Association of somatic DNA methylation variability with progression-free survival and toxicity in ovarian cancer patients

作者：Flanagan J M; Wilhelm Benartzi C S; Metcalf M; Kaye S B; Brown R^*

来源：Annals of Oncology, 2013, 24(11): 2813-2818.

DOI：10.1093/annonc/mdt370

• clinical trial
• DNA methylation
• ovarian cancer
• pharmacoepigenetics
• prognosis
• toxicity

We have addressed whether inter-individual methylation variation in somatic (white blood cells, WBCs) DNA of ovarian cancer patients provides potential for prognostic and/or pharmacoepigenetic stratification.
WBC DNA methylation was analysed by bisulphite pyrosequencing at ataxia telangiectasia mutated (ATM), estrogen receptor 1 (ESR1), progesterone receptor (PGR), mutL homologue 1 (MLH1), breast cancer susceptibility gene (BRCA1), secreted frizzled-related protein 1 (SFRP1), stratifin (SFN), retinoic acid receptor beta (RARB) loci and the repetitive element LINE1 in 880 SCOTROC1 trial patients [paclitaxel (Taxol)-carboplatin versus docetaxel (Taxotere)-carboplatin as primary chemotherapy for stage Ic-IV epithelial ovarian cancer].
We observed no significant associations (P < 0.005, after correction for multiple testing) for progression-free survival (PFS) using test and validation sets. However, we did identify mean SFN methylation associated with PFS (hazard ratio, HR = 1.01 per 1% increase in methylation, q = 0.028); particularly in the paclitaxel (HR = 1.01, q = 0.006), but not in the docetaxel arm in stratified analyses. Furthermore, higher methylation within the ESR1 gene was associated with CA125 response (odds ratio, OR = 1.06, q = 0.04) and with neuropathy (HR = 0.95, q = 0.002), but only in the paclitaxel arm of the trial.
This is the first study linking DNA methylation variability in WBC to clinical outcomes for any tumour type; the data generated on novel prognostic and pharmacoepigenetic DNA methylation biomarkers in the circulation now need independent further evaluation.

• 出版日期2013-11