Prognostic DNA methylation markers for hormone receptor breast cancer: a systematic review

Abstract

Background: In patients with hormone receptor-positive breast cancer, differentiating between patients with a low and a high risk of recurrence is an ongoing challenge. In current practice, prognostic clinical parameters are used for risk prediction. DNA methylation markers have been proven to be of additional prognostic value in several cancer types. Numerous prognostic DNA methylation markers for breast cancer have been published in the literature. However, to date, none of these markers are used in clinical practice.

Methods: We conducted a systematic review of PubMed and EMBASE to assess the number and level of evidence of published DNA methylation markers for hormone receptor-positive breast cancer. To obtain an overview of the reporting quality of the included studies, all were scored according to the REMARK criteria that were established as reporting guidelines for prognostic biomarker studies.

Results: A total of 74 studies were identified reporting on 87 different DNA methylation markers. Assessment of the REMARK criteria showed variation in reporting quality of the studies. Eighteen single markers and one marker panel were studied in multiple independent populations. Hypermethylation of the markers RASSF1, BRCA, PITX2, CDH1, RARB, PCDH10 and PGR, and the marker panel GSTP1, RASSF1 and RARB showed a statistically significant correlation with poor disease outcome that was confirmed in at least one other, independent study.

Conclusion: This systematic review provides an overview on published prognostic DNA methylation markers for hormone receptor-positive breast cancer and identifies eight markers that have been independently validated. Analysis of the reporting quality of included studies suggests that future research on this topic would benefit from standardised reporting guidelines.

Keywords: Biomarkers; Breast cancer; DNA methylation; Hormone receptor positive; Luminal breast cancer; Oestrogen receptor positive; Prognosis; Promoter CpG island methylation; Survival.

Fig. 1

Flowchart showing the study identification process. In total, 72 studies were included in this systematic review

Fig. 2

Quality assessment of included studies. The histogram depicts the completeness of reporting per remark item. The percentage of studies that reported any information is reported per item, as well as the percentage of studies that reported all required information

Fig. 3

Forest plots of all methylation markers reported in two or more independent study populations. HRs with a statistically significant association are depicted with a solid line; HRs of reported markers with no significant association are depicted with a dotted line; univariate HRs (^a) and confidence intervals (CI) are reported unless multivariate HRs (^b) were available. Per marker, if results are derived from the same cohort, but with differing characteristics, such as differing DNA origin or location of methylation, this is represented by a coloured population bar. Per marker, if results originated from the same research group, this is indicated by an asterisk (*). Due to the vast number of individual results for these markers, for visualisation purposes, per marker, this figure shows one result per investigated population and tissue type. For a full representation of markers reported in two or more independent study populations, see Additional file 5: Table S5

Fig. 4

Methylation markers studied in at least two independent populations, separated by relation to prognosis and achieved LOE. Underlined markers were analysed as hypomethylation markers. Italic markers do not correspond to Ref-Seq registered genes. Markers GSTP1 (*) and ESR (**) were both significantly correlated with good and poor prognosis in separate studies. The mentioned panel (***) is a multigene panel consisting of markers GSTP1, RASSF1 and RARB