{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:09:49Z","timestamp":1787317789781,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T00:00:00Z","timestamp":1691712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Social Fund\u2014the Human Capital Operational Programme","award":["POCU\/993\/6\/13\/154722"],"award-info":[{"award-number":["POCU\/993\/6\/13\/154722"]}]},{"name":"Romanian National Society of Medical Oncology (SNOMR)","award":["POCU\/993\/6\/13\/154722"],"award-info":[{"award-number":["POCU\/993\/6\/13\/154722"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.<\/jats:p>","DOI":"10.3390\/ijms241612679","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T10:20:16Z","timestamp":1691749216000},"page":"12679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania"],"prefix":"10.3390","volume":"24","author":[{"given":"Vlad-Adrian","family":"Afr\u0103s\u00e2nie","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"},{"name":"Department of Oncology, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-3059","authenticated-orcid":false,"given":"Mihai-Vasile","family":"Marinca","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"},{"name":"Department of Oncology, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Gafton","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"},{"name":"Department of Oncology, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2696-9568","authenticated-orcid":false,"given":"Teodora","family":"Alexa-Stratulat","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"},{"name":"Department of Oncology, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8674-5035","authenticated-orcid":false,"given":"Alexandra","family":"Rusu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza-Maria","family":"Froicu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"},{"name":"Department of Oncology, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0926-4614","authenticated-orcid":false,"given":"Daniel","family":"Sur","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Oncology Institute \u201cProf. Dr. Ion Chiricuta\u201d, 400015 Cluj-Napoca, Romania"},{"name":"11th Department of Medical Oncology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian Virgil","family":"Lungulescu","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Popovici","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei-Vlad","family":"Lefter","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Afr\u0103s\u00e2nie","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Emergency Clinical Hospital \u201cSf. Spiridon\u201d, 700111 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca-Viorica","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucian","family":"Miron","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Regional Institute of Oncology, 700483 Iasi, Romania"},{"name":"Department of Oncology, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rusu","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,11]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, July 14). Cancer, Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cancer."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1053\/j.gastro.2009.01.015","article-title":"Burden of digestive diseases in the United States part II: Lower gastrointestinal diseases","volume":"136","author":"Everhart","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hossain, M.S., Karuniawati, H., Jairoun, A.A., Urbi, Z., Ooi, D.J., John, A., Lim, Y.C., Kibria, K.M.K., Mohiuddin, A.K.M., and Ming, L.C. (2022). Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies. Cancers, 14.","DOI":"10.3390\/cancers14071732"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101174","DOI":"10.1016\/j.tranon.2021.101174","article-title":"Global colorectal cancer burden in 2020 and projections to 2040","volume":"14","author":"Xi","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s12029-020-00382-3","article-title":"Colorectal Cancer Trends of 2018 in Romania-an Important Geographical Variation Between Northern and Southern Lands and High Mortality Versus European Averages","volume":"52","author":"Ionescu","year":"2021","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41575-019-0230-y","article-title":"Epigenetics of colorectal cancer: Biomarker and therapeutic potential","volume":"17","author":"Jung","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_7","first-page":"581","article-title":"Prognostic significance of KRAS gene mutations in colorectal cancer-preliminary study","volume":"7","author":"Dinu","year":"2014","journal-title":"J. Med. Life"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/ijc.28955","article-title":"Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer","volume":"136","author":"Schirripa","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s12967-019-1879-2","article-title":"Clinico-pathological associations and concomitant mutations of the RAS\/RAF pathway in metastatic colorectal cancer","volume":"17","author":"Isnaldi","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.annonc.2022.10.003","article-title":"Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"34","author":"Cervantes","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kawazoe, A., Shitara, K., Fukuoka, S., Kuboki, Y., Bando, H., Okamoto, W., Kojima, T., Fuse, N., Yamanaka, T., and Doi, T. (2015). A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1276-z"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1093\/mutage\/ger067","article-title":"Mutations and polymorphisms in TP53 gene-an overview on the role in colorectal cancer","volume":"27","author":"Naccarati","year":"2012","journal-title":"Mutagenesis"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kim, K.M., Ahn, A.R., Park, H.S., Jang, K.Y., Moon, W.S., Kang, M.J., Ha, G.W., Lee, M.R., and Chung, M.J. (2022). Clinical significance of p53 protein expression and TP53 variation status in colorectal cancer. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-10039-y"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nature13968","article-title":"Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia","volume":"518","author":"Wong","year":"2015","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e004652","DOI":"10.1136\/bmjopen-2013-004652","article-title":"KRAS, NRAS and BRAF mutations in Greek and Romanian patients with colorectal cancer: A cohort study","volume":"4","author":"Negru","year":"2014","journal-title":"BMJ Open"},{"key":"ref_16","first-page":"26","article-title":"Research progress on KRAS mutations in colorectal cancer","volume":"7","author":"Epistolio","year":"2021","journal-title":"J. Cancer Metastasis Treat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1016\/j.ejca.2015.05.017","article-title":"Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials","volume":"51","author":"Peeters","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1054\/bjoc.2001.1964","article-title":"Kirsten ras mutations in patients with colorectal cancer: The \u2018RASCAL II\u2019 study","volume":"85","author":"Andreyev","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1055019","DOI":"10.3389\/fonc.2022.1055019","article-title":"Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer","volume":"12","author":"Lavacchi","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"826073","DOI":"10.3389\/fonc.2022.826073","article-title":"KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer","volume":"12","author":"Osterlund","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.critrevonc.2016.11.007","article-title":"Clinical relevance of colorectal cancer molecular subtypes","volume":"109","author":"Dominguez","year":"2017","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e124","DOI":"10.1038\/ctg.2017.48","article-title":"Increased Frequency of KRAS Mutations in African Americans Compared with Caucasians in Sporadic Colorectal Cancer","volume":"8","author":"Staudacher","year":"2017","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/apm.13091","article-title":"Frequency and coexistence of KRAS, NRAS, BRAF and PIK3CA mutations and occurrence of MMR deficiency in Danish colorectal cancer patients","volume":"129","author":"Poulsen","year":"2021","journal-title":"APMIS"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Molina-Cerrillo, J., San Rom\u00e1n, M., Pozas, J., Alonso-Gordoa, T., Pozas, M., Conde, E., Rosas, M., Grande, E., Garc\u00eda-Bermejo, M.L., and Carrato, A. (2020). BRAF Mutated Colorectal Cancer: New Treatment Approaches. Cancers, 12.","DOI":"10.3390\/cancers12061571"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4623","DOI":"10.1002\/cncr.26086","article-title":"Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer","volume":"117","author":"Tran","year":"2011","journal-title":"Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1093\/annonc\/mdx401","article-title":"BRAF mutant colorectal cancer: Prognosis, treatment, and new perspectives","volume":"28","author":"Argiles","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_27","first-page":"35","article-title":"PIK3CA in Colorectal Cancer","volume":"3","author":"Cathomas","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7518","DOI":"10.1200\/JCO.2005.00.471","article-title":"TP53-CRC Collaborative Study Group. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: Influence of tumor site, type of mutation, and adjuvant treatment","volume":"23","author":"Russo","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1097\/00000658-200204000-00006","article-title":"TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer","volume":"235","author":"Kandioler","year":"2022","journal-title":"Ann. Surg."},{"key":"ref_30","first-page":"166","article-title":"Prevalence of Molecular Alterations in a Swiss Cohort of 512 Colorectal Carcinoma Patients by Targeted Next-Generation Sequencing Analysis in Routine Diagnostics","volume":"6","author":"Haefliger","year":"2022","journal-title":"Pathobiology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S1470-2045(10)70130-3","article-title":"Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis","volume":"11","author":"Claes","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5843","DOI":"10.1158\/1078-0432.CCR-19-0863","article-title":"Mutation Status of RAS, TP53, and SMAD4 is Superior to Mutation Status of RAS Alone for Predicting Prognosis after Resection of Colorectal Liver Metastases","volume":"25","author":"Kawaguchi","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"251","DOI":"10.15403\/jgld-1003","article-title":"The Coexistence of RAS and BRAF Mutations in Metastatic Colorectal Cancer: A Case Report and Systematic Literature Review","volume":"29","author":"Gafton","year":"2020","journal-title":"J. Gastrointest. Liver Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2478\/fco-2018-0005","article-title":"Analysis of KRAS and NRAS mutations in Greek patients with metastatic Colorectal Cancer (mCRC) on the registry of the Gastro-intestinal Cancer Study Group (GIC-SG)","volume":"9","author":"Gouvas","year":"2018","journal-title":"Forum Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1093\/annonc\/mdw261","article-title":"Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: Pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group","volume":"27","author":"Modest","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2478\/raon-2019-0033","article-title":"KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer\u2014Practical implications for the clinician","volume":"53","author":"Marinca","year":"2019","journal-title":"Radiol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"121","DOI":"10.26502\/jcsct.5079149","article-title":"Clinical Characteristics and Prognostic Values of PIK3CA Mutation in Colorectal Cancer Patients","volume":"6","author":"Han","year":"2022","journal-title":"J. Cancer Sci. Clin. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s12029-018-0062-y","article-title":"Clinical Impact of PI3K\/BRAF Mutations in RAS Wild Metastatic Colorectal Cancer: Meta-analysis Results","volume":"50","author":"Mohamed","year":"2019","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S92","DOI":"10.1016\/j.jbiotec.2016.05.327","article-title":"KRAS, BRAF and TP53 mutations in Romanian colorectal cancer patients","volume":"231","author":"Murarasu","year":"2016","journal-title":"J. Biotechnol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:31:32Z","timestamp":1760128292000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,11]]},"references-count":39,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241612679"],"URL":"https:\/\/doi.org\/10.3390\/ijms241612679","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,11]]}}}