk stratification tool for patients with suspicious kidney masses.
We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, ...rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10−7 and P = 4 × 10−6) and replicated by the independent study series (P = 7 × 10−5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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