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Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation

BACKGROUND: Total mesorectal excision (TME) remains commonplace for T1–2 rectal cancer owing to fear of undertreating a small proportion of patients with node-positive disease. Molecular stratification may predict cancer progression. It could be used to select patients for organ-preserving surgery i...

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Autores principales: Leong, K J, Beggs, A, James, J, Morton, D G, Matthews, G M, Bach, S P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282074/
https://www.ncbi.nlm.nih.gov/pubmed/25052224
http://dx.doi.org/10.1002/bjs.9571
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author Leong, K J
Beggs, A
James, J
Morton, D G
Matthews, G M
Bach, S P
author_facet Leong, K J
Beggs, A
James, J
Morton, D G
Matthews, G M
Bach, S P
author_sort Leong, K J
collection PubMed
description BACKGROUND: Total mesorectal excision (TME) remains commonplace for T1–2 rectal cancer owing to fear of undertreating a small proportion of patients with node-positive disease. Molecular stratification may predict cancer progression. It could be used to select patients for organ-preserving surgery if specific biomarkers were validated. METHODS: Gene methylation was quantified using bisulphite pyrosequencing in 133 unirradiated rectal cancer TME specimens. KRAS mutation and microsatellite instability status were also defined. Molecular parameters were correlated with histopathological indices of disease progression. Predictive models for nodal metastasis, lymphovascular invasion (LVI) and distant metastasis were constructed using a multilevel reverse logistic regression model. RESULTS: Methylation of the retinoic acid receptor β gene, RARB, and that of the checkpoint with forkhead and ring finger gene, CHFR, was associated with tumour stage (RARB: 51·9 per cent for T1–2 versus 33·9 per cent for T3–4, P < 0·001; CHFR: 5·5 per cent for T1–2 versus 12·6 per cent for T3–4, P = 0·005). Gene methylation associated with nodal metastasis included RARB (47·1 per cent for N− versus 31·7 per cent for N+; P = 0·008), chemokine ligand 12, CXCL12 (12·3 per cent for N− versus 8·9 per cent for N+; P = 0·021), and death-associated protein kinase 1, DAPK1 (19·3 per cent for N− versus 12·3 per cent for N+; P = 0·022). RARB methylation was also associated with LVI (45·1 per cent for LVI− versus 31·7 per cent for LVI+; P = 0·038). Predictive models for nodal metastasis and LVI achieved sensitivities of 91·1 and 85·0 per cent, and specificities of 55·3 and 45·3 per cent, respectively. CONCLUSION: This methylation biomarker panel provides a step towards accurate discrimination of indolent and aggressive rectal cancer subtypes. This could offer an improvement over the current standard of care, whereby fit patients are offered radical surgery. May assist selection for organ preservation
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spelling pubmed-42820742015-01-15 Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation Leong, K J Beggs, A James, J Morton, D G Matthews, G M Bach, S P Br J Surg Original Articles BACKGROUND: Total mesorectal excision (TME) remains commonplace for T1–2 rectal cancer owing to fear of undertreating a small proportion of patients with node-positive disease. Molecular stratification may predict cancer progression. It could be used to select patients for organ-preserving surgery if specific biomarkers were validated. METHODS: Gene methylation was quantified using bisulphite pyrosequencing in 133 unirradiated rectal cancer TME specimens. KRAS mutation and microsatellite instability status were also defined. Molecular parameters were correlated with histopathological indices of disease progression. Predictive models for nodal metastasis, lymphovascular invasion (LVI) and distant metastasis were constructed using a multilevel reverse logistic regression model. RESULTS: Methylation of the retinoic acid receptor β gene, RARB, and that of the checkpoint with forkhead and ring finger gene, CHFR, was associated with tumour stage (RARB: 51·9 per cent for T1–2 versus 33·9 per cent for T3–4, P < 0·001; CHFR: 5·5 per cent for T1–2 versus 12·6 per cent for T3–4, P = 0·005). Gene methylation associated with nodal metastasis included RARB (47·1 per cent for N− versus 31·7 per cent for N+; P = 0·008), chemokine ligand 12, CXCL12 (12·3 per cent for N− versus 8·9 per cent for N+; P = 0·021), and death-associated protein kinase 1, DAPK1 (19·3 per cent for N− versus 12·3 per cent for N+; P = 0·022). RARB methylation was also associated with LVI (45·1 per cent for LVI− versus 31·7 per cent for LVI+; P = 0·038). Predictive models for nodal metastasis and LVI achieved sensitivities of 91·1 and 85·0 per cent, and specificities of 55·3 and 45·3 per cent, respectively. CONCLUSION: This methylation biomarker panel provides a step towards accurate discrimination of indolent and aggressive rectal cancer subtypes. This could offer an improvement over the current standard of care, whereby fit patients are offered radical surgery. May assist selection for organ preservation John Wiley & Sons, Ltd 2014-09 2014-07-23 /pmc/articles/PMC4282074/ /pubmed/25052224 http://dx.doi.org/10.1002/bjs.9571 Text en © 2014 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Leong, K J
Beggs, A
James, J
Morton, D G
Matthews, G M
Bach, S P
Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation
title Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation
title_full Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation
title_fullStr Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation
title_full_unstemmed Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation
title_short Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation
title_sort biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282074/
https://www.ncbi.nlm.nih.gov/pubmed/25052224
http://dx.doi.org/10.1002/bjs.9571
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