Oestrogen receptor gene (ESR1) amplification is frequent in endometrial carcinoma and its precursor lesions

Abstract

Oestrogen receptor alpha (ER) plays a critical, diverse and not fully understood role in endometrial carcinoma. Most endometrial carcinomas express ER and some of these tumours respond favourably to anti-oestrogen therapy. On the other hand, tamoxifen therapy constitutes a major risk factor for endometrial carcinoma development. Amplification of the ESR1 gene encoding ER was recently shown to constitute a mechanism for ER over-expression in breast carcinoma. This study was designed to determine the potential role of ESR1 amplifications in endometrial carcinoma. Tissue microarrays of 368 endometrial carcinomas and large sections of 43 cases of endometrial hyperplasia were analysed for ESR1 gene amplification and ER protein expression by means of fluorescence in situ hybridization (FISH) and immunohistochemistry. FISH revealed ESR1 amplification in 40/176 (23%) cancers, 6/19 (32%) atypical complex hyperplasias, 3/10 (30%) complex hyperplasias without atypia and 2/14 (14%) simple hyperplasias without atypia. Strong ER protein expression was significantly linked to ESR1 amplification in endometrial carcinoma (p = 0.0036). These data indicate that ESR1 amplification might be one mechanism for ER over-expression in endometrial carcinoma, and suggest an early role for ESR1 amplification in the development of a significant fraction of endometrial carcinoma. Given the predictive role of ESR1 amplification for tamoxifen response in breast carcinoma, it will be interesting to investigate the response of ESR1-amplified endometrial cancers to anti-oestrogenic drugs.

Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing

“…A closer look at the specific genes that contain somatic insertions reveals several known cancer genes, such as RUNX1, a putative tumor suppressor in gastric carcinoma (Silva et al 2003) that is subject to recurrent loss-of-function inactivation in breast cancer and esophageal adenocarcinoma (Banerji et al 2012;Dulak et al 2012;Koboldt et al 2012), as well as in the exon of REV3L, which has been implicated as a novel tumor suppressor in colorectal and lung cancers, and is involved in maintenance of genomic stability (Brondello et al 2008;Zhang et al 2013). One UCEC sample contains an intronic somatic L1 insertion in the ESR1 gene, an important hormone receptor often overexpressed in endometrial and breast cancers (Lebeau et al 2008). While previous studies found somatic insertion only in intronic regions, we identify 21 somatic events in or within 200 bp of exons of genes such as CYR61 and HSF2, with seven falling in the protein-coding sequence itself ( Fig.…”

Combined PTEN and p27kip1 Protein Expression Patterns Are Associated with Obesity and Prognosis in Endometrial Carcinomas

“…Recently, p27 has been studied by Horree et al (37) and showed a very heterogeneous expression in EEC. Although the tissue microarray approach has limitations in studying heterogeneous biomarkers, we have recently shown that tissue microarrays can reliably detect genetic alterations in heterogeneous cell populations of endometrial carcinoma (32). In this study, we aimed to determine the direct relationship of PTEN and p27 in welldefined cell populations, which is possible by tissue microarrays.…”

“…Selection criteria were based on availability, presence, and size of representative tumor areas in paraffin blocks. Tissue microarrays were constructed as described previously (31,32). Briefly, a tissue arraying instrument (Beecher Instruments) was used to create holes in a recipient paraffin block and to acquire tissue cores from the donor block by a thin-walled needle with an inner diameter of 0.6 mm, held in a X-Y precision guide.…”

Estrogen receptor 1 mRNA is a prognostic factor in ovarian carcinoma: determination by kinetic PCR in formalin-fixed paraffin-embedded tissue

“…Interesting research topics for future studies will be the evaluation of the mechanisms of ESR1 mRNA overexpression, such as ESR1 gene amplification that has been reported in breast and endometrial carcinoma (Holst et al 2007, Lebeau et al 2008. Similarly, progesterone receptor expression might be helpful in the prediction of patient prognosis and therapy response and should be investigated further.…”