Keywords
Diagnosis
Treatment
Biomarker
Submitted : 2024-12-04
Accepted : 2024-12-19
Published : 2025-01-03
Abstract
Rationale: The tumor suppressor FLCN gene mutations are the primary cause of the rare autosomal recessive genetic disorder known as Birt-Hogg-Dubé (BHD) syndrome. Early diagnosis of BHD is difficult since FLCN mutation-caused tumors can form in the skin, lungs, kidney, and other organs and are benign. These tumors generate a range of phenotypes. Methods: The UALCAN database was utilized to ascertain FLCN expression and methylation in LUAD. Additionally, using KM plotter, GEPIA2.0, and cBioPortal, respectively, the survival, validity, and mutation analysis of FLCN was ascertained in LUAD. Using STRING and DAVID tools, the pathway and gene enrichment were identified in the presence of FLCN. The muTarget database was used to identify the mutant genes. Results: The goal of the current study is to examine FLCN expression in LUAD tissues. In these patients with LUAD, the study compared the expression of FLCN to other clinic-pathological characteristics. When comparing LUAD patients’ clinical parameters to those of normal control samples, FLCN expression was higher. Additionally, it was discovered that a higher expression of FLCN in LUAD patients was linked to a shorter overall and disease-free survival. Results of gene ontology and pathway analysis demonstrated that genes linked with FLCN are significantly co-expressed with FLCN and are involved in a wide range of distinct molecular functions, biological processes, and pathways. FLCN expression was also correlated with promoter methylation levels, genetic alterations, other mutant genes. This crucial information demonstrated the important function that FLCN plays in the initiation and expansion of LUAD. Conclusion: This research emphasizes how crucial genetic analysis is to the diagnosis and the therapeutic treatment of LUAD.
References
Siegel RL, Miller KD, Jemal A, 2020, Cancer Statistics, 2020. CA: Cancer Journal for Clinicians, 70(1): 7–30.
Bray F, Ferlay J, Soerjomataram I, et al., 2018, Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer Journal for Clinicians, 68(6): 394–424.
Chen W, Zheng R, Baade PD, et al., 2016, Cancer Statistics in China, 2015. CA: Cancer Journal for Clinicians, 66(2): 115–132.
Herbst RS, Heymach JV, Lippman SM, 2008, Lung Cancer. The New England Journal of Medicine, 359(13): 1367–1380.
Chen Z, Fillmore CM, Hammerman PS, et al., 2014, Non-Small-Cell Lung Cancers: A Heterogeneous Set of Diseases. Nature Reviews Cancer, 14(8): 535–546.
Ucvet A, Yazgan S, Gursoy S, et al., 2020, Prognosis of Resected Non-Small Cell Lung Cancer with Ipsilateral Pulmonary Metastasis. Journal of Thoracic and Cardiovascular Surgery, 68(2): 176–182.
Ariozzi I, Paladini I, Gnetti L, et al., 2013, Computed Tomography-Histologic Correlations in Lung Cancer. Pathologica, 105(6): 329–336.
Kozielski J, Kaczmarczyk G, Porębska I, et al., 2012, Lung Cancer in Patients under the Age of 40 Years. Contemporary Oncology, 16(5): 413–415.
Kobayashi Y, Mitsudomi T, 2016, Not All Epidermal Growth Factor Receptor Mutations in Lung Cancer Are Created Equal: Perspectives for Individualized Treatment Strategy. Cancer Science, 107(9): 1179–1186.
Karachaliou N, Santarpia M, Gonzalez CM, et al., 2017, Anaplastic Lymphoma Kinase Inhibitors in Phase I and Phase II Clinical Trials for Non-Small Cell Lung Cancer. Expert Opinion on Investigational Drugs, 26(6): 713–722.
Sacco JJ, Al-Akhrass H, Wilson CM, 2016, Challenges and Strategies in Precision Medicine for Non-Small-Cell Lung Cancer. Current Pharmaceutical Design, 22(28): 4374–4385.
Lin JJ, Riely GJ, Shaw AT, 2017, Targeting ALK: Precision Medicine Takes on Drug Resistance. Cancer Discovery, 7(2): 137–155.
Zhang YL, Yuan JQ, Wang KF, et al., 2016, The Prevalence of EGFR Mutation in Patients with Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Oncotarget, 7(48): 78985–78993.
Zhou X, Shou J, Sheng J, et al., 2019, Molecular and Clinical Analysis of Chinese Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer. Cancer Science, 110(10): 3382–3390.
Schmidt LS, Linehan WM, 2018, FLCN: The Causative Gene for Birt-Hogg-Dubé Syndrome. Gene, 640: 28–42.
Nickerson ML, Warren MB, Toro JR, et al., 2002, Mutations in a Novel Gene Lead to Kidney Tumors, Lung Wall Defects, and Benign Tumors of the Hair Follicle in Patients with the Birt-Hogg-Dubé Syndrome. Cancer Cell, 2(2): 157–164.
Furuya M, Yao M, Tanaka R, et al., 2016, Genetic, Epidemiologic and Clinicopathologic Studies of Japanese Asian Patients with Birt-Hogg-Dubé Syndrome. Clinical Genetics, 90(5): 403–412.
Hasumi H, Baba M, Hasumi Y, et al., 2016, Birt-Hogg-Dubé Syndrome: Clinical and Molecular Aspects of Recently Identified Kidney Cancer Syndrome. International Journal of Urology, 23(3): 204–210.
Schmidt LS, Linehan WM, 2015, Molecular Genetics and Clinical Features of Birt–Hogg–Dubé Syndrome. Nature Reviews Urology, 12(10): 558–569.
Pavlovich CP, Walther MM, Eyler RA, et al., 2002, Renal Tumors in the Birt-Hogg-Dubé Syndrome. The American Journal of Surgical Pathology, 26(12): 1542–1552.
Houweling AC, Gijezen LM, Jonker MA, et al., 2011, Renal Cancer and Pneumothorax Risk in Birt–Hogg–Dubé Syndrome; an Analysis of 115 FLCN Mutation Carriers From 35 BHD Families. British Journal of Cancer, 105(12): 1912–1919.
Schmidt LS, Nickerson ML, Warren MB, et al., 2005, Germline BHD-Mutation Spectrum and Phenotype Analysis of a Large Cohort of Families With Birt-Hogg-Dube Syndrome. The American Journal of Human Genetics, 76(6): 1023–1033.
Toro JR, Wei MH, Glenn GM, et al., 2008, BHD Mutations, Clinical and Molecular Genetic Investigations of Birt–Hogg–Dubé Syndrome: A New Series of 50 Families and a Review of Published Reports. Journal of Medical Genetics, 45(6): 321–331.
Chandrashekar DS, Bashel B, Balasubramanya SAH, et al., 2017, UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia, 19(8): 649–658.
Maciejczyk A, Szelachowska J, Czapiga B, et al., 2013, Elevated BUBR1 Expression is Associated With Poor Survival in Early Breast Cancer Patients: 15-Year Follow-Up Analysis. Journal of Histochemistry and Cytochemistry, 61(5): 330–339.
Tang Z, Li C, Kang B, et al., 2017, GEPIA: A Web Server for Cancer and Normal Gene Expression Profiling and Interactive Analyses. Nucleic Acids Research, 45(W1): W98–W102.
Cerami E, Gao J, Dogrusoz U, et al., 2012, The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery, 2(5): 401–404.
Mering C, Huynen M, Jaeggi D, et al., 2003, STRING: A Database of Predicted Functional Associations Between Proteins. Nucleic Acids Research, 31(1): 258–261.
Huang DW, Sherman BT, Tan Q, et al., 2007, The DAVID Gene Functional Classification Tool: A Novel Biological Module-Centric Algorithm to Functionally Analyze Large Gene Lists. Genome Biology, 8(9): 2007–2008.
Nagy Á, Győrffy B, 2021, muTarget: A Platform Linking Gene Expression Changes and Mutation Status in Solid Tumors. International Journal of Cancer, 148(2): 502–511.
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al., 2013, Cancer Incidence and Mortality Patterns in Europe: Estimates for 40 Countries in 2012. European Journal of Cancer, 49(6): 1374–1403.
Arbour KC, Riely GJ, 2019, Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review. JAMA, 322(8): 764–774.
Li L, Yang L, Fan Z, et al., 2020, Hypoxia-Induced GBE1 Expression Promotes Tumor Progression Through Metabolic Reprogramming in Lung Adenocarcinoma. Signal Transduction and Targeted Therapy, 5(1): 54.
Li H, Tong L, Tao H, et al., 2020, Genome-Wide Analysis of the Hypoxia-Related DNA Methylation-Driven Genes in Lung Adenocarcinoma Progression. Bioscience Reports, 40(2): BSR20194200.
Zhao M, Zhang Y, Zhang H, et al., 2015, Hypoxia-Induced Cell Stemness Leads to Drug Resistance and Poor Prognosis in Lung Adenocarcinoma. Lung Cancer, 87(2): 98–106.
Lim DH, Rehal PK, Nahorski MS, et al., 2010, A New Locus-Specific Database (LSDB) for Mutations in the Folliculin (FLCN) Gene. Human Mutation, 31(1): 21130.
Gad S, Lefèvre SH, Khoo SK, et al., 2007, Mutations in BHD and TP53 Genes, but not in HNF1beta Gene, in a Large Series of Sporadic Chromophobe Renal Cell Carcinoma. British Journal of Cancer, 96(2): 336–340.
Okimoto K, Sakurai J, Kobayashi T, et al., 2004, A Germ-Line Insertion in the Birt-Hogg-Dubé (BHD) Gene Gives Rise to the Nihon Rat Model of Inherited Renal Cancer. Proceedings of the National Academy of Sciences of the United States of America, 101(7): 2023–2027.
Baba M, Furihata M, Hong SB, et al., 2008, Kidney-Targeted Birt-Hogg-Dube Gene Inactivation in a Mouse Model: Erk1/2 and Akt-mTOR Activation, Cell Hyperproliferation, and Polycystic Kidneys. Journal of the National Cancer Institute, 100(2): 140–154.
Chen J, Futami K, Petillo D, et al., 2008, Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia. PLOS One, 3(10): 30.