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Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer

BACKGROUND: More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has b...

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Autores principales: Liu, Xiao-ran, Zhang, Ru-yan, Gong, Hao, Rugo, Hope S., Chen, Ling-bo, Fu, Yuan, Che, Jian-wei, Tie, Jian, Shao, Bin, Wan, Feng-ling, Kong, Wei-yao, Song, Guo-hong, Jiang, Han-fang, Xu, Guo-bing, Li, Hui-ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057408/
https://www.ncbi.nlm.nih.gov/pubmed/32129154
http://dx.doi.org/10.1177/1533033819896331
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author Liu, Xiao-ran
Zhang, Ru-yan
Gong, Hao
Rugo, Hope S.
Chen, Ling-bo
Fu, Yuan
Che, Jian-wei
Tie, Jian
Shao, Bin
Wan, Feng-ling
Kong, Wei-yao
Song, Guo-hong
Jiang, Han-fang
Xu, Guo-bing
Li, Hui-ping
author_facet Liu, Xiao-ran
Zhang, Ru-yan
Gong, Hao
Rugo, Hope S.
Chen, Ling-bo
Fu, Yuan
Che, Jian-wei
Tie, Jian
Shao, Bin
Wan, Feng-ling
Kong, Wei-yao
Song, Guo-hong
Jiang, Han-fang
Xu, Guo-bing
Li, Hui-ping
author_sort Liu, Xiao-ran
collection PubMed
description BACKGROUND: More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has been implicated in oncogenesis and drug resistance. PURPOSE: We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy. METHODS: We prospectively recruited 16 patients who were receiving first-line therapy in our center. All patients received exemestane-based hormone therapy after enrollment. We collected blood samples at baseline, first follow-up (after 2 therapeutic cycles) and at detection of disease progression. Disease that progressed within 6 months under exemestane treatment was considered exemestane resistance but was considered relatively exemestane-sensitive otherwise. We obtained circulating tumor DNA-derived methylomes using the whole-genome bisulfide sequencing method. Methylation calling was done by BISMARK software; differentially methylated regions for exemestane resistance were calculated afterward. RESULTS: Median follow-up for the 16 patients was 19.0 months. We found 7 exemestane resistance-related differentially methylated regions, located in different chromosomes, with both significantly different methylation density and methylation ratio. Baseline methylation density and methylation ratio of chromosome 6 [32400000-32599999] were both high in exemestane resistance. High baseline methylation ratios of chromosome 3 [67800000-67999999] (P = .013), chromosome 3 [140200000-140399999] (P = .037), and chromosome 12 [101200000-101399999] (P = .026) could also predict exemestane resistance. During exemestane treatment, synchronized changes in methylation density and methylation ratio in chromosome 6 [32400000-32599999] could accurately stratify patients in terms of progression-free survival (P = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 [149600000-149799999] were 0.066 and 0.076, respectively. CONCLUSION: Methylation change in chromosome 6 [149600000-149799999] is an ideal predictor of exemestane resistance with great clinical potential.
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spelling pubmed-70574082020-03-16 Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer Liu, Xiao-ran Zhang, Ru-yan Gong, Hao Rugo, Hope S. Chen, Ling-bo Fu, Yuan Che, Jian-wei Tie, Jian Shao, Bin Wan, Feng-ling Kong, Wei-yao Song, Guo-hong Jiang, Han-fang Xu, Guo-bing Li, Hui-ping Technol Cancer Res Treat Original Article BACKGROUND: More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has been implicated in oncogenesis and drug resistance. PURPOSE: We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy. METHODS: We prospectively recruited 16 patients who were receiving first-line therapy in our center. All patients received exemestane-based hormone therapy after enrollment. We collected blood samples at baseline, first follow-up (after 2 therapeutic cycles) and at detection of disease progression. Disease that progressed within 6 months under exemestane treatment was considered exemestane resistance but was considered relatively exemestane-sensitive otherwise. We obtained circulating tumor DNA-derived methylomes using the whole-genome bisulfide sequencing method. Methylation calling was done by BISMARK software; differentially methylated regions for exemestane resistance were calculated afterward. RESULTS: Median follow-up for the 16 patients was 19.0 months. We found 7 exemestane resistance-related differentially methylated regions, located in different chromosomes, with both significantly different methylation density and methylation ratio. Baseline methylation density and methylation ratio of chromosome 6 [32400000-32599999] were both high in exemestane resistance. High baseline methylation ratios of chromosome 3 [67800000-67999999] (P = .013), chromosome 3 [140200000-140399999] (P = .037), and chromosome 12 [101200000-101399999] (P = .026) could also predict exemestane resistance. During exemestane treatment, synchronized changes in methylation density and methylation ratio in chromosome 6 [32400000-32599999] could accurately stratify patients in terms of progression-free survival (P = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 [149600000-149799999] were 0.066 and 0.076, respectively. CONCLUSION: Methylation change in chromosome 6 [149600000-149799999] is an ideal predictor of exemestane resistance with great clinical potential. SAGE Publications 2020-03-04 /pmc/articles/PMC7057408/ /pubmed/32129154 http://dx.doi.org/10.1177/1533033819896331 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Article
Liu, Xiao-ran
Zhang, Ru-yan
Gong, Hao
Rugo, Hope S.
Chen, Ling-bo
Fu, Yuan
Che, Jian-wei
Tie, Jian
Shao, Bin
Wan, Feng-ling
Kong, Wei-yao
Song, Guo-hong
Jiang, Han-fang
Xu, Guo-bing
Li, Hui-ping
Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer
title Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer
title_full Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer
title_fullStr Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer
title_full_unstemmed Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer
title_short Methylome Variation Predicts Exemestane Resistance in Advanced ER(+) Breast Cancer
title_sort methylome variation predicts exemestane resistance in advanced er(+) breast cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057408/
https://www.ncbi.nlm.nih.gov/pubmed/32129154
http://dx.doi.org/10.1177/1533033819896331
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