Genetic Variation and Metabolic Basis of Kidney Cancer: New Opportunities for Targeted Therapy
https://doi.org/10.24060/2076-3093-2024-14-3-264-274
Abstract
Renal cell carcinoma (RCC) has previously been considered as a single disease. However, it is currently characterized as a heterogeneous group of tumors that differ in histological features, genetic abnormalities, and variable clinical course. In normal cells, energy is produced by the cleavage of chemical bonds in nutrients through the oxidation of fats, proteins, or carbohydrates. Mutational alterations in genes associated with RCC, including VHL, FLCN, PTEN and SDH, lead to abnormal cellular adaptation to changes in oxygen status, iron metabolism and nutrients. The present paper reviews the known genetic abnormalities observed in RCC and their impact on metabolic alterations. Understanding the genetic and metabolic mechanisms underlying RCC is crucial for the development of effective therapies. Targeting specific genetic abnormalities or metabolic pathways represents a promising approach to the RCC treatment. In addition, studies into the metabolic basis of RCC contribute to the development of new biomarkers for early diagnosis and monitoring of the disease. Moreover, investigating the role of VHL, FLCN, PTEN, and SDH genes in the development of RCC provides valuable information on the molecular mechanisms behind the disease. As a result, it may lead to the development of new treatment strategies aimed at restoring the normal function of these genes or compensating for their abnormalities. Overall, an integrated approach to the study of RCC that considers genetic, metabolic, and clinical aspects will ensure that more effective treatments are developed and prognosis for patients with this disease are improved.
About the Authors
M. F. UrmantsevRussian Federation
Marat F. Urmantsev — Cand. Sci. (Med.), Assoc. Prof., Department of Urology and Oncology
Ufa
R. I. Tavabilov
Russian Federation
Radmir I. Tavabilov — Resident, Department of Urology and Oncology
Ufa
M. R. Bakeev
Russian Federation
Marat R. Bakeev — 6th year Student
Ufa
References
1. Shakhzadova A.O., Starinsky V.V., Lisichnikova I.V. Cancer care to the population of Russia in 2022. Siberian Journal of Oncology. 2023;22(5):5–13 (In Russ.) DOI: 10.21294/1814-4861-2023-22-5-5-13
2. Chen T.Y., Mihalopoulos M., Zuluaga L., Rich J., Ganta T., Mehrazin R., et al. Clinical significance of extracellular vesicles in prostate and renal cancer. Int J Mol Sci. 2023;24(19):14713. DOI: 10.3390/ijms241914713
3. Myers M.R., Ravipati C., Thangam V. Artificial intelligence-based non-invasive differentiation of distinct histologic subtypes of renal tumors with multiphasic multidetector computed tomography. Cureus. 2024;16(4):e57959. DOI: 10.7759/cureus.57959
4. Sun Z., Qin X., Fang J., Tang Y., Fan Y. Multi-omics analysis of the expression and prognosis for FKBP gene family in renal cancer. Front Oncol. 2021;11:697534. DOI: 10.3389/fonc.2021.697534
5. Curry L., Soleimani M. Belzutifan: a novel therapeutic for the management of von Hippel-Lindau disease and beyond. Future Oncol. 2024;20(18):1251–66. DOI: 10.2217/fon-2023-0679
6. Bender D.A., Mayes P.A. Chapter 18. Glycosis and the oxidation of pyruvate. In: Bender D.A., Botham K.M., Weil P.A., Kennelly P.J., Murray R.K., Rodwell V.W. (eds). Harper’s Illustrated Biochemistry. New York: McGraw-Hill; 2011.
7. Linehan W.M., Ricketts C.J. The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol. 2019;16(9):539–52. DOI: 10.1038/s41585-019-0211-5
8. Walter-Rodriguez B., Ricketts C.J., Linehan W.M., Merino M.J. Evaluating the urinary exosome microRNA profile of von hippel lindau syndrome patients with clear cell renal cell carcinoma. Genes (Basel). 2024;15(7):905. DOI: 10.3390/genes15070905
9. Fukushi A., Kim H.D., Chang Y.C., Kim C.H. Revisited metabolic control and reprogramming cancers by means of the warburg effect in tumor cells. Int J Mol Sci. 2022;23(17):10037. DOI: 10.3390/ijms231710037
10. Ding C., Song Z., Shen A., Chen T., Zhang A. Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway. Acta Pharm Sin B. 2020;10(12):2272–98. DOI: 10.1016/j.apsb.2020.03.001
11. Azimi F., Naseripour M., Aghajani A., Kasraei H., Chaibakhsh S. The genetic differences between types 1 and 2 in von HippelLindau syndrome: comprehensive meta-analysis. BMC Ophthalmol. 2024;24(1):343. DOI: 10.1186/s12886-024-03597-1
12. Zhu H., Wang X., Lu S., Ou K. Metabolic reprogramming of clear cell renal cell carcinoma. Front Endocrinol (Lausanne). 2023;14:1195500. DOI: 10.3389/fendo.2023.1195500
13. Sellner F., Compérat E., Klimpfinger M. Genetic and epigenetic characteristics in isolated pancreatic metastases of clear-cell renal cell carcinoma. Int J Mol Sci. 2023;24(22):16292. DOI: 10.3390/ijms242216292
14. Liu S. Bioinformatics analysis identifies GLUD1 as a prognostic indicator for clear cell renal cell carcinoma. Eur J Med Res. 2024;29(1):70. DOI: 10.1186/s40001-024-01649-2
15. Eberhart T., Schönenberger M.J., Walter K.M., Charles K.N., Faust P.L., Kovacs W.J. Peroxisome-deficiency and HIF-2α signaling are negative regulators of ketohexokinase expression. Front Cell Dev Biol. 2020;8:566. DOI: 10.3389/fcell.2020.00566
16. Chakraborty A.A. Coalescing lessons from oxygen sensing, tumor metabolism, and epigenetics to target VHL loss in kidney cancer. Semin Cancer Biol. 2020;67(Pt 2):34–42. DOI: 10.1016/j.semcancer.2020.03.012
17. Ricketts C.J., De Cubas A.A., Fan H., Smith C.C., Lang M., Reznik E., et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2024;43(4):113063. DOI: 10.1016/j.celrep.2023.113063
18. Kinslow C.J., Ll M.B., Cai Y., Yan J., Lorkiewicz P.K., Al-Attar A., et al. Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient. Metabolomics. 2024;20(4):87. DOI: 10.1007/s11306-024-02126-x
19. Kotecha R.R., Knezevic A., Arora K., Bandlamudi C., Kuo F., Carlo M.I., et al. Genomic ancestry in kidney cancer: Correlations with clinical and molecular features. Cancer. 2024;130(5):692–701. DOI: 10.1002/cncr.35074
20. Grimm F., Asuaje A., Jain A., Silva Dos Santos M., Kleinjung J., Nunes P.M., et al. Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia. EMBO J. 2024;43(8):1545–69. DOI: 10.1038/s44318-024-00065-w
21. Hao Y., Yi Q., XiaoWu X., WeiBo C., GuangChen Z., XueMin C. Acetyl-CoA: An interplay between metabolism and epigenetics in cancer. Front Mol Med. 2022;2:1044585. DOI: 10.3389/fmmed.2022.1044585
22. Culliford R., Lawrence S.E.D., Mills C., Tippu Z., Chubb D., Cornish A.J., et al. Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma. Nat Commun. 2024;15(1):5935. DOI: 10.1038/s41467-024-49692-1
23. Xing Z., Cui L., Feng Y., Yang Y., He X. Exploring the prognostic implications of cuproptosis-associated alterations in clear cell renal cell carcinoma via in vitro experiments. Sci Rep. 2024;14(1):16935. DOI: 10.1038/s41598-024-67756-6
24. Jokelainen O., Rintala T.J., Fortino V., Pasonen-Seppänen S., Sironen R., Nykopp T.K. Differential expression analysis identifies a prognostically significant extracellular matrix-enriched gene signature in hyaluronan-positive clear cell renal cell carcinoma. Sci Rep. 2024;14(1):10626. DOI: 10.1038/s41598-024-61426-3
25. Pichler R., Siska P.J., Tymoszuk P., Martowicz A., Untergasser G., Mayr R., et al. A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma. Front Immunol. 2023;14:1095195. DOI: 10.3389/fimmu.2023.1095195
26. Tang H., Xu W., Lu J., Anwaier A., Ye D., Zhang H. Heterogeneity and function of cancer-associated fibroblasts in renal cell carcinoma. J Natl Cancer Cent. 2023;3(2):100–5. DOI: 10.1016/j.jncc.2023.04.001
27. Considine B., Hurwitz M.E. Current status and future directions of immunotherapy in renal cell carcinoma. Curr Oncol Rep. 2019;21(4):34. DOI: 10.1007/s11912-019-0779-1
28. Webster B.R., Gopal N., Ball M.W. Tumorigenesis mechanisms found in hereditary renal cell carcinoma: a review. Genes (Basel). 2022;13(11):2122. DOI: 10.3390/genes13112122
29. Testa U., Pelosi E., Castelli G. Genetic alterations in renal cancers: identification of the mechanisms underlying cancer initiation and progression and of therapeutic targets. Medicines (Basel). 2020;7(8):44. DOI: 10.3390/medicines7080044
30. Naik P., Dudipala H., Chen Y.W., Rose B., Bagrodia A., McKay R.R. The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma. Ther Adv Urol. 2024;16:17562872241232578. DOI: 10.1177/17562872241232578
31. Guérin C., Tulasne D. Recording and classifying MET receptor mutations in cancers. Elife. 2024;13:e92762. DOI: 10.7554/eLife.92762
32. Lee T.S., Kim J.Y., Lee M.H., Cho I.R., Paik W.H., Ryu J.K., et al. Savolitinib: a promising targeting agent for cancer. Cancers (Basel). 2023;15(19):4708. DOI: 10.3390/cancers15194708
33. Koh C., Wong M., Tay S.B. Renal cell tumor and cystic lung disease: a genetic link for generalists to be aware of. Cureus. 2023;15(8):e43572. DOI: 10.7759/cureus.43572
34. Yanus G.A., Kuligina E.S., Imyanitov E.N. Hereditary renal cancer syndromes. Med Sci (Basel). 2024;12(1):12. DOI: 10.3390/medsci12010012
35. Miao J., Gao Q., Wang Z., Hou G. Familial pulmonary cysts: A clue to diagnose Birt-Hogg-Dubé syndrome: A case report and literature review. Respirol Case Rep. 2024;12(3):e01319. DOI: 10.1002/rcr2.1319
36. Bandini E., Zampiga V., Cangini I., Ravegnani M., Arcangeli V., Rossi T., et al. A novel FLCN variant in a suspected Birt-Hogg-Dubè syndrome patient. Int J Mol Sci. 2023;24(15):12418. DOI: 10.3390/ijms241512418
37. Singh S., Chaurasia A., Gopal N., Malayeri A., Ball M.W. Treatment strategies for hereditary kidney cancer: current recommendations and updates. Discov Med. 2022;34(173):205–20. PMID: 36602871
38. Di Malta C., Zampelli A., Granieri L., Vilardo C., De Cegli R., Cinque L., et al. TFEB and TFE3 drive kidney cystogenesis and tumorigenesis. EMBO Mol Med. 2023;15(5):e16877. DOI: 10.15252/emmm.202216877
39. Alesi N., Khabibullin D., Rosenthal D.M., Akl E.W., Cory P.M., Alchoueiry M., et al. TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex. Nat Commun. 2024;15(1):406. DOI: 10.1038/s41467-023-44229-4
40. Webster B.R., Gopal N., Ball M.W. Tumorigenesis mechanisms found in hereditary renal cell carcinoma: a review. Genes (Basel). 2022;13(11):2122. DOI: 10.3390/genes13112122
41. Andersen U.O., Rosenørn M.R., Homøe P. Recurrent multifocal adult rhabdomyoma in an elderly woman diagnosed with Birt-Hogg-Dubé syndrome: A case report. Front Surg. 2022;9:1017725. DOI: 10.3389/fsurg.2022.1017725. Erratum in: Front Surg. 2022;9:1058498. DOI: 10.3389/fsurg.2022.1058498
42. Atsukawa N., Yagi T., Kubo C., Nakanishi K., Osuga K. Birt-HoggDubé syndrome with renal cancer treated as multiple metastases of cancer of unknown primary. Intern Med. 2021;60(18):3047–50. DOI: 10.2169/internalmedicine.6309-20
43. Coffey N.J., Simon M.C. Metabolic alterations in hereditary and sporadic renal cell carcinoma. Nat Rev Nephrol. 2024;20(4):233–50. DOI: 10.1038/s41581-023-00800-2
44. Xiao L., Yin Y., Sun Z., Liu J., Jia Y., Yang L., et al. AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Sci Adv. 2024;10(6):eadj2752. DOI: 10.1126/sciadv.adj2752
45. Broome S.C., Whitfield J., Karagounis L.G., Hawley J.A. Mitochondria as nutritional targets to maintain muscle health and physical function during ageing. Sports Med. 2024 Jul 26. DOI: 10.1007/s40279-024-02072-7
46. De Bock T., Brussaard C., François S., François K., Seynaeve L., Jansen A., et al. Prevalence of liver steatosis in tuberous sclerosis complex patients: a retrospective cross-sectional study. J Clin Med. 2024;13(10):2888. DOI: 10.3390/jcm13102888
47. Wu F., Mukai S. Refractory choroidal neovascularization in a patient with pseudoxanthoma elasticum and cowden syndrome. J Vitreoretin Dis. 2022;7(1):70–3. DOI: 10.1177/24741264221117013
48. Osman H.A., Hassan M.H., Toema A.M., Abdelnaby A.A., Abozeid M.A., Mohamed M.A., et al. Prognostic role of immunohistochemical PTEN (phosphatase and tensin homolog) expression and PTEN (rs701848) genotypes among Egyptian patients with different stages of colorectal cancer. J Cancer. 2024;15(15):5046–57. DOI: 10.7150/jca.97553
49. Li H., Wen X., Ren Y., Fan Z., Zhang J., He G., et al. Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions. Mol Cancer. 2024;23(1):164. DOI: 10.1186/s12943-024-02072-1
50. Kim J.W., Shin J.W., Cho A., Huh C.H. Hereditary leiomyomatosis and renal cell cancer: a case report of pilar leiomyomatosis with history of kidney cancer and review of the literature. Ann Dermatol. 2023;35(Suppl 1):S14–8. DOI: 10.5021/ad.20.287
51. Ono A., Nakamura M., Takada T., Miura S., Tsuru I., Izumi T., et al. Bilateral fumarate hydratase deficient renal cell carcinoma in a patient with hereditary leiomyomatosis and renal cell cancer syndrome. IJU Case Rep. 2024;7(2):144–7. DOI: 10.1002/iju5.12688
52. Sun X., Wang G., Huang Z., Li P., Yang B., Wang T., et al. Succinate dehydrogenase defects giant renal cell carcinoma. Urol Int. 2023;107(8):819–22. DOI: 10.1159/000531059
53. Gobelli D., Serrano-Lorenzo P., Esteban-Amo M.J., Serna J., PérezGarcía M.T., Orduña A., et al. The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages. iScience. 2023;26(8):107473. DOI: 10.1016/j.isci.2023.107473
54. Liao M., Yao D., Wu L., Luo C., Wang Z., Zhang J., et al. Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer. Acta Pharm Sin B. 2024;14(3):953–1008. DOI: 10.1016/j.apsb.2023.12.003
55. De Martino M., Rathmell J.C., Galluzzi L., Vanpouille-Box C. Cancer cell metabolism and antitumour immunity. Nat Rev Immunol. 2024 Apr 22. DOI: 10.1038/s41577-024-01026-4. Erratum in: Nat Rev Immunol. 2024;24(7):537. DOI: 10.1038/s41577-024-01051-3
56. Grimm F., Asuaje A., Jain A., Silva Dos Santos M., Kleinjung J., Nunes P.M., et al. Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia. EMBO J. 2024;43(8):1545–69. DOI: 10.1038/s44318-024-00065-w
57. Wu K.K. Extracellular succinate: a physiological messenger and a pathological trigger. Int J Mol Sci. 2023;24(13):11165. DOI: 10.3390/ijms241311165
58. Ferreira A.V., Domínguez-Andrés J., Merlo Pich L.M., Joosten L.A.B., Netea M.G. Metabolic regulation in the induction of trained immunity. Semin Immunopathol. 2024;46(3–4):7. DOI: 10.1007/s00281-024-01015-8
59. Valcarcel-Jimenez L., Frezza C. Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism. Br J Cancer. 2023;129(10):1546–57. DOI: 10.1038/s41416-023-02412-w
60. Shim E.H., Livi C.B., Rakheja D., Tan J., Benson D., Parekh V., et al. L- 2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 2014;4:1290–8. DOI: 10.1158/2159-8290.CD-13-0696
61. Sullivan L.B., Martinez-Garcia E., Nguyen H., Mullen A.R., Dufour E., Sudarshan S., et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol Cell. 2013;51:236–48. DOI: 10.1016/j.molcel.2013.05.003
62. Zheng L., Cardaci S., Jerby L., MacKenzie E.D., Sciacovelli M., Johnson T.I., et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat Commun. 2015;6:6001. DOI: 10.1038/ncomms7001
63. Danziger M., Xu F., Noble H., Yang P., Roque D.M. Tubulin complexity in cancer and metastasis. Adv Exp Med Biol. 2024;1452:21–35. DOI: 10.1007/978-3-031-58311-7_2
64. 64. Bardella C., El-Bahrawy M., Frizzell N., Adam J., Ternette N., Hatipoglu E., et al. Aberrant succination of proteins in fumarate hydratasedeficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol 2011;225:4–11. DOI: 10.1002/path.2932
Review
For citations:
Urmantsev M.F., Tavabilov R.I., Bakeev M.R. Genetic Variation and Metabolic Basis of Kidney Cancer: New Opportunities for Targeted Therapy. Creative surgery and oncology. 2024;14(3):264-274. (In Russ.) https://doi.org/10.24060/2076-3093-2024-14-3-264-274