Keywords
STAD
Biomarker
Prognosis
Expression variations
Submitted : 2024-11-04
Accepted : 2024-11-19
Published : 2024-12-04
Abstract
This study analyzes Kirsten rat sarcoma viral oncogene (KRAS) expression heterogeneity, and biological and clinical relevance in stomach adenocarcinoma (STAD). The study utilized various tools including UALCAN, GEPIA2, Kaplan-Meier (KM) plotter, cBioPortal, STRING, DAVID, and TIMER 2.0 to conduct this analysis. The results illustrated overexpression of KRAS in STAD and the analysis based on various clinicopathological parameters also verified overexpression of KRAS in STAD. Eventually, this overexpression was linked to poor overall survival (OS) of STAD patients. These results suggested the role of KRAS is involved in the development and progression of STAD. The study also assessed several significant correlations of KRAS expression with promoter methylation tumor purity and immune cell infiltration. Genetic alteration of KRAS revealed to have a strong role in STAD initiation. Gene enrichment analysis highlighted the enrichment of KRAS with various pathways. In conclusion, the findings illustrated the potential of KRAS as a diagnostic, prognostic, and therapeutic biomarker in STAD.
References
Upadhyay A, 2021, Cancer: An Unknown Territory; Rethinking before Going Ahead. Genes & Diseases, 8(5): 655–661.
Fares J, Fares MY, Khachfe HH, et al., 2020, Molecular Principles of Metastasis: A Hallmark of Cancer Revisited. Signal Transduction and Targeted Therapy, 5(1): 28.
Bray F, Laversanne M, Sung H, et al., 2024, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 74(3): 229–263.
Deng W, Jin L, Zhuo H, et al., 2021, Alcohol Consumption and Risk of Stomach Cancer: A Meta-Analysis. Chemico-Biological Interactions, 2021(336): 109365.
Yao Q, Qi X, Xie SH, 2020, Sex Difference in the Incidence of Cardia and Non-cardia Gastric Cancer in the United States, 1992–2014. BMC Gastroenterology, 2020(20): 1–7.
Minami Y, Kanemura S, Oikawa T, et al., 2018, Associations of Cigarette Smoking and Alcohol Drinking with Stomach Cancer Survival: A Prospective Patient Cohort Study in Japan. International Journal of Cancer, 143(5):1072–1085.
Alagesan P, Goodwin JC, Garman KS, et al., 2023, Cancer Progress and Priorities: Gastric Cancer. Cancer Epidemiology, Biomarkers & Prevention, 32(4): 473–486.
Zhang R, Li H, Li N, et al., 2021, Risk Factors for Gastric Cancer: A Large-scale, Population-based Case-control Study. Chinese Medical Journal, 134(16): 1952–1958.
Shah D, Bentrem D, 2022, Environmental and Genetic Risk Factors for Gastric Cancer. Journal of Surgical Oncology, 125(7): 1096–1103.
Morgan E, Arnold M, Camargo MC, et al., 2022, The Current and Future Incidence and Mortality of Gastric Cancer in 185 Countries: A Population-based Modeling Study. eClinicalMedicine, 2022(47): 101404.
Sung H, Ferlay J, Siegel RL, et al., 2021, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3): 209–249.
Asplund J, Kauppila JH, Mattsson F, 2018, Survival Trends in Gastric Adenocarcinoma: A Population-based Study in Sweden. Annals of Surgical Oncology, 2018(25): 2693–2702.
Rogers JE, Ajani JA, 2023, Recent Advances in the Management of Gastric Adenocarcinoma Patients. Faculty Reviews, 2023(12): 2.
Ferlay J, Colombet M, Soerjomataram I, et al., 2021, Cancer Statistics for the Year 2020: An Overview. International Journal of Cancer, 149(4): 778–789.
Fitzmaurice C, Allen C, Barber RM, et al., 2017, Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived with Disability, and Disability-adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncology, 3(4): 524–548.
Ilic M, Ilic I, 2022, Epidemiology of Stomach Cancer. World Journal of Gastroenterology, 28(12): 1187–1203.
Sheffels E, Kortum RL, 2021, The Role of Wild-type RAS in Oncogenic RAS Transformation. Genes, 12(5): 662.
Kontomanolis EN, Koutras A, Syllaios A, et al., 2020, Role of Oncogenes and Tumor-suppressor Genes in Carcinogenesis: A Review. Anticancer Research, 40(11): 6009–6015.
Fernández-Medarde A, De Las Rivas J, Santos E, 2021, 40 Years of RAS: A Historic Overview. Genes, 12(5): 681.
Stalnecker CA, Der CJ, 2020, RAS, Wanted Dead or Alive: Advances in Targeting RAS Mutant Cancers. Science Signaling, 13(624): eaay6013.
Apken LH, Oeckinghaus A, 2021, The RAL Signaling Network: Cancer and Beyond. International Review of Cell and Molecular Biology, 2021(361): 21–105.
Timar J, Kashofer K, 2020, Molecular Epidemiology and Diagnostics of KRAS Mutations in Human Cancer. Cancer and Metastasis Reviews, 39(4): 1029–1038.
Won Y, Choi E, 2022, Mouse Models of Kras Activation in Gastric Cancer. Experimental & Molecular Medicine, 54(11): 1793–1798.
Zhou Y, Zeng Z, Li Z, et al., 2024, The Relationship of KRAS Expression with KRAS Status, Prognosis, and Tumor-infiltrated T Lymphocytes in Colorectal Cancer. Therapeutic Advances in Gastroenterology, 2024(17): 17562848241249387.
Pazik M, Zebrowska-Nawrocka M, Wosiak A, et al., 2023, Comprehensive Analysis of the Expression and Clinical Significance of RAS Family Members in Non-Small Cell Lung Cancer Based on Bioinformatics Data and the A549 Cell Line Model. Applied Sciences, 13(1): 166.
Polom K, Das K, Marrelli D, et al., 2019, KRAS Mutation in Gastric Cancer and Prognostication Associated with Microsatellite Instability Status. Pathology & Oncology Research, 25(1): 333–340.
Luo J, 2021, KRAS Mutation in Pancreatic Cancer. Seminars in Oncology, 48(1): 10–18.
Eklund EA, Wiel C, Fagman H, et al., 2022, KRAS Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer. Cancers, 14(9): 2063.
Chandrashekar DS, Karthikeyan SK, Korla PK, et al., 2022, UALCAN: An Update to the Integrated Cancer Data Analysis Platform. Neoplasia, 2022(25): 18–27.
Lanczky A, Gyorffy B, 2021, Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation. Journal of Medical Internet Research, 23(7): e27633.
Tang Z, Kang B, Li C, et al., 2019, GEPIA2: An Enhanced Web Server for Large-scale Expression Profiling and Interactive Analysis. Nucleic Acids Research, 47(W1): 556–560.
Ramos M, Geistlinger L, Oh S, et al., 2020, Multiomic Integration of Public Oncology Databases in Bioconductor. JCO Clinical Cancer Informatics, 2020(1): 958–971.
Szklarczyk D, Gable AL, Lyon D, et al., 2019, STRING v11: Protein-protein Association Networks with Increased Coverage, Supporting Functional Discovery in Genome-wide Experimental Datasets. Nucleic Acids Research, 47(D1): 607–613.
Sherman BT, Hao M, Qiu J, et al., 2022, DAVID: A Web Server for Functional Enrichment Analysis and Functional Annotation of Gene Lists (2021 Update). Nucleic Acids Research, 50(W1): 216–221.
Li T, Fu J, Zeng Z, et al., 2020, TIMER 2. 0 for Analysis of Tumor-infiltrating Immune Cells. Nucleic Acids Research, 48(W1): 509–514.
Wagner JR, Busche S, Ge B, et al., 2014, The Relationship between DNA Methylation, Genetic and Expression Inter-individual Variation in Untransformed Human Fibroblasts. Genome Biology, 2014(15): 1–17.
Alzahrani SM, Al Doghaither HA, Al-Ghafari AB, 2021, General Insight into Cancer: An Overview of Colorectal Cancer (Review). Molecular and Clinical Oncology, 15(6): 271.
Tuo JY, Bi JH, Yuan HY, et al., 2022, Trends of Stomach Cancer Survival: A Systematic Review of Survival Rates from Population-based Cancer Registration. Journal of Digestive Diseases, 23(1): 22–32.
Iwu CD, Iwu-Jaja CJ, 2023, Gastric Cancer Epidemiology: Current Trend and Future Direction. Hygiene, 3(3): 256–268.
Chhichholiya Y, Singh HV, Vashistha R, et al., 2024, Deciphering the Role of KRAS Gene in Oncogenesis: Focus on Signaling Pathways, Genetic Alterations in 3’UTR, KRAS Specific miRNAs and Therapeutic Interventions. Critical Reviews in Oncology/Hematology, 2024(194): 104250.
Huang L, Guo Z, Wang F, et al., 2021, KRAS Mutation: from Undruggable to Druggable in Cancer. Signal Transduction and Targeted Therapy, 6(1): 386.
Xiao C, Yang L, Jin L, et al., 2022, MAGEA11 as a STAD Prognostic Biomarker Associated with Immune Infiltration. Diagnostics, 12(10): 2506.
Yang Y, Gao Y, Liu XS, et al., 2024, FASTKD1 as a Diagnostic and Prognostic Biomarker for STAD: Insights into M6a Modification and Immune Infiltration. Experimental and Therapeutic Medicine, 28(2): 1–16.
Xiao R, Wang S, Guo J, et al., 2022, Ferroptosis-related Gene NOX4, CHAC1, and HIF1A are Valid Biomarkers for Stomach Adenocarcinoma. Journal of Cellular and Molecular Medicine, 26(4): 1183–1193.
Kolch W, Berta D, Rosta E, 2023, Dynamic Regulation of RAS and RAS Signaling. The Biochemical Journal, 480(1): 1–23.
Uribe ML, Marrocco I, Yarden Y, 2021, EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance. Cancers (Basel), 13(11): 2748.
Singh B, Kosuru R, Lakshmikanthan S, et al., 2021, Endothelial Rap1 (Ras-Association Proximate 1) Restricts Inflammatory Signaling to Protect from the Progression of Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 41(2): 638–650.