5c4954d9cc421ca84462beefa3893423 pmc_9735648.pdf 210fbe9db9f261f82b9143072ffc5d1243395808 pmc_9735648.pdf 9528eafbdd9c43a75a9341eef3c710fa5391d532d203372203e8abdca5507271 pmc_9735648.pdf Title: Mutational Status of SMAD4 and FBXW7 Affects Clinical Outcome in TP53–Mutated Metastatic Colorectal Cancer Subject: Next–generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first–line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time–dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%), and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (p = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (p = 0.02; HR, 3.31) as well as double–mutated TP53 and SMAD4 (p = 0.03; HR, 2.91). Analysis of the MSK–IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time–dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53–defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53–altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first–line regimens. Keywords: metastatic colorectal cancer; next–generation sequencing; mutational profiling; prognosis; left–sided colorectal cancer; machine learning Author: Sara Lahoz, Adela Rodríguez, Laia Fernández, Teresa Gorría, Reinaldo Moreno, Francis Esposito, Helena Oliveres, Santiago Albiol, Tamara Saurí, David Pesantez, Gisela Riu, Miriam Cuatrecasas, Pedro Jares, Leire Pedrosa, Estela Pineda, Antonio Postigo, Antoni Castells, Aleix Prat, Joan Maurel and Jordi Camps Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Nov 30 12:11:48 2022 CET ModDate: Wed Nov 30 12:13:59 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2322845 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SSNIUI+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 XOBWKP+VnURWPalladioL Type 1 Custom yes yes no 15 0 UFFKYT+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 NWAKGP+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 ZDHDEN+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 GTLCFP+URWPalladioL-BoldItal Type 1 Custom yes yes no 32 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 96 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 100 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 104 0 BCDHEE+PalatinoLinotype-BoldItalic TrueType WinAnsi yes yes no 108 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 112 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 119 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 138 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 142 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 146 0 BCDHEE+PalatinoLinotype-BoldItalic TrueType WinAnsi yes yes no 150 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 154 0 FXXUVH+CMSY10 Type 1 Builtin yes yes no 165 0 QDCWHF+EURM10 Type 1 Builtin yes yes no 169 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 191 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 195 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 199 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 203 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-08 02:34:14 CET RepresentationInformation: pmc_9735648.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-08-03 02:25:21 CEST Size: 2322845 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 444 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Cohort of Patients, Clinical Information, and Ethics Statement Destination: subsection.2.1 Item: Title: Datasets Obtained from Public Repositories Destination: subsection.2.2 Item: Title: Targeted Next Generation Sequencing Destination: subsection.2.3 Item: Title: Whole Exome Sequencing Data Analysis Destination: subsection.2.4 Item: Title: RNA Seq Data Analysis Destination: subsection.2.5 Item: Title: Study Endpoints and Statistical Analysis Destination: subsection.2.6 Item: Title: Machine Learning Based Classifier Model Destination: subsection.2.7 Item: Title: Results Destination: section.3 Children: Item: Title: Clinico Pathological Description of the Study Population Destination: subsection.3.1 Item: Title: Recurrently Mutated Genes in mCRC Destination: subsection.3.2 Item: Title: Prognostic Estimates of PFS and OS by Individual Mutated Genes Destination: subsection.3.3 Item: Title: Survival Modelling Based on the Combination of Mutated Genes Destination: subsection.3.4 Item: Title: Gene Expression Profiling Underlying Double Mutation Genotypes for TP53/SMAD4 and TP53/FBXW7 Destination: subsection.3.5 Item: Title: Discriminative Performance of the Clinico Genetic Biomarkers Destination: subsection.3.6 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Mutational Status of SMAD4 and FBXW7 Affects Clinical Outcome in TP53 Mutated Metastatic Colorectal Cancer Author: Sara Lahoz, Adela Rodríguez, Laia Fernández, Teresa Gorría, Reinaldo Moreno, Francis Esposito, Helena Oliveres, Santiago Albiol, Tamara Saurí, David Pesantez, Gisela Riu, Miriam Cuatrecasas, Pedro Jares, Leire Pedrosa, Estela Pineda, Antonio Postigo, Antoni Castells, Aleix Prat, Joan Maurel and Jordi Camps Subject: Next generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%), and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (p = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (p = 0.02; HR, 3.31) as well as double mutated TP53 and SMAD4 (p = 0.03; HR, 2.91). Analysis of the MSK IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53 defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53 altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first line regimens. 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