Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome

Abstract

BackgroundAberrant promoter CpG island hypermethylation is associated with transcriptional silencing. Tumor suppressor genes are the key targets of hypermethylation in breast cancer and therefore may lead to malignancy by deregulation of cell growth and division. Our previous pilot study with pairs of malignant and normal breast tissues identified correlated methylation of two pairs of genes - HIN-1/RASSFIA and RIL/CDH13 - with expression of estrogen receptors (ER), progesterone receptors (PR), and HER2 (HER2). To determine the impact of methylation on clinical outcome, we have conducted a larger study with breast cancers for which time to first recurrence and overall survival are known.MethodsTumors from 193 patients with early stage breast cancer who received no adjuvant systemic therapy were used to analyze methylation levels of RIL, HIN-1, RASSF1A and CDH13 genes for associations with known predictive and prognostic factors and for impact on time to first recurrence and overall survival.ResultsIn this study, we found that ER was associated with RASSF1A methylation (p < 0.001) and HIN-1 methylation (p = 0.002). PR was associated with RIL methylation (p = 0.012), HIN-1 (p = 0.002), and RASSF1A methylation (p = 0.019). Tumor size was associated with RIL and CDH13 methylation (both p = 0.002), and S-phase was associated with RIL methylation (p = 0.036). Only RASSF1A was associated with worse time to first recurrence (p = 0.045) and worse overall survival (p = 0.016) after adjusting for age, tumor size, S-phase, estrogen receptor and progesterone receptor.ConclusionsMethylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancers was associated with clinical characteristics, but only RASSF1A methylation was associated with time to first recurrence and overall survival. Our data suggest that RASSF1A methylation could be a potential prognostic biomarker.

Analysis of PDLIM4 Expression in Different Subtypes of Breast Cancer

“…Several data provide information about the correlation between the level of PDLIM4 and status of one of the main biomarkers, used in clinical practice -progesterone receptors (PR) (Xu, Shetty et al 2012). High methylation level of PDLIM4 associated with transcriptional silencing, was found in PR negative cancer, in receptorpositive tumors methylation level of PDLIM4 was lower on average (Xu, Shetty et al 2012).…”

Epigenetic alterations in endocrine-related cancer

“…Other tumor suppressor genes such as P16 and RASSF1A or solute carrier family 25A member 43 (SLC25A43) have also been found hypermethylated in breast cancer (Lindqvist et al 2012, Xu et al 2012; RASSF1A in particular could be used as a prognostic marker in the diagnosis of breast cancer (Lindqvist et al 2012, Xu et al 2012, and its role in cancer has also been described (see earlier sections) in non-small cell lung and thyroid tumors. Recently, Faryna et al (2012) have demonstrated higher methylation in BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 genes in low-grade breast tumors.…”

Modern approach of breast cancer diagnostics

“…К таким генам относятся: регуляторы клеточного цикла (CDKN2A, CDKN2В, р14/ARF, RB1, циклины D1 и D2), гены, ответственные за апоптоз (TP53, CDKN1, HOX5, MDM2, DAPK1, TWIST1, YTMS1, FHIT, RASSF1A, HIC-1, HIN-1), гены, ответственные за инвазию и метастазирование опухолевых клеток (CDH1, CDH13, CTNB), гены гормон-и рецептор-опосредованной передачи сигналов (ESR1, PR, ER, RAR, NORE1), а также гены систем репарации ДНК (BRCA1, MGMT) и детоксикации ксенобиотиков (GSTP1) [93][94][95][96][97]. Сведения о частоте выявления эпигенетических изменений в ДНК клеток опухоли представлены в таблице 3 [98][99][100][101][102][103][104][105][106][107][108][109][110]. …”