X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Collection
2.2. Defining a Gene List of Interest and Identifying Regulatory Networks
2.3. Gene Enrichment Analysis of DEGs
2.4. Correlation of DEGs with Immune Infiltrates
2.5. Statistical Analysis
2.6. Association Analysis between DEGs and Patient Prognosis
3. Results
3.1. Genetic Differences Analyses
3.1.1. Sex-Specific Molecular Signature of LUAD
3.1.2. Altered Warburg Metabolism Seems to Inhibit AMPK but Activate mTOR and MAPK Signalling in Our Female Cohort
3.1.3. Metabolism of Xenobiotic by Cytochrome p450 and DNA Repair Seem to Be Upregulated in Our Male Cohort
3.1.4. Expression of 22 DEGs Strongly Associates with Tumour Infiltration Abundance of Immune Cells
3.1.5. High Level of Infiltrated Regulatory T Cells Accompanied by DEGs Correlates with Better LUAD Prognosis
3.2. Hormone-Related Analyses
3.2.1. Circulating Hormonal Transcriptional Targets Affect LUAD Tumour Proliferation and Progression
3.2.2. Association of Oestrogen Protection in Males and Premenopausal and Postmenopausal Females
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Cell Cycle | STK11, BIRC7, CROCC,AKR1B10, C19orf21, MST4, PTP4A1 |
Proliferation | AKR1C2, AKR1C3, ID1, IRS2, PPARGC1A, PTHLH, TFF1,AKR1B10, FOXP2,APOE, BOK, CBFA2T3, CD79A, CX3CL1,ENG, MAPK11, MS4A1, STK11, TNFRSF13B, TNFSF14, ICOSLG, MATK |
Apoptosis | BOK, STK11, CD14,PPARGC1A, AKR1E2, ATP1B1, MST4,SLCO1A2 |
PI3K-AKT Signalling Pathway | CDKN1A, EGFR, MTOR, PIK3CD, PIK3R2,CDKN1B, CHUK, IRS2, KIT |
MAPK signalling pathway | MAP2K1, PRKACB, CHUK, DUSP4, KRAS,MAPK11, CD14,TGFB1, EGFR, MAPK1, MAPK3, NFATC2, RELA, TGFB2, GADD45A, TGFBR2, CACNA1I |
ATP-dependent transporter of the ATP-binding cassette (ABC) | MGST1, AKR1C3, ALDH3B1, TAT, AKR1C1, AKR1C2,ITIH4, IGFBP1, GSR, ABCC2, PGD, ENPEP, MCCC2,GABARAPL1, GSTM4, GSTO2, GSTA2, PTGES3, AHCY,CYP2C8, CBR1,APOE, PINK1, ALDH1A3, GSTA3, PPARD,TGFB2 |
HIF PID signalling pathway | ENG, GATA2, FURIN,IGFBP1 |
FOXO signalling pathway | ARG1, APOE, ATM, CDKN1A, EGFR, GABARAP, GADD45A, MAPK11, MAPK1, MAPK3, PIK3CD, PIK3R2, TGFB1, TGFB2, TGFBR2, STK11,SREBF1, CCNB3, CCND1,CDKN1B, CHUK, GABARAPL1, INSR, IRS2, KRAS,MAP2K1, PRKAB2, PRKAG2, PRMT1, SIRT1, SMAD4, EIF4E, ULK2, FOXP2, PPARGC1A |
AMPK signalling pathway | CCND1, GYS2, INSR, IRS2, LEP, PPARGC1A, PPP2CB, PPP2R1A, PPP2R1B, PPP2R5C, PRKAB2, PRKAG2, SIRT1, SREBF1,STK11, CCNA1, PPP2R5B, CREB3, PFKL, PIK3CD,PIK3R2, RAB8A, STK11, STRADB, TBC1D1 |
mTOR signalling pathway | EIF4B, INSR, SEH1L, CHUK, MAP2K1, ATP6V1G1, EIF4E,ULK2, PTHLH,STK11, MAPK1, PIK3R2, WNT6, ATP6V1E1, FZD7, STK11, TELO2, MAPK3, WNT5B, FZD2,MTOR, FLCN, PIK3CD, WDR24, NPRL2, STRADB, PIK3CG |
TIMER2.0 immune related genes | RENBP, ARHGAP22, CD79A, CXCR5, FCER2, GIPR,MS4A1, NCR3, PRG2, RYR1, SLC15A3, TNFRSF13B, TNFSF14, VPREB3, FGD3, FXYD5, HLA-DQB1, HMHA1,ICOSLG, TMC8, TNFAIP2,HAL |
Warburg Effect | ACSS1, PFKL, PIK3CD, GLS, EGFR, HK1, MAPK1, PGAM2,MAPK3, PIK3R2,PDHB, KIT, KRAS, G6PD, MAP2K1S |
ARH signalling pathway | CDKN1A, EGFR, RELA, TGFB1, MAPK1,GSTA2, IGFBP1,KRAS, MAP2K1, CDKN1B |
Metabolism of xenobiotics by cytochrome P450 | CYP2C8, MGST1, AKR1C3, ALDH3B1, AKR1C2, AKR1C1,GSTM4, GSTO2, GSTA2,ALDH1A3, CYP2S1, GSTA3 |
RAS signalling pathway | APOE, MAPK11, RTN4R, SHC3, STMN3, TIAM1, SHC2 |
Wnt signalling pathway | NFATC3, WNT6, FZD7,TBL1Y, NFATC2, CCND1, WNT5B,PRKACB, FZD2 |
Reactive Oxygen Species pathway | ABCC1, G6PD, GLRX2, GSR, MGST1, NDUFB4, PRDX4,PRDX6, TXNRD2 |
DEGs | Purity | B Lymphocytes | CD8+ T cell | CD4+ T cell | Macrophages | NEUTROPHILES | DC | Tregs | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R2 | P | R2 | P | R2 | P | R2 | P | R2 | P | R2 | P | R2 | P | R2 | P | |
ARHGAP22 | −0.229 | 2.65 × 10−7 | 0.175 | 9.26 × 10−5 | 0.063 | 1.63 × 10−1 | 0−0.204 | 5.07 × 10−6 | 0.1 | 2.65 × 10−2 | 0.045 | 3.22 × 10−1 | 0.141 | 1.66 × 10−3 | 0.189 | 2.37 × 10−5 |
CD79A | −0.457 | 7.17 × 10−27 | 0.718 | 1.89 × 10−79 | 0.403 | 1.06 × 10−20 | −0.161 | 3.36 × 10−4 | −0.013 | 7.79 × 10−1 | −0.142 | 1.56 × 10−3 | 0.071 | 1.15 × 10−1 | 0.482 | 4.26 × 10−30 |
CXCR5 | −0.505 | 2.24 × 10−33 | 0.731 | 1.66 × 10−83 | 0.45 | 6.43 × 10−26 | −0.115 | 1.03 × 10−2 | 0.135 | 2.69 × 10−3 | −0.025 | 5.84 × 10−1 | −0.004 | 9.27 × 10−1 | 0.501 | 1.04 × 10−32 |
FCER2 | −0.424 | 5.88 × 10−23 | 0.58 | 1.33 × 10−45 | 0.271 | 1.01 × 10−9 | −0.022 | 6.23 × 10−1 | 0.104 | 2.06 × 10−2 | 0.004 | 9.34 × 10−1 | −0.073 | 1.06 × 10−1 | 0.376 | 5.14 × 10−18 |
FGD3 | −0.423 | 7.46 × 10−23 | 0.455 | 1.58 × 10−26 | 0.498 | 3.08 × 10−32 | −0.215 | 1.52 × 10−6 | 0.282 | 1.72 × 10−10 | 0.02 | 6.65 × 10−1 | 0.009 | 8.40 × 10−1 | 0.516 | 7.64 × 10−35 |
FXYD5 | −0.267 | 1.60 × 10−9 | 0.031 | 4.89 × 10−1 | 0.06 | 1.83 × 10−1 | −0.026 | 5.70 × 10−1 | 0.328 | 8.45 × 10−14 | 0.233 | 1.77 × 10−7 | −0.198 | 9.33 × 10−6 | 0.069 | 1.28 × 10−1 |
GIPR | −0.104 | 2.12 × 10−2 | 0.21 | 2.61 × 10−6 | 0.044 | 3.20 × 10−1 | −0.148 | 9.68 × 10−4 | 0.205 | 4.46 × 10−6 | 0.171 | 1.39 × 10−4 | −0.079 | 7.89 × 10−2 | 0.362 | 1.09 × 10−16 |
HAL | 0.047 | 2.90 × 10−1 | −0.063 | 1.59 × 10−1 | −0.158 | 4.23 × 10−4 | 0.129 | 4.04 × 10−13 | −0.191 | 1.93 × 10−5 | 0.071 | 1.16 × 10−1 | 0.08 | 7.64 × 10−2 | −0.122 | 6.48 × 10−3 |
HLA−DQB1 | −0.353 | 6.30 × 10−16 | 0.247 | 2.90 × 10−8 | 0.226 | 3.87 × 10−7 | −0.126 | 4.99 × 10−3 | 0.445 | 2.51 × 10−25 | 0.1 | 2.70 × 10−2 | −0.204 | 4.82 × 10−6 | 0.342 | 5.78 × 10−15 |
HMHA1 | −0.277 | 3.97 × 10−10 | 0.218 | 1.06 × 10−6 | 0.21 | 2.54 × 10−6 | −0.234 | 1.39 × 10−7 | 0.359 | 2.02 × 10−16 | 0.063 | 1.65 × 10−1 | −0.056 | 2.13 × 10−1 | 0.408 | 3.49 × 10−21 |
ICOSLG | −0.233 | 1.59 × 10−7 | 0.3 | 1.06 × 10−11 | 0.12 | 7.55 × 10−3 | −0.042 | 3.49 × 10−1 | 0.181 | 5.51 × 10−5 | 0.038 | 3.97 × 10−1 | 0.023 | 6.11 × 10−1 | 0.401 | 1.80 × 10−20 |
MS4A1 | −0.502 | 7.29 × 10−33 | 0.74 | 1.19 × 10−86 | 0.441 | 7.14 × 10−25 | −0.086 | 5.76 × 10−2 | 0.082 | 6.93 × 10−2 | −0.068 | 1.30 × 10−1 | −0.028 | 5.32 × 10−1 | 0.454 | 2.22 × 10−26 |
NCR3 | −0.503 | 4.88 × 10−33 | 0.607 | 5.62 × 10−51 | 0.63 | 5.46 × 10−56 | −0.101 | 2.46 × 10−2 | 0.155 | 5.68 × 10−4 | −0.092 | 4.01 × 10−2 | −0.079 | 7.94 × 10−2 | 0.431 | 9.64 × 10−24 |
PRG2 | −0.122 | 6.43 × 10−3 | −0.022 | 6.32 × 10−1 | −0.061 | 1.76 × 10−1 | −0.236 | 1.11 × 10−7 | 0.25 | 1.95 × 10−8 | 0.197 | 1.06 × 10−5 | −0.085 | 5.97 × 10−2 | 0.179 | 6.57 × 10−5 |
RENBP | −0.237 | 9.51 × 10−8 | 0.173 | 1.18 × 10−4 | 0.236 | 1.16 × 10−7 | −0.178 | 7.16 × 10−5 | 0.268 | 1.42 × 10−9 | 0.071 | 1.16 × 10−1 | 0.01 | 8.28 × 10−1 | 0.265 | 2.28 × 10−9 |
RYR1 | −0.112 | 1.31 × 10−2 | 0.05 | 2.63 × 10−1 | 0.092 | 4.18 × 10−2 | −0.113 | 1.20 × 10−2 | 0.341 | 6.33 × 10−15 | 0.234 | 1.47 × 10−7 | −0.094 | 3.68 × 10−2 | 0.203 | 5.50 × 10−6 |
SLC15A3 | −0.431 | 9.65 × 10−24 | 0.269 | 1.23 × 10−9 | 0.345 | 2.90 × 10−15 | −0.132 | 3.35 × 10−3 | 0.383 | 1.16 × 10−18 | 0.071 | 1.18 × 10−1 | −0.107 | 1.76 × 10−2 | 0.461 | 2.38 × 10−27 |
TMC8 | −0.432 | 8.18 × 10−23 | 0.404 | 8.79 × 10−21 | 0.406 | 5.60 × 10−21 | −0.169 | 1.68 × 10−4 | 0.344 | 4.07 × 10−15 | 0.071 | 1.18 × 10−1 | −0.19 | 2.10 × 10−5 | 0.472 | 1.17 × 10−28 |
TNFAIP2 | −0.311 | 1.51 × 10−12 | 0.167 | 2.01 × 10−4 | 0.3 | 1.03 × 10−11 | −0.19 | 2.25 × 10−5 | 0.312 | 1.44 × 10−12 | 0.041 | 3.59 × 10−1 | −0.029 | 5.26 × 10−1 | 0.275 | 5.45 × 10−10 |
TNFRSF13B | −0.438 | 1.37 × 10−24 | 0.717 | 3.98 × 10−79 | 0.365 | 5.76 × 10−17 | −0.096 | 3.23 × 10−2 | 0.041 | 3.69 × 10−1 | −0.039 | 3.84 × 10−1 | −0.066 | 1.46 × 10−1 | 0.478 | 1.79 × 10−29 |
TNFSF14 | −0.356 | 3.34 × 10−16 | 0.21 | 2.67 × 10−6 | 0.206 | 4.18 × 10−6 | 0.292 | 3.95 × 10−11 | 0.181 | 6.01 × 10−5 | 0.045 | 3.22 × 10−1 | −0.109 | 1.52 × 10−2 | 0.264 | 2.70 × 10−9 |
VPREB3 | −0.442 | 5.33 × 10−25 | 0.688 | 2.18 × 10−70 | 0.308 | 2.53 × 10−12 | −0.116 | 1.01 × 10−2 | −0.042 | 3.47 × 10−1 | −0.132 | 3.26 × 10−3 | 0.042 | 3.50 × 10−1 | 0.284 | 1.34 × 10−10 |
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Hammouz, R.Y.; Orzechowska, M.; Anusewicz, D.; Bednarek, A.K. X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma. Curr. Oncol. 2023, 30, 1395-1415. https://doi.org/10.3390/curroncol30020107
Hammouz RY, Orzechowska M, Anusewicz D, Bednarek AK. X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma. Current Oncology. 2023; 30(2):1395-1415. https://doi.org/10.3390/curroncol30020107
Chicago/Turabian StyleHammouz, Raneem Yaseen, Magdalena Orzechowska, Dorota Anusewicz, and Andrzej K. Bednarek. 2023. "X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma" Current Oncology 30, no. 2: 1395-1415. https://doi.org/10.3390/curroncol30020107
APA StyleHammouz, R. Y., Orzechowska, M., Anusewicz, D., & Bednarek, A. K. (2023). X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma. Current Oncology, 30(2), 1395-1415. https://doi.org/10.3390/curroncol30020107