ANALYSIS OF COMMON SOMATIC MUTATIONS IN COLORECTAL CARCINOMA AND ASSOCIATED DYSREGULATED PATHWAYS
Keywords:Genetic mutations, Biological Pathways, insilico, BRAF, KRAS
AbstractBackground: Identification of gene targets and biological pathways involved in colorectal carcinoma (CRC) is essential for better management of patients. Our study aims to highlight common somatic mutations in colorectal carcinoma and to identify dysregulated pathways and gene enrichment based on KRAS and BRAF interaction network analysis. Methods: By using cancer browser tool in COSMIC database, mutation frequencies of the top 20 mutated genes listed for colorectal adenocarcinoma were identified. The most frequent variants of selected genes were explored with ClinVar database which led to identification of protein change along with its cytogenic location, variant type, variant length and the associated single nucleotide polymorphism (SNP). These identified SNPs were searched in Pakistani database using 1000genome in an attempt to identify common polymorphisms. Using the database ClinicalTrial.gov the number of clinical trials based upon these selected mutations was explored. Enrichment and protein interaction (PI) analysis of KRAS and BRAF was carried out to reveal significant biological pathways associated with these genes. Results: In cumulative data, among all variants about 57% of substitution mutations are observed to be G>A including mutations in KRAS, Tp53, SMAD4, PI3K and NRAS. The mutations of KRAS (c.35G>A), TP53 (c.524G>A) and APC (c.4348C>T) were found to be pathogenic with single nucleotide variation and variant length of 1bp. Searching 1000genome database revealed that 100 % of alleles found in East Asian population studied are ‘C’(frequency=1). Significant biological pathways (<0.05) identified by our search include Trk receptor signalling mediated by the MAPK pathway, signalling to p38 via RIT and RIN, signalling to ERKs, Frs2-mediated activation, ARMS-mediated activation and prolonged ERK activation events. Conclusion: Our study highlights the role of genetic profiling in CRC, with emphasis on mutations which may define treatment outcome. Targeting several collateral pathways simultaneously may be further explored to improve colorectal cancer therapeutics.
Peng J, Huang D, Poston G, Ma X, Wang R, Sheng W, et al. The molecular heterogeneity of sporadic colorectal cancer with different tumor sites in Chinese patients. Oncotarget 2017;8(30):49076.
Onyoh EF, Hsu WF, Chang LC, Lee YC, Wu MS, Chiu HM. The rise of colorectal cancer in Asia: epidemiology, screening, and management. Curr Gastroenterol Rep 2019;21(8):36.
Idrees R, Fatima S, Abdul-Ghafar J, Raheem A, Ahmad Z. Cancer prevalence in Pakistan: meta-analysis of various published studies to determine variation in cancer figures resulting from marked population heterogeneity in different parts of the country. World J Surg Oncol 2018;16(1):129.
Liao W, Overman MJ, Boutin AT, Shang X, Zhao D, Dey P, et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 2019;35(4):559–72.
Ladabaum U, Dominitz JA, Kahi C, Schoen RE. Strategies for colorectal cancer screening. Gastroenterology 2020;158(2):418–32.
Geng F, Wang Z, Yin H, Yu J, Cao B. Molecular targeted drugs and treatment of colorectal cancer: recent progress and future perspectives. Cancer Biother Radiopharm 2017;32(5):149–60.
Wang J, Shen J, Huang C, Cao M, Shen L. Clinicopathological significance of BRAFV600E mutation in colorectal cancer: an updated meta-analysis. J Cancer 2019;10(10):2332–41.
Li W, Qiu T, Guo L, Ying J, Zhou A. NGS-based oncogenic mutations analysis in advanced colorectal cancer patients improves targeted therapy prediction. Pathol Res Pract 2019;215(3):483–9.
Rachiglio AM, Lambiase M, Fenizia F, Roma C, Cardone C, Iannaccone A, et al. Genomic profiling of KRAS/NRAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patients reveals novel mutations in genes potentially associated with resistance to anti-EGFR agents. Cancers (Basel) 2019;11(6):859.
Isnaldi E, Garuti A, Cirmena G, Scabini S, Rimini E, Ferrando L, et al. Clinico-pathological associations and concomitant mutations of the RAS/RAF pathway in metastatic colorectal cancer. J Transl Med 2019;17(1):137.
Dienstmann R, Tabernero J. Spectrum of gene mutations in colorectal cancer: implications for treatment. Cancer J 2016;22(3):149–55.
Fanelli GN, Dal Pozzo CA, Depetris I, Schirripa M, Brignola S, Biason P, et al. The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer. Cancer Cell Int 2020;20(1):30.
van Brummelen EM, de Boer A, Beijnen JH, Schellens JH. BRAF mutations as predictive biomarker for response to anti‐EGFR monoclonal antibodies. Oncologist 2017;22(7):864–72.
Bond CE, Whitehall VL. How the BRAF V600E mutation defines a distinct subgroup of colorectal cancer: molecular and clinical implications. Gastroenterol Res Pract 2018;2018:9250757.
Wang Q, Shi YL, Zhou K, Wang LL, Yan ZX, Liu YL, et al. PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis 2018;9(7):739.
Fonseka P, Pathan M, Chitti SV, Kang T, Mathivanan S. FunRich enables enrichment analysis of OMICs datasets. J Mol Biol 2021;433(11):166747.
Nguyen LH, Goel A, Chung DC. Pathways of colorectal carcinogenesis. Gastroenterology 2020;158(2):291–302.
Kawada K, Toda K, Sakai Y. Targeting metabolic reprogramming in KRAS-driven cancers. Int J Clin Oncol 2017;22(4):651–9.
Guo F, Gong H, Zhao H, Chen J, Zhang Y, Zhang L, et al. Mutation status and prognostic values of KRAS, NRAS, BRAF and PIK3CA in 353 Chinese colorectal cancer patients. Sci Rep 2018;8(1):6076.
Ternet C, Kiel C. Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage. Cell Commun Signal 2021;19(1):31.
Sakamoto N, Feng Y, Stolfi C, Kurosu Y, Green M, Lin J, et al. "BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis." Elife 2017;6:e20331.
Barras D, Missiaglia E, Wirapati P, Sieber OM, Jorissen RN, Love C, et al. BRAF V600E mutant colorectal cancer subtypes based on gene expression. Clin Cancer Res 2017;23(1):104–15.
Morris VK, Bekaii-Saab T. Improvements in clinical outcomes for BRAFV600E-mutant metastatic colorectal cancer. Clin Cancer Res 2020;26(17):4435–41.
Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017;23(6):703–13.
Jones JC, Renfro LA, Al-Shamsi HO, Schrock AB, Rankin A, Zhang BY, et al. Non-V600BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol 2017;35(23):2624–30.
Sayagués JM, Del Carmen S, Abad MD, Corchete LA, Bengoechea O, Anduaga MF, et al. Combined assessment of the TNM stage and BRAF mutational status at diagnosis in sporadic colorectal cancer patients. Oncotarget 2018;9(35):24081.
Johnson B, Cooke L, Mahadevan D. Next generation sequencing identifies ‘interactome’signatures in relapsed and refractory metastatic colorectal cancer. J Gastrointest Oncol 2017;8(1):20–31.
Brandt R, Sell T, Lüthen M, Uhlitz F, Klinger B, Riemer P, et al. Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium. Nat Commun 2019;10(1):2919.
Suen KM, Lin CC, Seiler C, George R, Poncet-Montange G, Biter AB, Ahmed Z, Arold ST, Ladbury JE. Phosphorylation of threonine residues on Shc promotes ligand binding and mediates crosstalk between MAPK and Akt pathways in breast cancer cells. Int J Biochem Cell Biol 2018;94:89–97.
Cocco E, Schram AM, Kulick A, Misale S, Won HH, Yaeger R, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med 2019;25(9):1422–7.