Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Nair A BonitoRobert Brown

Abstract

Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P < 0.05, q < 0.05, n = 78), have poor RECIST response (P < 0.05, q < 0.05, n = 61), and are associated with PFS in an independent cohort (n = 146). A decrease in m...Continue Reading

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Citations

Jan 1, 2017·Convergent Science Physical Oncology·Paula CunneaChristina Fotopoulou
Aug 10, 2017·Cell Biochemistry and Function·Ya-Lei CaoQin Li
Mar 9, 2019·Molecular and Clinical Oncology·Julie L HentzeEstrid V Høgdall
Oct 15, 2019·Frontiers in Cell and Developmental Biology·Alka SinghManisha Sachan
Apr 24, 2020·Cancer Cell International·Tian-Fu LiYing Lin
Sep 25, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·James M FlanaganRobert Brown
Jan 10, 2021·Seminars in Cancer Biology·Lei GuoYun Huang
Mar 18, 2021·Scientific Reports·Jesus Gonzalez BosquetKimberly K Leslie
Sep 26, 2020·Biochemical Pharmacology·Ying ZhouLushan Yu
Apr 26, 2017·Endocrinología, Diabetes Y Nutrición·Sandra Rodríguez-RoderoEdelmiro Menéndez Torre

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