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Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome

Although hypomethylating therapy (HMT) is the first line therapy in higher-risk myelodysplastic syndromes (MDS), predicting response to HMT remains an unresolved issue. We aimed to identify mutations associated with response to HMT and survival in MDS. A total of 107 Korean patients with MDS who und...

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Autores principales: Jung, Seung-Hyun, Kim, Yoo-Jin, Yim, Seon-Hee, Kim, Hye-Jung, Kwon, Yong-Rim, Hur, Eun-Hye, Goo, Bon-Kwan, Choi, Yun-Suk, Lee, Sug Hyung, Chung, Yeun-Jun, Lee, Je-Hwan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342416/
https://www.ncbi.nlm.nih.gov/pubmed/27419369
http://dx.doi.org/10.18632/oncotarget.10526
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author Jung, Seung-Hyun
Kim, Yoo-Jin
Yim, Seon-Hee
Kim, Hye-Jung
Kwon, Yong-Rim
Hur, Eun-Hye
Goo, Bon-Kwan
Choi, Yun-Suk
Lee, Sug Hyung
Chung, Yeun-Jun
Lee, Je-Hwan
author_facet Jung, Seung-Hyun
Kim, Yoo-Jin
Yim, Seon-Hee
Kim, Hye-Jung
Kwon, Yong-Rim
Hur, Eun-Hye
Goo, Bon-Kwan
Choi, Yun-Suk
Lee, Sug Hyung
Chung, Yeun-Jun
Lee, Je-Hwan
author_sort Jung, Seung-Hyun
collection PubMed
description Although hypomethylating therapy (HMT) is the first line therapy in higher-risk myelodysplastic syndromes (MDS), predicting response to HMT remains an unresolved issue. We aimed to identify mutations associated with response to HMT and survival in MDS. A total of 107 Korean patients with MDS who underwent HMT (57 responders and 50 non-responders) were enrolled. Targeted deep sequencing (median depth of coverage 1,623X) was performed for 26 candidate MDS genes. In multivariate analysis, no mutation was significantly associated with response to HMT, but a lower hemoglobin level (<10g/dL, OR 3.56, 95% CI 1.22-10.33) and low platelet count (<50,000/μL, OR 2.49, 95% CI 1.05-5.93) were independent markers of poor response to HMT. In the subgroup analysis by type of HMT agents, U2AF1 mutation was significantly associated with non-response to azacitidine, which was consistent in multivariate analysis (OR 14.96, 95% CI 1.67-134.18). Regarding overall survival, mutations in DNMT1 (P=0.031), DNMT3A (P=0.006), RAS (P=0.043), and TP53 (P=0.008), and two clinical variables (male-gender, P=0.002; IPSS-R H/VH, P=0.026) were independent predicting factors of poor prognosis. For AML-free survival, mutations in DNMT3A (P<0.001), RAS (P=0.001), and TP53 (P=0.047), and two clinical variables (male-gender, P=0.024; IPSS-R H/VH, P=0.005) were independent predicting factors of poor prognosis. By combining these mutations and clinical predictors, we developed a quantitative scoring model for response to azacitidine, overall- and AML-free survival. Response to azacitidine and survival rates became worse significantly with increasing risk-scores. This scoring model can make prognosis prediction more reliable and clinically applicable.
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spelling pubmed-53424162017-03-22 Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome Jung, Seung-Hyun Kim, Yoo-Jin Yim, Seon-Hee Kim, Hye-Jung Kwon, Yong-Rim Hur, Eun-Hye Goo, Bon-Kwan Choi, Yun-Suk Lee, Sug Hyung Chung, Yeun-Jun Lee, Je-Hwan Oncotarget Research Paper Although hypomethylating therapy (HMT) is the first line therapy in higher-risk myelodysplastic syndromes (MDS), predicting response to HMT remains an unresolved issue. We aimed to identify mutations associated with response to HMT and survival in MDS. A total of 107 Korean patients with MDS who underwent HMT (57 responders and 50 non-responders) were enrolled. Targeted deep sequencing (median depth of coverage 1,623X) was performed for 26 candidate MDS genes. In multivariate analysis, no mutation was significantly associated with response to HMT, but a lower hemoglobin level (<10g/dL, OR 3.56, 95% CI 1.22-10.33) and low platelet count (<50,000/μL, OR 2.49, 95% CI 1.05-5.93) were independent markers of poor response to HMT. In the subgroup analysis by type of HMT agents, U2AF1 mutation was significantly associated with non-response to azacitidine, which was consistent in multivariate analysis (OR 14.96, 95% CI 1.67-134.18). Regarding overall survival, mutations in DNMT1 (P=0.031), DNMT3A (P=0.006), RAS (P=0.043), and TP53 (P=0.008), and two clinical variables (male-gender, P=0.002; IPSS-R H/VH, P=0.026) were independent predicting factors of poor prognosis. For AML-free survival, mutations in DNMT3A (P<0.001), RAS (P=0.001), and TP53 (P=0.047), and two clinical variables (male-gender, P=0.024; IPSS-R H/VH, P=0.005) were independent predicting factors of poor prognosis. By combining these mutations and clinical predictors, we developed a quantitative scoring model for response to azacitidine, overall- and AML-free survival. Response to azacitidine and survival rates became worse significantly with increasing risk-scores. This scoring model can make prognosis prediction more reliable and clinically applicable. Impact Journals LLC 2016-07-11 /pmc/articles/PMC5342416/ /pubmed/27419369 http://dx.doi.org/10.18632/oncotarget.10526 Text en Copyright: © 2016 Jung et al. http://creativecommons.org/licenses/by/2.5/ 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.
spellingShingle Research Paper
Jung, Seung-Hyun
Kim, Yoo-Jin
Yim, Seon-Hee
Kim, Hye-Jung
Kwon, Yong-Rim
Hur, Eun-Hye
Goo, Bon-Kwan
Choi, Yun-Suk
Lee, Sug Hyung
Chung, Yeun-Jun
Lee, Je-Hwan
Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
title Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
title_full Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
title_fullStr Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
title_full_unstemmed Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
title_short Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
title_sort somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342416/
https://www.ncbi.nlm.nih.gov/pubmed/27419369
http://dx.doi.org/10.18632/oncotarget.10526
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