Deciphering the post-transcriptional mechanisms (PTM) regulating gene expression is critical to understand the dynamics underlying transcriptomic regulation in cancer. Alternative polyadenylation ...(APA)-regulation of mRNA 3'UTR length by alternating poly(A) site usage-is a key PTM mechanism whose comprehensive analysis in cancer remains an important open challenge. Here we use a method and analysis pipeline that sequences 3'end-enriched RNA directly to overcome the saturation limitation of traditional 5'-3' based sequencing. We comprehensively map the APA landscape in lung cancer in a cohort of 98 tumor/non-involved tissues derived from European American and African American patients. We identify a global shortening of 3'UTR transcripts in lung cancer, with notable functional implications on the expression of both coding and noncoding genes. We find that APA of non-coding RNA transcripts (long non-coding RNAs and microRNAs) is a recurrent event in lung cancer and discover that the selection of alternative polyA sites is a form of non-coding RNA expression control. Our results indicate that mRNA transcripts from EAs are two times more likely than AAs to undergo APA in lung cancer. Taken together, our findings comprehensively map and identify the important functional role of alternative polyadenylation in determining transcriptomic heterogeneity in lung cancer.
In recent years, the anti-cancer properties of several commonly used drugs have been explored, with drugs such as aspirin and beta-blockers associated with improved cancer outcomes. Previous ...preclinical work demonstrated that tricyclic anti-depressants have antitumor efficacy in lung cancer. Our goal was to examine the association between anti-depressant use and survival in lung cancer.
We examined the association between use of common anti-depressants and survival in 1097 lung cancer patients from the NCI-Maryland lung cancer study. The types of anti-depressants included in the study were norepinephrine and dopamine reuptake inhibitors, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, and tricyclic anti-depressants. Anti-depressant use was extracted from the medical history section of a detailed interviewer-administered questionnaire. Specific use in the three months before a lung cancer diagnosis was determined. Cox portioned hazards modeling was used to estimate the association between anti-depressant use with lung cancer-specific death with adjustment for potential confounding co-factors.
Anti-depressant use was associated with extended lung cancer-specific survival. In an analysis of specific classes of anti-depressant use, NDRIs and TCAs were associated with improved survival. Importantly, the extended survival associated with anti-depressants was maintained after adjustment for the clinical indications for these drugs, suggestive of a direct effect on lung cancer biology.
Considering the manageable and largely tolerable side effects of anti-depressants, and the low cost of these drugs, these results indicate that evaluation of anti-depressants as adjunct therapeutics with chemotherapy may have a translational effect for lung cancer patients.
•Catecholamine signaling is increasingly recognized in connection with cancer.•The relationship between antidepressant use and survival was assessed in 1097 lung cancer patients.•Antidepressants, which modulate catecholamines, are associated with lung cancer survival.•Of the six drug classes tested, TCAs and NDRIs are the main forms associated with outcome.•Both TCAs and NDRIs are associated with prolonged patient survival.
The ADAMs are a family of membrane proteins possessing a disintegrin and metalloprotease domain. One of their main functions
is shedding of membrane proteins. The aim of this study was to test the ...hypothesis that ADAM-17 (also known as tumor necrosis
factor-α converting enzyme) is involved in breast cancer progression. Overexpression of ADAM-17 in MCF-7 breast cancer cells
increased in vitro invasion and proliferation, whereas down-regulation of ADAM-17 expression in MDA-MB-435 cells decreased invasion and proliferation.
At both mRNA and protein levels, ADAM-17 expression was significantly up-regulated in breast cancer compared with normal breast
tissue. Using Western blotting, ADAM-17 protein in breast cancer was shown to exist in two forms migrating with approximate
molecular masses of 100 and 120 kDa. Based on their known molecular mass, these bands were taken to represent the active and
precursor forms of ADAM-17, respectively. The proportion of active to total ADAM-17 increased progressively from normal breast
tissue to primary breast cancer to lymph node metastases ( P = 0.017, Kruskal-Wallis test). In primary cancers, the active form was expressed more frequently in node-positive compared
with node-negative tumors ( P = 0.034, χ 2 test). Furthermore, in primary carcinomas, both forms of ADAM-17 correlated significantly (Spearman correlation analysis)
with levels of urokinase plasminogen activator (precursor form: r = 0.246, P = 0.032, n = 83 and active form: r = 0.428, P = 0.0001, n = 83) and proliferating cell nuclear antigen (precursor form: r = 0.524, P < 0.0001, n = 73 and active form: r = 0.365, P = 0.002, n = 73). Our results support the hypothesis that ADAM-17 is involved in breast cancer progression.
Reducing or eliminating persistent disparities in lung cancer incidence and survival has been challenging because our current understanding of lung cancer biology is derived primarily from ...populations of European descent. Here we show results from a targeted sequencing panel using NCI-MD Case Control Study patient samples and reveal a significantly higher prevalence of PTPRT and JAK2 mutations in lung adenocarcinomas among African Americans compared with European Americans. This increase in mutation frequency was validated with independent WES data from the NCI-MD Case Control Study and TCGA. We find that patients carrying these mutations have a concomitant increase in IL-6/STAT3 signaling and miR-21 expression. Together, these findings suggest the identification of these potentially actionable mutations could have clinical significance for targeted therapy and the enrollment of minority populations in clinical trials.
Lung cancer is the leading cause of cancer-related mortality worldwide. Low-dose CT (LDCT) imaging is now recommended to screen high-risk lung cancer individuals in the USA. LDCT has resulted in ...increased detection of stage I lung cancer for which the current standard of care is surgery alone. However, approximately 30% of these patients develop recurrence and therefore are in need of further treatment upon diagnosis. This study aims to explore blood-based inflammatory biomarkers to identify patients at high-risk of mortality for which additional treatment modalities can be offered at time of diagnosis.
Recent work on a small panel of circulating cytokines identified elevated levels of IL-6, a pro-inflammatory cytokine, as an indicator of poor survival for lung cancer patients. To reflect the broader role of inflammation in lung cancer, we examined a large panel of 33 inflammatory proteins in the sera of 129 lung cancer patients selected from the National Cancer Institute-Maryland case-control study. To reduce heterogeneity, we specifically focused our study on stage I lung adenocarcinoma patients.
We replicated the previous observations that IL-6 is associated with prognosis of lung cancer and extended its utility to prognosis in this highly-selected population of stage I lung adenocarcinoma patients. In addition, we developed a multi-marker, combined prognostic classifier that includes the pro-inflammatory Th-17 cell effector cytokine, IL-17. Patients with high levels of IL-6 and IL-17A had a significantly adverse survival compared with patients with low levels (P for trend <0.0001). Patients in the high risk group, with high levels of both proteins had a 5-year survival rate of 46% in comparison to 93% for those with low levels of both markers. Furthermore, we validated the same trends for the IL-6 and IL-17A prognostic signature in an independent data set.
The results identified here justify further investigation of this novel, combined cytokine prognostic classifier for the identification of high-risk stage I lung adenocarcinoma patients. This classifier has the much-needed potential to identify patients at high risk of recurrence and thus prospectively identify the subset of patients requiring more aggressive treatment regimens at the time of diagnosis.
Colorectal cancer is the third most incident cancer and cause of cancer-related death in the United States. MicroRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis and ...prognosis of colorectal cancer, although few studies have examined the relationship between germline mutation in the microRNAs with risk and prognosis. We therefore investigated the association between a SNP in hsa-mir-608, which lies within the 10q24 locus, and colorectal cancer.
A cohort consisting of 245 cases and 446 controls was genotyped for rs4919510. The frequency of the GG genotype was significantly higher in African Americans (15%) compared to Caucasians (3%) controls. There was no significant association between rs4919510 and colorectal cancer risk (African American: OR(GG vs. CC) 0.89 95% CI, 0.41-1.80) (Caucasian: OR(GG vs. CC) 1.76, (95% CI, 0.48-6.39). However, we did observe an association with survival. The GG genotype was associated with an increased risk of death in Caucasians (HR(GG vs. CC) 3.54 (95% CI, 1.38-9.12) and with a reduced risk of death in African Americans (HR(GG vs. CC) 0.36 (95% CI 0.12-1.07).
These results suggest that rs4910510 may be associated with colorectal cancer survival in a manner that is dependent on race.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
LKB1 loss of function is one key oncogenic event in lung cancer. Clinical data suggest that LKB1 loss of function is associated with patients' smoking status. The responsible ingredients and ...molecular mechanisms in tobacco for LKB1 loss of function, however, are not defined. In this study, we reported that NNAL, a major metabolite of a tobacco-specific carcinogen NNK, induces LKB1 phosphorylation and its loss of function via the β-AR/PKA signaling pathway in an isomer-dependent manner in human lung cancer cells. NNAL exposure also resulted in enhanced lung cancer cell migration and chemoresistance in an LKB1-dependent manner. A 120-day NNAL exposure in lung cancer cells, mimicking its chronic exposure among smokers, resulted in more prominent LKB1 phosphorylation, cell migration, and chemoresistance even in the absence of NNAL, indicating the long-lasting LKB1 loss of function although such an effect eventually disappeared after NNAL was removed for two months. These observations were confirmed in a lung cancer xenograft model. More importantly, human lung cancer tissues revealed elevated LKB1 phosphorylation in comparison to the paired normal lung tissues. These results suggest that LKB1 loss of function in human lung cancer could be extended to its phosphorylation, which may be mediated by NNAL from tobacco smoke in an isomer-dependent manner via the β-AR/PKA signaling pathway.
Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States, especially among men. Although significant progress has been made profiling ...the genomic makeup of lung cancer in EAs, AAs continue to be underrepresented. Our objective was to chart the genome-wide landscape of somatic mutations in lung cancer tumors from AAs.
In this study, we used the whole-exome sequencing of 82 tumor and noninvolved tissue pairs from AAs. Patients were selected from an ongoing case-control study conducted by the National Cancer Institute and the University of Maryland.
Among all samples, we identified 178 significantly mutated genes (p < 0.05), five of which passed the threshold for false discovery rate (p < 0.1). In lung adenocarcinoma (LUAD) tumors, mutation rates in STK11 (p = 0.05) and RB1 (p = 0.008) were significantly higher in AA LUAD tumors (25% and 13%, respectively) compared with The Cancer Genome Atlas EA samples (14% and 4%, respectively). In squamous cell carcinomas, mutation rates in STK11 (p = 0.002) were significantly higher among AA (8%) than EA tumors from The Cancer Genome Atlas (1%). Integrated somatic mutation data with CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) data analysis revealed LUAD tumors from AAs carrying STK11 mutations have decreased interferon signaling.
Although a considerable degree of the somatic mutation landscape is shared between EAs and AAs, discrete differences in mutation frequency in potentially important oncogenes and tumor suppressors exist. A better understanding of the molecular basis of lung cancer in AA patients and leveraging this information to guide clinical interventions may help reduce disparities.
Purpose
African Americans, especially men, have a higher incidence of lung cancer compared with all other racial and ethnic groups in the US. Self-reported race is frequently used in genomic research ...studies to capture an individual’s race or ethnicity. However, it is clear from studies of genetic admixture that human genetic variation does not segregate into the same biologically discrete categories as socially defined categories of race. Previous studies have suggested that the degree of West African ancestry among African Americans can contribute to cancer risk in this population, though few studies have addressed this question in lung cancer.
Methods
Using a genetic ancestry panel of 100 SNPs, we estimated West African, European, and Native American ancestry in 1,407 self-described African Americans and 2,413 European Americans.
Results
We found that increasing West African ancestry was associated with increased risk of lung cancer among African American men (OR
Q5 vs Q1
= 2.55 (1.45–4.48),
p
= 0.001), while no association was observed in African American women (OR
Q5 vs Q1
= 0.90 (0.51–1.59),
p
= 0.56). This relationship diminished following adjustment for income and education.
Conclusions
Genetic ancestry is not a major contributor to lung cancer risk or survival disparities.
Vitamin D is an essential micronutrient required for normal physiological function and recognized for its role regulating calcium metabolism. Recent work is beginning to emerge demonstrating a role ...for vitamin D in chronic illnesses, such as cancer. Circulating serum levels of 25(OH)D2/3 were quantitatively measured using sensitive ultraperformance liquid chromatography coupled to tandem mass spectrometry (UPLC‐MS/MS) in 406 lung cancer cases and 437 population controls, while 1,25(OH)2D2/3 levels were measured in a subset of 90 cases and 104 controls using the same method, from the NCI‐MD case–control cohort. 25(OH)D3 levels were inversely associated with lung cancer status across quartiles (Q2 vs. Q1: ORadjusted = 0.5, 95% CI = 0.3–0.8; Q3 vs. Q1: ORadjusted = 0.5, 95% CI = 0.3–0.8; Q4 vs. Q1: ORadjusted = 0.5, 95% CI = 0.2–0.9; Ptrend = 0.004). Levels of 1,25(OH)2D3 were also inversely associated with lung cancer status (Q2 vs. Q1: ORadjusted = 0.2, 95% CI = 0.03–0.7; Q3 vs. Q1: ORadjusted = 0.1, 95% CI = 0.01–0.4; Q4 vs. Q1: ORadjusted = 0.04, 95% CI = 0.01–0.3; Ptrend<0.0001). Although the observed trends were similar for the 25(OH)D2 (Ptrend = 0.08), no significant associations were seen between vitamin D2 and lung cancer status. Additionally, genotyping of 296 SNPs in the same subjects resulted in findings that 27 SNPs, predominantly in CYP24A1 and VDR genes, were significantly associated with lung cancer status, affected mRNA expression, and modulated vitamin D levels. These findings suggest a protective role for vitamin D3 in lung cancer, with similar trends but insignificant findings for D2. Vitamin D3 levels appeared to be modulated by genetic variation in CYP24A1 and VDR genes. Additional research to illuminate the mechanism(s) through which vitamin D exacerbates effects against lung carcinogenesis is warranted.
Inverse association between 25(OH)D3 and hormonally active form 1,25(OH)D3 and lung cancer was observed in a case control study. Associations between vitamin D2 and lung cancer were not statistically significant. Single nucleotide polymorphisms in CYP24A1 and VDR may modulate the observed associations.
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