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Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer

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dc.contributor.author Hamaya, Yasushi
dc.contributor.author Guarinos, Carla
dc.contributor.author Tseng-Rogenski, Stephanie S.
dc.contributor.author Iwaizumi, Moriya
dc.contributor.author Das, Ritabrata
dc.contributor.author Jover, Rodrigo
dc.contributor.author Castells, Antoni
dc.contributor.author Llor, Xavier
dc.contributor.author Andreu García, Montserrat
dc.contributor.author Carethers, John M.
dc.date.accessioned 2015-09-30T11:28:36Z
dc.date.available 2015-09-30T11:28:36Z
dc.date.issued 2015
dc.identifier.citation Hamaya Y, Guarinos C, Tseng-Rogenski SS, Iwaizumi M, Das R, Jover R. et al. Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer. PLoS One. 2015 May 21;10(5):e0127591. DOI: 10.1371/journal.pone.0127591.
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10230/24783
dc.description.abstract Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone. We tested if patients with EMAST CRCs (hMutSβ defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings. We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk. We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P<0.05). We observed no difference in survival between patients with stage II/III EMAST and non-EMAST cancers (P = 0.36). There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status. The loss of contribution of hMSH3 for 5-FU cytotoxicity may not adversely affect patient outcome, contrasting patients whose tumors completely lack DNA MMR function (MSI-H).
dc.description.sponsorship This work was supported by the United States Public Health Service (DK067287 and CA162147) and the A. Alfred Taubman Medical Research Institute of the University of Michigan.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science
dc.relation.ispartof PLoS One. 2015 May 21;10(5):e0127591
dc.rights © 2015 Hamaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Còlon -- Càncer
dc.title Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0127591
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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