{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:48:17Z","timestamp":1785912497423,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","award":["TCRD-TPE-111-36"],"award-info":[{"award-number":["TCRD-TPE-111-36"]}]},{"name":"Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","award":["TCRD-TPE-111-04"],"award-info":[{"award-number":["TCRD-TPE-111-04"]}]},{"name":"Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","award":["TCRD-TPE-MOST-109-17"],"award-info":[{"award-number":["TCRD-TPE-MOST-109-17"]}]},{"name":"Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","award":["TCRD-TPE-110-RT-1"],"award-info":[{"award-number":["TCRD-TPE-110-RT-1"]}]},{"name":"Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","award":["TCMF-CM3-111-01"],"award-info":[{"award-number":["TCMF-CM3-111-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study investigated whether oncogenic and tumor-suppressive gene mutations are involved in the differential outcomes of patients with rectal carcinoma receiving neoadjuvant chemoradiotherapy (nCRT). Genomic DNA was obtained from formalin-fixed paraffin-embedded (FFPE) specimens of patients with rectal carcinoma who received a complete nCRT course. Gene mutation status was examined in specimens from patients before and after nCRT by using the AmpliSeq platform. Our data revealed that the nonsynonymous p53, APC, KRAS, CDKN2A, and EGFR mutations were observed in 93.1%, 65.5%, 48.6%, and 31% of the patients with rectal adenocarcinoma, respectively. BRAF, FBXW7, PTEN, and SMAD4 mutations were observed in 20.7% of patients with rectal carcinoma. The following 12 gene mutations were observed more frequently in the patients exhibiting a complete response than in those demonstrating a poor response before nCRT: ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4, and TP53. In addition, APC, BRAF, FBXW7, KRAS, SMAD4, and TP53 mutations were retained after nCRT. Our results indicate a complex mutational profile in rectal carcinoma, suggesting the involvement of BRAF, SMAD4, and TP53 genetic variants in the outcomes of patients with nCRT.<\/jats:p>","DOI":"10.3390\/ijms231810353","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T04:18:32Z","timestamp":1662610712000},"page":"10353","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeted Next-Generation Sequencing-Based Multiple Gene Mutation Profiling of Patients with Rectal Adenocarcinoma Receiving or Not Receiving Neoadjuvant Chemoradiotherapy"],"prefix":"10.3390","volume":"23","author":[{"given":"You-Kang","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan"},{"name":"College of Medicine, Tzu Chi University, Hualien City 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Hwa","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Man","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung 81341, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7062-8560","authenticated-orcid":false,"given":"Kuo-Cheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 97004, Taiwan"},{"name":"Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9028-9834","authenticated-orcid":false,"given":"Kuo-Wang","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"CD006041","article-title":"Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer","volume":"28","author":"Ceelen","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1056\/NEJMoa060829","article-title":"Chemotherapy with preoperative radiotherapy in rectal cancer","volume":"355","author":"Bosset","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/DCR.0000000000000558","article-title":"Pathologic Complete Response in Rectal Cancer: Can We Detect It? Lessons Learned From a Proposed Randomized Trial of Watch-and-Wait Treatment of Rectal Cancer","volume":"59","author":"Nahas","year":"2016","journal-title":"Dis. Colon Rectum"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/sj.bjc.6602960","article-title":"Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: Should we be more cautious?","volume":"94","author":"Grainger","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.clcc.2015.05.014","article-title":"Biomarkers and Molecular Imaging as Predictors of Response to Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer","volume":"14","author":"Molinari","year":"2015","journal-title":"Clin. Colorectal Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chen, M.B., Wu, X.Y., Yu, R., Li, C., Wang, L.Q., Shen, W., and Lu, P.H. (2012). P53 status as a predictive biomarker for patients receiving neoadjuvant radiation-based treatment: A meta-analysis in rectal cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045388"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1245\/s10434-013-2910-0","article-title":"Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma","volume":"20","author":"Duldulao","year":"2013","journal-title":"Ann. Surg. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.3748\/wjg.v22.i25.5678","article-title":"New trends in molecular and cellular biomarker discovery for colorectal cancer","volume":"22","author":"Aghagolzadeh","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_10","first-page":"149014","article-title":"Colorectal Cancer Biomarkers: Where Are We Now?","volume":"2015","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41571-019-0241-1","article-title":"Biomarker-guided therapy for colorectal cancer: Strength in complexity","volume":"17","author":"Sveen","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6856","DOI":"10.7150\/thno.37794","article-title":"Genome landscapes of rectal cancer before and after preoperative chemoradiotherapy","volume":"9","author":"Yang","year":"2019","journal-title":"Theranostics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5561","DOI":"10.1158\/1078-0432.CCR-19-0908","article-title":"Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer","volume":"25","author":"Kamran","year":"2019","journal-title":"Clin Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1245\/s10434-016-5205-4","article-title":"KRAS and Combined KRAS\/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy","volume":"23","author":"Chow","year":"2016","journal-title":"Ann. Surg. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1073\/pnas.74.12.5463","article-title":"DNA sequencing with chain-terminating inhibitors","volume":"74","author":"Sanger","year":"1977","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.5858\/arpa.2015-0261-SA","article-title":"Next-Generation Sequencing of Matched Primary and Metastatic Rectal Adenocarcinomas Demonstrates Minimal Mutation Gain and Concordance to Colonic Adenocarcinomas","volume":"140","author":"Crumley","year":"2015","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1309\/AJCPU3J7FGAYQBRL","article-title":"Endoscopic ultrasound fine-needle aspiration cytology mutation profiling using targeted next-generation sequencing: Personalized care for rectal cancer","volume":"143","author":"Gleeson","year":"2015","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"McCourt, C.M., McArt, D.G., Mills, K., Catherwood, M.A., Maxwell, P., Waugh, D.J., Hamilton, P., O\u2019Sullivan, J.M., and Salto-Tellez, M. (2013). Validation of next generation sequencing technologies in comparison to current diagnostic gold standards for BRAF, EGFR and KRAS mutational analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069604"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19096","DOI":"10.1073\/pnas.0910672106","article-title":"Genetic diagnosis by whole exome capture and massively parallel DNA sequencing","volume":"106","author":"Choi","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"D\u2019Haene, N., Le Mercier, M., De Neve, N., Blanchard, O., Delaunoy, M., El Housni, H., Dessars, B., Heimann, P., Remmelink, M., and Demetter, P. (2015). Clinical Validation of Targeted Next Generation Sequencing for Colon and Lung Cancers. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138245"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.lungcan.2014.08.020","article-title":"Genetic profiling of thymic carcinoma using targeted next-generation sequencing","volume":"86","author":"Shitara","year":"2014","journal-title":"Lung Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1634\/theoncologist.2013-0180","article-title":"Profiling cancer gene mutations in clinical formalin-fixed, paraffin-embedded colorectal tumor specimens using targeted next-generation sequencing","volume":"19","author":"Zhang","year":"2014","journal-title":"Oncologist"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.celrep.2016.03.075","article-title":"Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma","volume":"15","author":"Giannakis","year":"2016","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ccell.2017.12.004","article-title":"Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer","volume":"33","author":"Yaeger","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1053\/j.gastro.2020.07.041","article-title":"Specific Mutations in APC, but Not Alterations in DNA Damage Response, Associate with Outcomes of Patients with Metastatic Colorectal Cancer","volume":"159","author":"Mondaca","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1056\/NEJMoa040694","article-title":"Preoperative versus postoperative chemoradiotherapy for rectal cancer","volume":"351","author":"Sauer","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/SLA.0b013e31822b8cfa","article-title":"Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer","volume":"254","author":"Chen","year":"2011","journal-title":"Ann. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.ijrobp.2010.06.043","article-title":"KRAS and BRAF mutations and PTEN expression do not predict efficacy of cetuximab-based chemoradiotherapy in locally advanced rectal cancer","volume":"81","author":"Erben","year":"2011","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/1748-717X-6-114","article-title":"Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy","volume":"6","author":"Davies","year":"2011","journal-title":"Radiat. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1007\/s12029-013-9546-y","article-title":"Mutational and clinical predictors of pathologic complete response in the treatment of locally advanced rectal cancer","volume":"45","author":"Russo","year":"2014","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nature11252","article-title":"Comprehensive molecular characterization of human colon and rectal cancer","volume":"487","year":"2012","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1158\/1541-7786.MCR-19-0525","article-title":"Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan","volume":"18","author":"Wong","year":"2020","journal-title":"Mol. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/sj.bjc.6600511","article-title":"SMAD4 is a.a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer","volume":"87","author":"Boulay","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6311","DOI":"10.1158\/1078-0432.CCR-05-0244","article-title":"SMAD4 levels and response to 5-fluorouracil in colorectal cancer","volume":"11","author":"Alhopuro","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3176","DOI":"10.1158\/1078-0432.CCR-17-3435","article-title":"SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy","volume":"24","author":"Wang","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Fang, T., Liang, T., Wang, Y., Wu, H., Liu, S., Xie, L., Liang, J., Wang, C., and Tan, Y. (2021). Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal cancer: A systematic review and meta-analysis. BMC Gastroenterol., 21.","DOI":"10.1186\/s12876-021-01864-9"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1002\/cam4.4533","article-title":"Smad4 and p53 synergize in suppressing autochthonous intestinal cancer","volume":"11","author":"Park","year":"2022","journal-title":"Cancer Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e20331","DOI":"10.7554\/eLife.20331","article-title":"BRAF(V600E) cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis","volume":"6","author":"Sakamoto","year":"2017","journal-title":"Elife"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1016\/j.celrep.2017.11.104","article-title":"Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer","volume":"21","author":"Tong","year":"2017","journal-title":"Cell Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10353\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:25:30Z","timestamp":1760142330000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10353"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":42,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810353"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810353","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]}}}