Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers

Abstract

IntroductionMetastasis represents a major adverse step in the progression of breast carcinoma. Lymph node invasion is the most relevant prognostic factor; however little is known on the molecular events associated with lymph node metastasis process. This study is to investigate the status and role of methylation in lymph node metastatic tumors.Materials and methodsBisulfite pyrosequencing is used to screen 6 putative tumor suppressor genes (HIN-1, RASSF1A, RIL, CDH13, RARβ2 and E-cadherin) in 38 pairs of primary breast tumors and lymph node metastases.ResultsWe found that HIN-1, CDH13, RIL, RASSF1A and RARβ2 were frequently methylated both in primary and metastatic tissues (range: 55.3%~89.5%). E-cadherin was not frequently methylated in either setting (range: 18.4%~23.7%). The methylation status of HIN-1, CDH13, RIL, and RARβ2 in lymph nodes metastasis were correlated with that in primary tumors. The Pearson correlation values ranged from 0.624 to 0.472 (p values < 0.01 to 0.001). Interestingly, we observed an association between HIN-1 methylation and hormone status in metastatic lymph nodes. Hypermethylation of HIN-1 in metastasis lymph nodes was significantly associated with expression of ER (odds ratio, 1.070; P = 0.024) and with PR (odds ratio, 1.046; P = 0.026).ConclusionsThis study suggests that hypermethylation of tumor suppressor genes is extended from primary to metastatic tumors during tumor progression.

Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array

“…Localized within a ~0.11 Mb overlap (3, 50352133-50461061) and altered in 29% of our cohort, is the putative RASSF1 TSG that produces two main splice variants. RASSF1A is very frequently silenced via CpG island hypermethylation in breast cancer cases (53). It has also been suggested to regulate the G1-S transition via the modulation of the CCND1 level (54).…”

The Electronics of HER2/neu Positive Breast Cancer Cells

“…Generally, genes important in apoptosis, metastasis, cell cycle regulation, angiogenesis and genes that encode non-coding RNAs (ncRNAs) are differentially methylated in breast cancer (Jovanovic et al 2010). This improper methylation pattern begins in the primary tumor and increases upon metastasis, leading to alterations in gene expression (Feng et al 2010). This change occurs in concert with an alteration in histone methylation, leading to a decrease in the expression of tumor suppressor genes in breast cancer (Sharma et al 2010).…”

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]. …”