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GPM6A Is Differentially Expressed in Non-Small Cell Lung Cancer And

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GPM6A Is Differentially Expressed in Non-Small Cell Lung Cancer And 1 Glycoprotein M6A is differentially expressed in non-small cell lung cancer and associates 2 with patient survival. 3 Shahan Mamoor, MS1 4 [email protected] East Islip, NY USA 5 6 Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States1. 7 We mined published microarray data2,3,4 to identify differentially expressed genes in NSCLC. 8 We found that gene encoding glycoprotein M6A, GPM6A, was among those whose expression 9 was most quantitatively different in human NSCLC tumors as compared to the lung. GPM6A expression levels were significantly decreased in NSCLC tumors as compared to the lung, and 10 lower expression of GPM6A in patient tumors was significantly associated with worse overall 11 survival. GPM6A may be important for initiation or progression of non-small cell lung cancer in humans. 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Keywords: GPM6A, NSCLC, non-small cell lung cancer, systems biology of NSCLC, targeted 27 therapeutics in NSCLC. 28 1 OF 16 1 In 2016, lung cancer resulted in the death of 158,000 Americans; 81% of all patients 2 diagnosed with lung cancer will expire within 5 years5. Non-small cell lung cancer (NSCLC) is 3 4 the most common type of lung cancer, diagnosed in 84% of patients with lung cancer, and 76% 5 of all patients with NSCLC will expire within 5 years5. The rational development of targeted 6 therapeutics to treat patients with NSCLC can be supported by an enhanced understanding of 7 8 fundamental transcriptional features of NSCLC tumors. To discover genes associated with 9 NSCLC tumors in an unbiased fashion and at the systems-level, we mined independently 10 published microarray data2,3,4 to compare global gene expression profiles of NSCLC tumors to 11 12 that of the normal lung. We found recurrent and significant differential expression of the gene 13 encoding glycoprotein M6A, GPM6A, in adenocarcinoma tumors from patients with NSCLC, 14 15 suggesting GPM6A may be important for NSCLC tumor initiation or progression. 16 17 Methods 18 We utilized microarray datasets, GSE434582, GSE3353243 and GSE747064 for this 19 differential gene expression analysis of NSCLC tumors in conjunction with GEO2R. GSE43458 20 21 was generated using Affymetrix Human Gene 1.0 ST Array technology; for this analysis, we 22 used with n=30 control lung tissue and n=80 NSCLC tumors, and the analysis was performed 23 24 using platform GPL6244. GSE33532 was generated using Affymetrix Human Genome U133 25 Plus 2.0 Array technology; for this analysis, we used n=20 control lung tissue and n=10 NSCLC 26 tumors, and the analysis was performed using platform GPL570. GSE74706 was generated 27 28 using Agilent-026652 Whole Human Genome Microarray 4x44K v2 technology; for this 2 OF 16 1 analysis, we used n=18 control lung tissue and n=10 NSCLC tumors, and the analysis was 2 performed using platform GPL13497. All tumors utilized for differential gene expression 3 4 analysis here were of the adenocarcinoma type. 5 The Benjamini and Hochberg method of p-value adjustment was used for ranking of 6 differential expression but raw p-values were used to assess statistical significance of global 7 8 differential expression. Log-transformation of data was auto-detected, and the NCBI 9 generated category of platform annotation was used. A statistical test was performed to evaluate 10 whether GPM6A expression was significantly between normal lung tissue and NSCLC tumors 11 12 using a two-tailed, unpaired t-test with Welch’s correction. We used PRISM for all statistical 13 analyses of differential gene expression in NSCLC tumors (Version 8.4.0)(455). For Kaplan- 14 6 15 Meier survival analysis, we used the Kaplan-Meier plotter online tool for correlation of GPM6A 16 mRNA expression levels with overall survival in n=1925 non-small cell lung cancer patients. 17 18 Results 19 We harnessed the power of multiple, independently published microarray datasets2,3,4 to 20 21 discover in an unbiased fashion and at the transcriptome-level the most striking gene expression 22 features of NSCLC tumors. 23 24 GPM6A is differentially expressed in non-small cell lung cancers. 25 26 We found significant differential expression of the gene encoding glycoprotein M6A, 27 GPM6A, in NSCLC tumors when compared to the lung2 (Table 1). When sorting each of the 28 3 OF 16 1 transcripts measured based on significance of difference in expression of GPM6A between 2 NSCLC tumors and the normal lung, in this dataset, GPM6A ranked 12 out of 25906 total 3 4 transcripts (Table 1), equating to 99.95% differential expression. Differential expression of 5 GPM6A in NSCLC tumors was statistically significant (Table 1; p=3.36E-31). 6 We queried a second microarray dataset3 to determine if we could validate differential 7 8 expression of GPM6A in non-small cell lung cancers (Table 2). We found significant differential 9 expression of GPM6A in NSCLC tumors of the adenocarcinoma type when compared to the 10 normal lung (Table 2). When sorting each of the transcripts measured based on significance of 11 12 difference in expression of GPM6A between NSCLC tumors and the normal lung, GPM6A 13 ranked 17 of 33252 total transcripts (Table 2), equating to 99.95% differential expression. 14 15 Differential expression of GPM6A in NSCLC tumors was statistically significant (Table 2; 16 p=1.53E-17). 17 Analysis of a third microarray dataset4 again revealed significant differential expression 18 19 of GPM6A in NSCLC tumors of the adenocarcinoma type. When sorting each of the transcripts 20 measured based on significance of difference in expression of GPM6A between NSCLC tumors 21 and the normal lung, GPM6A ranked 1960 out of 34183 total transcripts (Table 3), equating to 22 23 94.3% differential expression. Differential expression of GPM6A in NSCLC tumors was 24 statistically significant (Table 3; p=2.46E-06). 25 26 GPM6A is expressed at significantly lower levels in NSCLC tumors as compared to the lung. 27 28 We obtained exact mRNA levels for GPM6A from NSCLC tumors and from the lung to 4 OF 16 1 directly compare GPM6A expression between tumor and control lung tissue and assess for 2 statistical significance. GPM6A was expressed at significantly lower levels in NSCLC tumors as 3 4 compared to the normal lung in each dataset queried, respectively (Figure 1: p<0.0001 and 5 Figure 2: p<0.0001). We calculated a mean fold change of 0.7152 ± 0.0830 and 0.4440 ± 0.0914 6 in GPM6A expression when comparing NSCLC tumors to the lung (Table 1 and Table 2, 7 8 respectively). 9 10 GPM6A expression in NSCLC tumors correlates with overall survival. 11 We performed Kaplan-Meier survival analysis using GPM6A mRNA expression in 12 13 NSCLC tumors coupled with paired overall survival data from each patient, in 1925 NSCLC 14 patients in total, to determine whether GPM6A tumor expression was correlated with survival 15 outcomes in NSCLC. We found that patients whose tumors expressed lower levels of GPM6A 16 17 possessed significantly shorter overall survival than patients with high tumor expression of 18 GPM6A (Figure 3). Median overall survival (OS) of patients in the low expression cohort was 19 62.2 months, while median OS in patients in the high GPM6A expression cohort was 98.5 20 21 months (Table 4); this difference in median OS based on GPM6A tumor expression in NSCLC 22 was statistically significant (Figure 3; logrank p-value: 9.8e-7; hazard ratio: 0.68 (0.58 - 0.79); 23 24 false discovery rate=0.01). 25 Thus, blind comparative transcriptome analysis of non-small cell lung cancers revealed 26 differential expression of glycoprotein M6A as among the most significant transcriptional 27 28 features of NSCLC tumors, and GPM6A expression was significantly correlated with patient 5 OF 16 1 outcomes, as patients with lower tumor expression of GPM6A possessed significantly worse 2 overall survival. 3 4 Discussion 5 6 Human GPM6A is a membrane glycoprotein of 274 amino acids and was originally 7 described to possess specific expression in the brain7,8. GPM6A contains four transmembrane 8 domains, two extracellular loops, and a small intracellular loop9. Ectopic expression of GPM6A 9 10 in a human embryonic stem cell line (hES) results in expression of genes associated with the 11 neuroectoderm, like Pax2 and Sox2, as well as an increase in the number of neural stem cells 12 10 13 derived from hES cells . M6A is expressed in the hippocampus, and ectopic expression of M6A 14 in hippocampal neurons results in formation of neurites and an increase in filopodia density11. 15 Over-expression of GPM6A in neurons also results in an increase in the number of dendritic 16 17 spines and synapses12. Another interaction partner of GPM6A is coronin-1; Rac-1 can 18 immunoprecipitate along with GPM6A,where they can function together with Pak-1 in 19 generation of filopodium13. In rat hippocampal neurons from rat, GPM6A can be found localized 20 21 within lipid rafts, co-localizing with ganglioside GM-1 and described to be “floating” with 22 flotillin-1 in a detergent-insoluble fraction14. GPM6A can also interact with the µ-opioid 23 15 24 receptor and promote is endocytosis . Thus, GPM6A is a membrane protein most abundantly 25 expressed in the brain, including in the hippocampus, functions in neurite growth, generation of 26 dendritic spines, synapse formation, and formation of filopodium, can promote neuroectoderm 27 28 gene expression and is found in lipid rafts. 6 OF 16 1 GPM6A has been described as differentially expressed in thyroid cancer, expressed at 2 higher levels in papillary thyroid carcinoma as compared to normal thyroid tissue16.
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