{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T22:30:28Z","timestamp":1770330628985,"version":"3.49.0"},"reference-count":56,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,13]],"date-time":"2023-08-13T00:00:00Z","timestamp":1691884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bulgarian National Science Fund","award":["K\u03a0-06-H23\/6"],"award-info":[{"award-number":["K\u03a0-06-H23\/6"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>RAS somatic variants are predictors of resistance to anti-EGFR therapy for colorectal cancer (CRC) and affect the outcome of the disease. Our study aimed to evaluate the frequency of RAS, with a focus on KRAS variants, and their association with tumor location and some clinicopathological characteristics in Bulgarian CRC patients. We prospectively investigated 236 patients with advanced and metastatic CRC. Genomic DNA was extracted from FFPE tumor tissue samples, and commercially available kits were used to detect RAS gene somatic mutations via real-time PCR. A total of 115 (48.73%) patients tested positive for RAS mutations, with 106 (44.92%) testing positive for KRAS mutations. The most common mutation in exon 2 was c.35G&gt;T p.Gly12Val (32.56%). We did not find a significant difference in KRAS mutation frequency according to tumor location. However, patients with a mutation in exon 4 of KRAS were 3.23 times more likely to have a tumor in the rectum than in other locations (95% CI: 1.19\u20138.72, p = 0.021). Studying the link between tumor location and KRAS mutations in exon 4 is crucial for better characterizing CRC patients. Further research with larger cohorts, especially in rectal cancer patients, could provide valuable insights for patient follow-up and treatment selection.<\/jats:p>","DOI":"10.3390\/ijms241612753","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T10:13:57Z","timestamp":1692008037000},"page":"12753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["KRAS Mutation Status in Bulgarian Patients with Advanced and Metastatic Colorectal Cancer"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0941-6139","authenticated-orcid":false,"given":"Maria","family":"Radanova","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galya","family":"Mihaylova","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6950-0615","authenticated-orcid":false,"given":"George St.","family":"Stoyanov","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Complex Oncology Center\u2014Shumen, 9700 Shumen, Bulgaria"},{"name":"Department of Surgery Diseases, Medical University of Varna, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vyara","family":"Draganova","sequence":"additional","affiliation":[{"name":"Department of Surgery Diseases, Medical University of Varna, 9000 Varna, Bulgaria"},{"name":"Second Clinic of Surgery, UMHAT \u201cSt. Marina\u201d, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandar","family":"Zlatarov","sequence":"additional","affiliation":[{"name":"Department of General and Operative Surgery, Medical University of Varna, 9000 Varna, Bulgaria"},{"name":"First Clinic of Surgery, UMHAT \u201cSt. Marina\u201d, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6548-2712","authenticated-orcid":false,"given":"Nikola","family":"Kolev","sequence":"additional","affiliation":[{"name":"Department of General and Operative Surgery, Medical University of Varna, 9000 Varna, Bulgaria"},{"name":"First Clinic of Surgery, UMHAT \u201cSt. Marina\u201d, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Dimitrova","sequence":"additional","affiliation":[{"name":"Department of Oncology, Medical University of Varna, 9000 Varna, Bulgaria"},{"name":"Clinic of Medical Oncology, UMHAT \u201cSt. Marina\u201d, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolay","family":"Conev","sequence":"additional","affiliation":[{"name":"Department of Oncology, Medical University of Varna, 9000 Varna, Bulgaria"},{"name":"Clinic of Medical Oncology, UMHAT \u201cSt. Marina\u201d, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4502-081X","authenticated-orcid":false,"given":"Diana","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9000 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/S1470-2045(21)00199-6","article-title":"Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: An international population-based study","volume":"22","author":"Cardoso","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18678","DOI":"10.1038\/srep18678","article-title":"Molecular spectrum of KRAS, NRAS, BRAF and PIK3CA mutations in Chinese colorectal cancer patients: Analysis of 1110 cases","volume":"5","author":"Zhang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"22257","DOI":"10.18632\/oncotarget.8076","article-title":"Mutations of KRAS\/NRAS\/BRAF predict cetuximab resistance in metastatic colorectal cancer patients","volume":"7","author":"Hsu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6076","DOI":"10.1038\/s41598-018-24306-1","article-title":"Mutation status and prognostic values of KRAS, NRAS, BRAF and PIK3CA in 353 Chinese colorectal cancer patients","volume":"8","author":"Guo","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sanchez-Ibarra, H.E., Jiang, X., Gallegos-Gonzalez, E.Y., Cavazos-Gonz\u00e1lez, A.C., Chen, Y., Morcos, F., and Barrera-Salda\u00f1a, H.A. (2020). KRAS, NRAS, and BRAF mutation prevalence, clinicopathological association, and their application in a predictive model in Mexican patients with metastatic colorectal cancer: A retrospective cohort study. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235490"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mahdi, Y., Khmou, M., Souadka, A., Agouri, H.E., Ech-Charif, S., Mounjid, C., and Khannoussi, B.E. (2023). Correlation between KRAS and NRAS mutational status and clinicopathological features in 414 cases of metastatic colorectal cancer in Morocco: The largest North African case series. BMC Gastroenterol., 23.","DOI":"10.1186\/s12876-023-02694-7"},{"key":"ref_8","first-page":"1","article-title":"Frequency of Ras Mutations (Kras, Nras, Hras) in Human Solid Cancer","volume":"1","author":"Kodaz","year":"2017","journal-title":"EJMO"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/modpathol.2017.119","article-title":"Association between clinicopathological characteristics and RAS mutation in colorectal cancer","volume":"31","author":"Rimbert","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/modpathol.2012.240","article-title":"Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features","volume":"26","author":"Rosty","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1097\/PAT.0000000000000300","article-title":"KRAS, NRAS, BRAF mutations and high counts of poorly differentiated clusters of neoplastic cells in colorectal cancer: Observational analysis of 175 cases","volume":"47","author":"Barresi","year":"2015","journal-title":"Pathology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"768","DOI":"10.4161\/cbt.28550","article-title":"Characterization of rare transforming KRAS mutations in sporadic colorectal cancer","volume":"15","author":"Tong","year":"2014","journal-title":"Cancer Biol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1002\/cam4.2747","article-title":"Prevalence of RAS and BRAF mutations in metastatic colorectal cancer patients by tumor sidedness: A systematic review and meta-analysis","volume":"9","author":"Bylsma","year":"2020","journal-title":"Cancer Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3722","DOI":"10.1038\/s41467-019-11530-0","article-title":"Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients","volume":"10","author":"Serebriiskii","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Boleij, A., Tack, V., Taylor, A., Kafatos, G., Jenkins-Anderson, S., Tembuyser, L., Dequeker, E., and van Krieken, J.H. (2016). RAS testing practices and RAS mutation prevalence among patients with metastatic colorectal cancer: Results from a Europe-wide survey of pathology centres. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2810-3"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e389574","DOI":"10.1200\/EDBK_389574","article-title":"Update on Emerging Therapies for Advanced Colorectal Cancer","volume":"43","author":"Alese","year":"2023","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2174\/1574887113666180328104109","article-title":"Impact of Primary Tumor Location on First-line Bevacizumab or Cetuximab in Metastatic Colorectal Cancer","volume":"13","author":"Snyder","year":"2018","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.2478\/raon-2023-0014","article-title":"The five-year KRAS, NRAS, and BRAF analysis results and treatment patterns in daily clinical practice in Slovenia in 1st line treatment of metastatic colorectal (mCRC) patients with RAS wild-type tumour (wtRAS)\u2014A real-life data report 2013\u20132018","volume":"57","author":"Mesti","year":"2023","journal-title":"Radiol. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1158\/1078-0432.CCR-09-2446","article-title":"Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases","volume":"16","author":"Baldus","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_20","first-page":"116","article-title":"The role of K-RAS and B-RAF mutations as biomarkers in metastatic colorectal cancer","volume":"18","author":"Selcukbiricik","year":"2013","journal-title":"J. BUON"},{"key":"ref_21","first-page":"128","article-title":"KRAS discordance between primary and metastatic tumor in patients with metastatic colorectal carcinoma","volume":"20","author":"Demirci","year":"2015","journal-title":"J. BUON"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3892\/mco.2014.448","article-title":"Association between specific KRAS mutations and the clinicopathological characteristics of colorectal tumors","volume":"3","author":"Kodaz","year":"2015","journal-title":"Mol. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1309\/LWDY1AXHXUULNVHQ","article-title":"High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer","volume":"130","author":"Simi","year":"2008","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e366","DOI":"10.5301\/JBM.2012.9765","article-title":"Survey of KRAS, BRAF and PIK3CA mutational status in 209 consecutive Italian colorectal cancer patients","volume":"27","author":"Bozzao","year":"2012","journal-title":"Int. J. Biol. Markers"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","unstructured":"Martianov, A.S., Mitiushkina, N.V., Ershova, A.N., Martynenko, D.E., Bubnov, M.G., Amankwah, P., Yanus, G.A., Aleksakhina, S.N., Tiurin, V.I., and Venina, A.R. (2023). KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054868"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Afr\u0103s\u00e2nie, V., Marinca, M., Gafton, B., Alexa-Stratulat, T., Rusu, A., Froicu, E., Sur, D., Lungulescu, C.V., Popovici, L., and Lefter, A. (IJMS, 2023). Clinical Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania, IJMS, forthcoming article.","DOI":"10.3390\/ijms241612679"},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1007\/s10555-020-09915-5","article-title":"Molecular epidemiology and diagnostics of KRAS mutations in human cancer","volume":"9","author":"Timar","year":"2020","journal-title":"Cancer Metastasis Rev."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhang, M., Meng, L., Zhang, Z., Wu, J., Chen, X., Wang, Y., and He, J. (2022). The relationships of OSBPL3 expression with KI-67 expression and KRAS mutations in CRC: Implications for diagnosis and prognosis. BMC Med. Genom., 15.","DOI":"10.1186\/s12920-022-01402-w"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1200\/JCO.2022.40.4_suppl.173","article-title":"The prevalence of common KRAS variants and associated outcomes in patients with metastatic colorectal cancer (mCRC)","volume":"40","author":"Musselwhite","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4753","DOI":"10.1158\/1078-0432.CCR-11-3210","article-title":"Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers","volume":"18","author":"Imamura","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41591-023-02240-8","article-title":"Codon-specific KRAS mutations predict survival benefit of trifluridine\/tipiracil in metastatic colorectal cancer","volume":"29","author":"Ma","year":"2023","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"213","DOI":"10.31083\/j.fbl2707213","article-title":"KRAS Mutation: Characterization and Its Impact on Survival Outcome of Patients with Metastatic Colorectal Cancer","volume":"27","author":"Damit","year":"2022","journal-title":"Front Biosci (Landmark Ed.)"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5331","DOI":"10.7150\/jca.59193","article-title":"Prognostic Value of KRAS Exon 3 and Exon 4 Mutations in Colorectal Cancer Patients","volume":"12","author":"Guo","year":"2021","journal-title":"J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2698","DOI":"10.1002\/cncr.30085","article-title":"Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases","volume":"122","author":"Margonis","year":"2016","journal-title":"Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.surg.2016.07.032","article-title":"Is hepatectomy justified for patients with RAS mutant colorectal liver metastases? An analysis of 524 patients undergoing curative liver resection","volume":"161","author":"Passot","year":"2017","journal-title":"Surgery"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100511","DOI":"10.1016\/j.esmoop.2022.100511","article-title":"Effect of KRAS codon 12 or 13 mutations on survival with trifluridine\/tipiracil in pretreated metastatic colorectal cancer: A meta-analysis","volume":"7","author":"Yoshino","year":"2022","journal-title":"ESMO Open"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd.2016.139","article-title":"Direct small-molecule inhibitors of KRAS: From structural insights to mechanism-based design","volume":"15","author":"Ostrem","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/s41568-018-0076-6","article-title":"A model for RAS mutation patterns in cancers: Finding the sweet spot","volume":"18","author":"Li","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1200\/PO.20.00256","article-title":"Comprehensive Clinical and Molecular Characterization of KRASG12C-Mutant Colorectal Cancer","volume":"5","author":"Henry","year":"2021","journal-title":"JCO Precis. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1056\/NEJMoa2212419","article-title":"Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C","volume":"388","author":"Yaeger","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","unstructured":"Lee, Y.C., Lee, Y.L., Chuang, J.P., and Lee, J.C. (2013). Differences in survival between colon and rectal cancer from SEER data. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078709"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E114","DOI":"10.1111\/ans.13730","article-title":"Improved survival for rectal cancer compared to colon cancer: The four cohort study","volume":"88","author":"Buchwald","year":"2018","journal-title":"ANZ J. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1634\/theoncologist.2019-0552","article-title":"Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer","volume":"25","author":"Salem","year":"2020","journal-title":"Oncologist"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e01330","DOI":"10.1016\/j.heliyon.2019.e01330","article-title":"KRAS and NRAS pyrosequencing screening in Tunisian colorectal cancer patients in 2015","volume":"5","author":"Jouini","year":"2019","journal-title":"Heliyon"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"El Agy, F., El Bardai, S., El Otmani, I., Benbrahim, Z., Karim, M.H., Mazaz, K., Benjelloun, E.B., Ousadden, A., El Abkari, M., and Ibrahimi, S.A. (2021). Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0248522"},{"key":"ref_49","first-page":"26","article-title":"Predominance of G to A codon 12 mutation K-ras gene in Dukes\u2019 B colorectal cancer","volume":"53","author":"Zulhabri","year":"2012","journal-title":"Singap. Med. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3233\/HAB-210451","article-title":"Effect of KRAS and BRAF mutations in metastatic colorectal cancer patients: A systematic review and meta-analysis based on tumor sidedness and KRAS subtypes","volume":"29","author":"Saravani","year":"2021","journal-title":"Hum. Antibodies"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s12943-018-0923-9","article-title":"Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles","volume":"17","author":"Imperial","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Nicolazz, C., Belardinilli, F., Vestri, A., Magri, V., De Renzi, G., De Meo, M., Caponnetto, S., Di Nicolantonio, F., Cortesi, E., and Giannini, G. (2022). RAS Mutation Conversion in Bevacizumab-Treated Metastatic Colorectal Cancer Patients: A Liquid Biopsy Based Study. Cancers, 14.","DOI":"10.3390\/cancers14030802"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"v586","DOI":"10.1093\/annonc\/mdx390.044","article-title":"ctDNA might expand therapeutic options for second line treatment of KRAS mutant mCRC","volume":"28","author":"Gazzaniga","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"viii183","DOI":"10.1093\/annonc\/mdy281.095","article-title":"Second line EGFR-inhibitors in RAS mutant metastatic colorectal cancer: The plasma RAS wild type \u201cwindow of opportunity\u201d","volume":"29","author":"Gazzaniga","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.3389\/fonc.2020.01115","article-title":"Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer","volume":"10","author":"Wahner","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_56","first-page":"137","article-title":"The Ideal Reporting of RAS Testing in Colorectal Adenocarcinoma: A pathologists\u2019 Perspective","volume":"115","author":"Malapelle","year":"2023","journal-title":"Pathologica"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12753\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:32:51Z","timestamp":1760128371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,13]]},"references-count":56,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241612753"],"URL":"https:\/\/doi.org\/10.3390\/ijms241612753","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,13]]}}}