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Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer

SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1–20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with t...

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Autores principales: Sarshekeh, Amir Mehrvarz, Advani, Shailesh, Overman, Michael J., Manyam, Ganiraju, Kee, Bryan K., Fogelman, David R., Dasari, Arvind, Raghav, Kanwal, Vilar, Eduardo, Manuel, Shanequa, Shureiqi, Imad, Wolff, Robert A., Patel, Keyur P., Luthra, Raja, Shaw, Kenna, Eng, Cathy, Maru, Dipen M., Routbort, Mark J., Meric-Bernstam, Funda, Kopetz, Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340382/
https://www.ncbi.nlm.nih.gov/pubmed/28267766
http://dx.doi.org/10.1371/journal.pone.0173345
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author Sarshekeh, Amir Mehrvarz
Advani, Shailesh
Overman, Michael J.
Manyam, Ganiraju
Kee, Bryan K.
Fogelman, David R.
Dasari, Arvind
Raghav, Kanwal
Vilar, Eduardo
Manuel, Shanequa
Shureiqi, Imad
Wolff, Robert A.
Patel, Keyur P.
Luthra, Raja
Shaw, Kenna
Eng, Cathy
Maru, Dipen M.
Routbort, Mark J.
Meric-Bernstam, Funda
Kopetz, Scott
author_facet Sarshekeh, Amir Mehrvarz
Advani, Shailesh
Overman, Michael J.
Manyam, Ganiraju
Kee, Bryan K.
Fogelman, David R.
Dasari, Arvind
Raghav, Kanwal
Vilar, Eduardo
Manuel, Shanequa
Shureiqi, Imad
Wolff, Robert A.
Patel, Keyur P.
Luthra, Raja
Shaw, Kenna
Eng, Cathy
Maru, Dipen M.
Routbort, Mark J.
Meric-Bernstam, Funda
Kopetz, Scott
author_sort Sarshekeh, Amir Mehrvarz
collection PubMed
description SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1–20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC.
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spelling pubmed-53403822017-03-29 Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer Sarshekeh, Amir Mehrvarz Advani, Shailesh Overman, Michael J. Manyam, Ganiraju Kee, Bryan K. Fogelman, David R. Dasari, Arvind Raghav, Kanwal Vilar, Eduardo Manuel, Shanequa Shureiqi, Imad Wolff, Robert A. Patel, Keyur P. Luthra, Raja Shaw, Kenna Eng, Cathy Maru, Dipen M. Routbort, Mark J. Meric-Bernstam, Funda Kopetz, Scott PLoS One Research Article SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1–20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC. Public Library of Science 2017-03-07 /pmc/articles/PMC5340382/ /pubmed/28267766 http://dx.doi.org/10.1371/journal.pone.0173345 Text en © 2017 Sarshekeh et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sarshekeh, Amir Mehrvarz
Advani, Shailesh
Overman, Michael J.
Manyam, Ganiraju
Kee, Bryan K.
Fogelman, David R.
Dasari, Arvind
Raghav, Kanwal
Vilar, Eduardo
Manuel, Shanequa
Shureiqi, Imad
Wolff, Robert A.
Patel, Keyur P.
Luthra, Raja
Shaw, Kenna
Eng, Cathy
Maru, Dipen M.
Routbort, Mark J.
Meric-Bernstam, Funda
Kopetz, Scott
Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
title Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
title_full Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
title_fullStr Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
title_full_unstemmed Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
title_short Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
title_sort association of smad4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340382/
https://www.ncbi.nlm.nih.gov/pubmed/28267766
http://dx.doi.org/10.1371/journal.pone.0173345
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