Significance of estrogen receptor 1 (ESR-1) gene imbalances in colon and hepatocellular carcinomas based on tissue microarrays analysis

Abstract

Estrogen receptor alpha-encoded by ESR1 gene-overexpression correlates with prognosis and response to specific chemotherapy in breast adenocarcinoma cases. Mechanisms of ESR-1 deregulation in carcinomas remain under investigation. To analyze ESR1 in carcinomas of different histogenesis. Using tissue microarray technology, 172 primary carcinomas including breast ductal adenocarcinomas (n=60), hepatocellular carcinomas (n=52), and colon adenocarcinomas (n=60) were cored and re-embedded in three paraffin blocks. Initial diagnosis was based on liquid based cytology (LiquiPrep/ThinPrep). Immunohistochemistry and fluorescence in situ hybridization were performed. Quantitative evaluation of ER-a protein levels was assessed by applying digital image analysis. ER-a overexpression was observed in 41/60 (68.3%), 23/52 (44.2%) and 4/60 (6.6%) cases, respectively. ESR1 gene multiple copies were confirmed in 13/60 (21.6%) breast adenocarcinomas, but high amplification only in 8/13 (62.8%). Allelic absence was identified in 3/52 (5.7%) hepatocellular carcinomas, whereas colon adenocarcinomas demonstrated gene gains in 5/60 (8.3%) cases referred to chr 6 aneuploidy and not to amplification. ER-a overall expression was associated strongly to ESR1 gene copies only in breast carcinoma (P=0.036). ESR-1 gene overexpression happens frequently in breast cancer, but only a subset of them are high amplified cases correlated to increased response rates in hormonal therapy (tamoxifen). Absence of this mechanism in hepatocellular and colon carcinomas maybe is a negative factor for applying this therapy. This is a pattern of histo-genetic depended targeted therapeutic strategy.

Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology

“…In contrast, wildtype ER-␤ was expressed more often in HCV patients than in HBV patients (95.7% vs. 44.4%; p < 0.05). Within Western population, 33-46% of HCC samples showed overexpression of ER (Tsiambas et al, 2011;Garcia-Leiva et al, 2006;Moon et al, 2004). In summary, aberrant ER, both in Asian (Sheng et al, 2014) and Western (Villa et al, 1995) population have been described and shown to have an impact in patients prognosis.…”

Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate

“…For example, using a cut off of > 2.0 instead of ≥ 2.0 for amplification calling, or a ratio 2.2 instead of 1.8, can change the amplification frequency by almost 50% [22,49,50] . In a recent study done with use of next-generation sequencing (NGS), the threshold of ≥ 6 average copies [as recommended for ERBB2 (HER2) testing [46] ] in tissue samples with tumor purity of > 20% resulted in only 0.8% ESR1 amplification across samples [51] .…”

“…However, regardless of the prevalence of gene amplification across a tumor type, the increase in copy number for a given gene is a well-known mechanism for increasing its expression [16,17,44,92,93] ; accordingly, gene amplification is assumed to be a marker for a tumor's addiction to the expression of the amplified gene [18,19] . Several reports, including those that use DNA-specific methods for ESR1 copy number determination, have documented a significant correlation between ESR1 gene amplification and ERα protein expression [24,25,28,50,67,[83][84][85][86][87][88][89][90][91][92][93][94][95][96][97] ( Table 1).…”

“…The controversy about the frequency of [41] . Tsiambas et al [50] 60 21.6 -FISH 6 Dunbier et al [95] 44 20.5 0 Gene chip 7 Laenkholm et al [96] 220 42.4 8.8 FISH 8…”

“…While the established FISH method seems suggested to be a valuable approach for studying the clinical relevance of ESR1 amplification or gene status in breast cancer [3,[24][25][26]40,41,50,96] (Figure 7), there is no established consensus on how the interpretation of signal patterns or of gene status classification thresholds and definitions. As such, the nature of the ESR1 gene status on the level of nucleic acids (DNA or RNA) might appear to be of secondary importance when considering a reproducible phenomenon that has an established standard diagnostic method and that is potentially applicable as a clinical marker [3] .…”