Novel somatic mutations of <em>PIK3CA</em> in patients with colorectal cancer

Vatte,Chittibabu; Cyrus,Cyril; Chathoth,Shahanas; Alsayyah,Ahmed; Aldossary,Nada Jaber; Albisher,Hassan Mohammed; Alali,Rudaynah A.; Alrubaish,Mohammed Abdullah; Al Amri,Ali M.

doi:10.3892/wasj.2025.335

May-June 2025 Volume 7 Issue 3

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May-June 2025 Volume 7 Issue 3

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Article Open Access

Novel somatic mutations of PIK3CA in patients with colorectal cancer

Authors:
- Chittibabu Vatte
- Cyril Cyrus
- Shahanas Chathoth
- Ahmed Alsayyah
- Nada Jaber Aldossary
- Hassan Mohammed Albisher
- Rudaynah A. Alali
- Mohammed Abdullah Alrubaish
- Ali M. Al Amri
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Affiliations: Department of Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Kingdom of Saudi Arabia, Department of Pathology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Al Khobar 34445, Kingdom of Saudi Arabia, Department of General Surgery, College of Medicine, Imam Abdulrahman Bin Faisal University, Al Khobar 34445, Kingdom of Saudi Arabia, Department of Internal Medicine, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Al Khobar 34445, Kingdom of Saudi Arabia, Department of Ophthalmology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Al Khobar 34445, Kingdom of Saudi Arabia

Copyright: © Vatte et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
Article Number: 47
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Published online on: March 18, 2025

https://doi.org/10.3892/wasj.2025.335
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Abstract

Colorectal cancer (CRC) is a heterogenous disease with varying genetic and epigenetic backgrounds. The phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA) gene encodes for the catalytic subunit p110α of phosphatidylinositol 3‑kinase (PI3K). Determining the frequency of PIK3CA mutations in CRC in different populations may enhance the current understanding of the pathogenicity of CRC and may aid in the prognosis of affected patients. The present study included 71 male and female patients with clinically confirmed CRC (58 colon cancer cases and 13 rectal cancer cases). Mutations in exon 9 and 20 of the PIK3CA gene were identified using Sanger capillary sequencing. A total of 6 patients carried mutations in either exon 9 or 20 of the PIK3CA gene. The majority of the colon tumors (83.3%) with the PIK3CA mutation presented at an advanced stage of the disease and the mutations were found more frequently among women (66.6%). All missense mutations (E545A and L1001V) and novel mutations (two) were only observed in the samples from female patients. The two novel PIK3CA gene mutations that were identified in the present study are a missense mutation leading to a c.3001C>G, p.L1001V amino acid change and a nonsense mutation c.3153 G>A, W1051Ter leading to protein termination in exon 20. The patients with these mutations presented with a poor prognosis. The novel mutations identified in the kinase domain of PIK3CA may induce the hyperactivation of the protein in the PI3K pathway, leading to a poor prognosis. CRC screening is recommended at an early age (>40 years) for all patients, but particularly for females who carry these mutations.

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1	Kuipers EJ, Grady WM, Lieberman D, Seufferlein T, Sung JJ, Boelens PG, van de Velde CJH and Watanabe T: Colorectal cancer. Nat Rev Dis Primers. 1(15065)2015.PubMed/NCBI View Article : Google Scholar
2	Hossain MS, Karuniawati H, Jairoun AA, Urbi Z, Ooi J, John A, Lim YC, Kibria KMK, Mohiuddin AKM, Ming LC, et al: Colorectal cancer: A review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers (Basel). 14(1732)2022.PubMed/NCBI View Article : Google Scholar
3	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar
4	Saudi Health Council, National Cancer Center and Saudi Cancer Registry: Cancer incidence report from Saudi Arabia 2018. Saudi Health Council, 2022. https://shc.gov.sa/Arabic/NCC/Activities/AnnualReports/2018.pdf. Accessed July 23, 2023.
5	World Health Organization (WHO): Cancer Saudi Arabia 2020 country profile. WHO, Geneva, 2020. https://cdn.who.int/media/docs/default-source/country-profiles/cancer/sau-2020.pdf?sfvrsn=37936f36_2&download=true. Accessed July 23, 2023.
6	Messersmith WA: NCCN guidelines updates: Management of metastatic colorectal cancer. J Natl Compr Canc Netw. 17:599–601. 2019.PubMed/NCBI View Article : Google Scholar
7	Keum N and Giovannucci E: Global burden of colorectal cancer: Emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 16:713–732. 2019.PubMed/NCBI View Article : Google Scholar
8	Xie YH, Chen YX and Fang JY: Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 5(22)2020.PubMed/NCBI View Article : Google Scholar
9	Triantafillidis JK, Nasioulas G and Kosmidis PA: Colorectal cancer and inflammatory bowel disease: Epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res. 29:2727–2737. 2009.PubMed/NCBI
10	Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, Jemal A, Schymura MJ, Lansdorp-Vogelaar I, Seeff LC, et al: Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 116:544–573. 2010.PubMed/NCBI View Article : Google Scholar
11	Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012.PubMed/NCBI View Article : Google Scholar
12	Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, et al: Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American society for clinical pathology, college of American pathologists, association for molecular pathology, and American society of clinical oncology. Arch Pathol Lab Med. 141:625–657. 2017.PubMed/NCBI View Article : Google Scholar
13	Krasinskas AM: EGFR signaling in colorectal carcinoma. Patholog Res Int. 2011(932932)2011.PubMed/NCBI View Article : Google Scholar
14	Novellasdemunt L, Antas P and Li VS: Targeting Wnt signaling in colorectal cancer. A review in the theme: Cell signaling: Proteins, pathways and mechanisms. Am J Physiol Cell Physiol. 309:C511–C521. 2015.PubMed/NCBI View Article : Google Scholar
15	Malapelle U, Pisapia P, Sgariglia R, Vigliar E, Biglietto M, Carlomagno C, Giuffrè G, Bellevicine C and Troncone G: Less frequently mutated genes in colorectal cancer: Evidences from next-generation sequencing of 653 routine cases. J Clin Pathol. 69:767–771. 2016.PubMed/NCBI View Article : Google Scholar
16	Inamura K: Colorectal Cancers: An update on their molecular pathology. Cancers (Basel). 10(26)2018.PubMed/NCBI View Article : Google Scholar
17	Zhou R, Huang Y, Cheng B, Wang Y and Xiong B: TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells. Oncol Lett. 15:3971–3976. 2018.PubMed/NCBI View Article : Google Scholar
18	Koveitypour Z, Panahi F, Vakilian M, Peymani M, Seyed Forootan F, Nasr Esfahani MH and Ghaedi K: Signaling pathways involved in colorectal cancer progression. Cell Biosci. 9(97)2019.PubMed/NCBI View Article : Google Scholar
19	Kwak MS, Cha JM, Yoon JY, Jeon JW, Shin HP, Chang HJ, Kim HK, Joo KR and Lee JI: Prognostic value of KRAS codon 13 gene mutation for overall survival in colorectal cancer: Direct and indirect comparison meta-analysis. Medicine (Baltimore). 96(e7882)2017.PubMed/NCBI View Article : Google Scholar
20	De Roock W, De Vriendt V, Normanno N, Ciardiello F and Tejpar S: KRAS, BRAF, PIK3CA, and PTEN mutations: Implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 12:594–603. 2011.PubMed/NCBI View Article : Google Scholar
21	Hamada T, Nowak JA and Ogino S: PIK3CA mutation and colorectal cancer precision medicine. Oncotarget. 8:22305–22306. 2017.PubMed/NCBI View Article : Google Scholar
22	Samuels Y and Waldman T: Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol. 347:21–41. 2010.PubMed/NCBI View Article : Google Scholar
23	Al-Amri AM, Vatte C, Cyrus C, Chathoth S, Hashim TM, Mohamed YS, Al Ali R, Alsaid A and Al Ali A: Novel mutations of PIK3CA gene in head and neck squamous cell carcinoma. Cancer Biomark. 16:377–383. 2016.PubMed/NCBI View Article : Google Scholar
24	Vatte C, Al Amri AM, Cyrus C, Chathoth S, Alsayyah A, Ahmad A, Akhtar MS, Alrashidi NF, Jayaseeli N, Al Wadani H, et al: Helical and kinase domain mutations of PIK3CA, and their association with hormone receptor expression in breast cancer. Oncol Lett. 18:2427–2433. 2019.PubMed/NCBI View Article : Google Scholar
25	Qiu W, Tong GX, Manolidis S, Close LG, Assaad AM and Su GH: Novel mutant-enriched sequencing identified high frequency of PIK3CA mutations in pharyngeal cancer. Int J Cancer. 122:1189–1194. 2008.PubMed/NCBI View Article : Google Scholar
26	Xi Y and Xu P: Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol. 14(101174)2021.PubMed/NCBI View Article : Google Scholar
27	Lu XQ, Li Y, Wang W, Feng WT, Shi OM and Wang Q: International incidence trends in early- and late-onset colorectal cancer: A population-based study. Int J Colorectal Dis. 35:1077–1086. 2020.PubMed/NCBI View Article : Google Scholar
28	Saad El Din K, Loree JM, Sayre EC, Gill S, Brown CJ, Dau H and De Vera MA: Trends in the epidemiology of young-onset colorectal cancer: A worldwide systematic review. BMC Cancer. 20(288)2020.PubMed/NCBI View Article : Google Scholar
29	Zaborowski AM, Murphy B, Creavin B, Rogers AC, Kennelly R, Hanly A, Martin ST, O'Connell PR, Sheahan K and Winter DC: Clinicopathological features and oncological outcomes of patients with young-onset rectal cancer. Br J Surg. 107:606–612. 2020.PubMed/NCBI View Article : Google Scholar
30	Dekker E, Tanis PJ, Vleugels JLA, Kasi PM and Wallace MB: Colorectal cancer. Lancet. 394:1467–1480. 2019.PubMed/NCBI View Article : Google Scholar
31	Ogino S, Chan AT, Fuchs CS and Giovannucci E: Molecular pathological epidemiology of colorectal neoplasia: An emerging transdisciplinary and interdisciplinary field. Gut. 60:397–411. 2011.PubMed/NCBI View Article : Google Scholar
32	Reddy D, Ghosh P and Kumavath R: Strophanthidin attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling pathways in human cancers. Front Oncol. 9(1469)2019.PubMed/NCBI View Article : Google Scholar
33	Wang Y, Li J and Che G: Clinical significance of PIK3CA gene in non-small-cell lung cancer: A systematic review and meta-analysis. Biomed Res Int. 2020(3608241)2020.PubMed/NCBI View Article : Google Scholar
34	Kumar R, Kumar R, Goel H, Kumar S, Ningombam SS, Haider I, Agrawal U, Deo S, Gogia A, Batra A, et al: Whole exome sequencing identifies novel variants of PIK3CA and validation of hotspot mutation by droplet digital PCR in breast cancer among Indian population. Cancer Cell Int. 23(236)2023.PubMed/NCBI View Article : Google Scholar
35	Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, Bahl S, Cao Y, Amin-Mansour A, Yamauchi M, et al: Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15:857–865. 2016.PubMed/NCBI View Article : Google Scholar
36	Yaeger R, Chatila WK, Lipsyc MD, Hechtman JF, Cercek A, Sanchez-Vega F, Jayakumaran G, Middha S, Zehir A, Donoghue MTA, et al: Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 33:125–136.e3. 2018.PubMed/NCBI View Article : Google Scholar
37	Voutsadakis IA: The landscape of PIK3CA mutations in colorectal cancer. Clin Colorectal Cancer. 20:201–215. 2021.PubMed/NCBI View Article : Google Scholar
38	Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, et al: High frequency of mutations of the PIK3CA gene in human cancers. Science. 304(554)2004.PubMed/NCBI View Article : Google Scholar
39	Gong J, Cho M, Sy M, Salgia R and Fakih M: Molecular profiling of metastatic colorectal tumors using next-generation sequencing: A single-institution experience. Oncotarget. 8:42198–42213. 2017.PubMed/NCBI View Article : Google Scholar
40	Shetty O, Vengurlekar V, Kapoor A, Kamble V, Gurav M, Bhargava P, Srinivas S, Ramaswamy A, Ramadwar M, Saklani AP, et al: The prevalence of BRAF, PIK3CA, and RAS mutations in indian patients with colorectal cancer. South Asian J Cancer. 11:190–194. 2022.PubMed/NCBI View Article : Google Scholar
41	Reggiani Bonetti L, Barresi V, Maiorana A, Manfredini S, Caprera C and Bettelli S: Clinical impact and prognostic role of KRAS/BRAF/PIK3CA mutations in stage I colorectal cancer. Dis Markers. 2018(2959801)2018.PubMed/NCBI View Article : Google Scholar
42	Li X, Yang T, Li CS, Song Y, Lou H, Guan D and Jin L: Surface enhanced raman spectroscopy (SERS) for the multiplex detection of Braf, Kras, and Pik3ca mutations in plasma of colorectal cancer patients. Theranostics. 8:1678–1689. 2018.PubMed/NCBI View Article : Google Scholar
43	Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, et al: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 68:1953–1961. 2008.PubMed/NCBI View Article : Google Scholar
44	Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, et al: PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 69:1851–1857. 2009.PubMed/NCBI View Article : Google Scholar
45	Barault L, Veyrie N, Jooste V, Lecorre D, Chapusot C, Ferraz JM, Lièvre A, Cortet M, Bouvier AM, Rat P, et al: Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer. 122:2255–2259. 2008.PubMed/NCBI View Article : Google Scholar
46	Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S, Chan AT, Engelman JA, Kraft P, Cantley LC, et al: PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 27:1477–1484. 2009.PubMed/NCBI View Article : Google Scholar
47	Foltran L, De Maglio G, Pella N, Ermacora P, Aprile G, Masiero E, Giovannoni M, Iaiza E, Cardellino GG, Lutrino SE, et al: Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer. Future Oncol. 11:629–640. 2015.PubMed/NCBI View Article : Google Scholar
48	Phipps AI, Ahnen DJ, Cheng I, Newcomb PA, Win AK and Burnett T: PIK3CA somatic mutation status in relation to patient and tumor factors in racial/ethnic minorities with colorectal cancer. Cancer Epidemiol Biomarkers Prev. 24:1046–1051. 2015.PubMed/NCBI View Article : Google Scholar
49	Dirican E, Akkiprik M and Özer A: Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer. Tumour Biol. 37:7033–7045. 2016.PubMed/NCBI View Article : Google Scholar