APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes

Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that APC and TP53 as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity a...

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Autores principales:	Ramya Thota, Mingli Yang, Lance Pflieger, Michael J. Schell, Malini Rajan, Thomas B. Davis, Heiman Wang, Angela Presson, Warren Jack Pledger, Timothy J. Yeatman
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	colorectal cancer <i>APC</i> <i>TP53</i> mutations CMS classification EGFR inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/83b5ca18ff454dabb1beb852018f41e2
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spelling	oai:doaj.org-article:83b5ca18ff454dabb1beb852018f41e22021-11-11T15:29:56Z<i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes10.3390/cancers132153942072-6694https://doaj.org/article/83b5ca18ff454dabb1beb852018f41e22021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5394https://doaj.org/toc/2072-6694Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that <i>APC</i> and <i>TP53</i> as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use <i>APC</i> and <i>TP53</i> mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across <i>all</i> CMS classes. Similar results were also obtained in independent TCGA tumor collections (<i>n</i> = 531) and in PDMR PDX/PDO/PDC models (<i>n</i> = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.Ramya ThotaMingli YangLance PfliegerMichael J. SchellMalini RajanThomas B. DavisHeiman WangAngela PressonWarren Jack PledgerTimothy J. YeatmanMDPI AGarticlecolorectal cancer<i>APC</i><i>TP53</i>mutationsCMS classificationEGFR inhibitorsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5394, p 5394 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	colorectal cancer <i>APC</i> <i>TP53</i> mutations CMS classification EGFR inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	colorectal cancer <i>APC</i> <i>TP53</i> mutations CMS classification EGFR inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ramya Thota Mingli Yang Lance Pflieger Michael J. Schell Malini Rajan Thomas B. Davis Heiman Wang Angela Presson Warren Jack Pledger Timothy J. Yeatman <i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
description	Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that <i>APC</i> and <i>TP53</i> as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use <i>APC</i> and <i>TP53</i> mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across <i>all</i> CMS classes. Similar results were also obtained in independent TCGA tumor collections (<i>n</i> = 531) and in PDMR PDX/PDO/PDC models (<i>n</i> = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.
format	article
author	Ramya Thota Mingli Yang Lance Pflieger Michael J. Schell Malini Rajan Thomas B. Davis Heiman Wang Angela Presson Warren Jack Pledger Timothy J. Yeatman
author_facet	Ramya Thota Mingli Yang Lance Pflieger Michael J. Schell Malini Rajan Thomas B. Davis Heiman Wang Angela Presson Warren Jack Pledger Timothy J. Yeatman
author_sort	Ramya Thota
title	<i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
title_short	<i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
title_full	<i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
title_fullStr	<i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
title_full_unstemmed	<i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
title_sort	<i>apc</i> and <i>tp53</i> mutations predict cetuximab sensitivity across consensus molecular subtypes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/83b5ca18ff454dabb1beb852018f41e2
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<i>APC</i> and <i>TP53</i> Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes

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