Proteogenomic landscape of squamous cell lung cancer

Stewart, Paul A.; Welsh, Eric A.; Slebos, Robbert J.C.; Fang, Bin; Izumi, Victoria; Chambers, Matthew; Zhang, Guolin; Cen, Ling; Pettersson, Fredrik; Zhang, Yonghong; Chen, Zhihua; Cheng, Chia-Ho; Thapa, Ram; Thompson, Zachary; Fellows, Katherine; Francis, Jewel M; Saller, James J.; Mesa, Tania; Zhang, Chaomei; Yoder, Sean; DeNicola, Gina M.; Beg, Amer A.; Boyle, Theresa A.; Teer, Jamie K.; Chen, Yian Ann; Koomen, John M.; Eschrich, Steven A.; Haura, Eric B.

doi:10.1038/s41467-019-11452-x

Cited by 91 publications

(85 citation statements)

References 79 publications

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“…For example, one of the most enriched biological processes seen in our NRF2 signature is that of extracellular matrix (ECM) signalling. Recent proteogenomic work from squamous cell lung cancer [47] noted that somatic mutations of NFE2L2/KEAP1 are enriched for transcriptional programs in ECM similar to the data presented here. Open questions include whether the cancer cell exerts an outward influence on the ECM by increasing NRF2 signalling and creating a protumorigenic environment, or is it an inward effect, with the ECM altering the biology of the cancer cell.…”

Section: Discussionsupporting

confidence: 81%

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

et al. 2020

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We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer. Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights. Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms. Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR = 1.55, 95% C.I 1.2-2.004, p = 0.0008; GSE39582 HR = 1.24, 95% C.I 1.086-1.416, p = 0.001; GSE87211 HR = 1.431, 95% C.I 1.06-1.93, p = 0.056; MRC FOCUS trial HR = 1.14, 95% C.I 1.04-1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particular ly enr iched in Consensus Molecular Subtype (CMS) 4. Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study.

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Section: Discussionsupporting

confidence: 81%

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

et al. 2020

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“…The Fructose-Bisphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis, which is suppressed in kidney tumors and thus feeds ccRCC; FBP1 is associated with impaired cell proliferation, glycolysis and the pentose phosphate pathway in ccRCC in a catalytic-activity-independent manner via direct interaction with the HIF inhibitory domain 18 . PSAT1 is up-regulated in many cancers and acts as an oncogene that exerts a vital role in cancer progression and metastasis 19 – 21 . Interestingly, through mining public database and RT-qPCR, we found that PSAT1 in ccRCC patients is down-regulated compared with normal tissue.…”

Section: Discussionmentioning

confidence: 99%

A cluster of metabolism-related genes predict prognosis and progression of clear cell renal cell carcinoma

Liu

Pan

Xiao

et al. 2020

Sci Rep

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Clear cell renal cell carcinoma (ccRCC) has long been considered as a metabolic disease characterized by metabolic reprogramming due to the abnormal accumulation of lipid droplets in the cytoplasm. However, the prognostic value of metabolism-related genes in ccRCC remains unclear. In our study, we investigated the associations between metabolism-related gene profile and prognosis of ccRCC patients in the Cancer Genome Atlas (TCGA) database. Importantly, we first constructed a metabolism-related prognostic model based on ten genes (ALDH6A1, FBP1, HAO2, TYMP, PSAT1, IL4I1, P4HA3, HK3, CPT1B, and CYP26A1) using Lasso cox regression analysis. The Kaplan-Meier analysis revealed that our model efficiently predicts prognosis in TCGA_KIRC Cohort and the clinical proteomic tumor analysis consortium (CPTAC_ccRCC) Cohort. Using time-dependent ROC analysis, we showed the model has optimal performance in predicting long-term survival. Besides, the multivariate Cox regression analysis demonstrated our model is an independent prognostic factor. The risk score calculated for each patient was significantly associated with various clinicopathological parameters. Notably, the gene set enrichment analysis indicated that fatty acid metabolism was enriched considerably in low-risk patients. In contrast, the high-risk patients were more associated with nonmetabolic pathways. In summary, our study provides novel insight into metabolism-related genes' roles in ccRCC. Clear cell renal cell carcinoma (ccRCC), the most common renal cell carcinoma (RCC) subtype, exhibits global health issues due to its growing incidence, extreme heterogeneity among patients and high mortality. It is estimated that 90% of the ccRCC patients died of tumor-specific recurrence and metastasis 1. Regarding this, considerable research efforts have focused on developing a model to predict the prognosis of ccRCC patients; however, these prognosis tools still require improvements to attain a high degree of accuracy 2-4. Therefore, novel and robust prognostic models are urgently needed in clinical practice. Metabolism is fundamental in maintaining all the biological processes necessary for life 5. Tumors are typified by metabolic abnormalities as proliferating cells rewire their mechanism to sustain growth 6. Notably, the rapidly proliferating cells in malignancies take up abundant glucose and glutamine to generate the proteins, lipids, and nucleic acids to support cell growth 7. RCC is regarded as a metabolic disease with diabetes, obesity, and atherosclerosis considered as the risk factors 8,9. CcRCC is a unique RCC subtypes based on the abnormally accumulated lipid droplets in the cytoplasm with research evidence implicating the lipid accumulation in disease progression 10,11. Nevertheless, the underlying mechanism and the prognostic role of these metabolic genes remain largely unknown. In the present study, we screened the differentially expressed metabolism-related genes and evaluated their clinical value based on the cancer genome atlas (TCGA) kidney renal clear ...

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“…Lung cancer represents the leading cause of worldwide cancer‐related death (Ferlay et al., 2015). It is an aetiologically multifactorial disease, including genetic and environmental factors (Stewart et al., 2019). During tumour development, multiple immune evasion mechanisms may lead to insufficient cancer immunosurveillance process (Vinay et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Association of BTLA rs1982809 polymorphism with lung cancer risk in Tunisian population

Khadhraoui

Kaabachi

Tritar

et al. 2020

Int J Immunogenetics

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B and T lymphocyte attenuator (BTLA) is an immune‐inhibitory receptor that negatively regulates the lymphocyte activation. A few studies have been devoted to the relationship between BTLA gene variations and cancer's risk. It has been essentially demonstrated to be involved in increasing cancer risk in chronic lymphocyte leukaemia, renal cell carcinoma, breast and colorectal cancer predispositions in Asian population. The aim of this study was to evaluate the association between BTLA gene polymorphisms and the risk of lung cancer in the Tunisian population. In a case–control study, three BTLA single‐nucleotide polymorphism (SNP): rs1982809 (A > G), rs9288952 (G > A) and rs9288953(C > T) were genotyped with the use of TaqMan probes in 169 lung cancer patients and in 300 controls. The rs1982809 SNP was significantly associated with an increased risk of lung cancer compared with controls in codominant and dominant models. The heterozygous rs1982809‐AG genotype carriers had a higher risk of developing lung cancer when compared to AA genotype carriers in Tunisian population (OR (95%CI) = 1.63 (1.09–2.42), p = .01]. The AG genotype is an important risk factor associated with lymphatic invasion (OR = 3.71) and large‐sized lung tumour (OR = 1.80). It is also a risk factor for the development of an adenocarcinoma subtype (OR = 2.08). However, the BTLA rs9288953 and rs9288952 SNPs were not associated with susceptibility for lung cancer (p > .05). Haplotype comparison did not show any significant association in our research. For the survival analysis, there was no impact of BTLA SNPs on the mortality risk associated to lung cancer in Tunisian patients. The current study is the first to demonstrate an association between BTLA rs1982809 polymorphism and an increased lung cancer risk in the Tunisian population.

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Proteogenomic landscape of squamous cell lung cancer

Cited by 91 publications

References 79 publications

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

A cluster of metabolism-related genes predict prognosis and progression of clear cell renal cell carcinoma

Association of BTLA rs1982809 polymorphism with lung cancer risk in Tunisian population

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