Abstract
Endometrioid endometrial cancer (EEC) is the commonest form of endometrial cancer and can be divided into estrogen receptor (ER) positive and negative subtypes. The mutational profiles of EEC have been shown to aid in tailoring treatment; however, little is known about the differences between the gene mutation profiles between these two subtypes. This study aims to investigate the gene mutation profile in ER positive and negative EEC, and to further elucidate the role of WHSC1 mutations in this cancer. EEC and normal endometrial tissues were obtained from 29 patients and subjected to next-generation sequencing (NGS) using Ion Ampliseq Comprehensive Cancer PanelTM targeting 409 cancer related. A total of 741 non-synonymous alterations were identified from 272 genes in ER positive subtype while 448 non-synonymous variants were identified from 221 genes in ER negative subtype. PTEN is the most frequently altered gene in ER positive subtype (64%, 7/11) while ARID1A is the most frequently altered gene in ER negative subtype (50%, 4/8). We also identified alterations in ERRB3 (36%, 4/11), GNAS (36%, 4/11), and WHSC1 (27%, 3/11) in the ER positive subtype. WHSC1 R1126H and L1268P were shown to significantly increase cell viability, proliferation, migration, and survival. In addition, reduction in ER expression sensitized EEC-1 cell with WHSC1 L1268P mutant to Fulvestrant treatment. We revealed the mutational spectra of ER positive and ER negative EEC that could lead to better understanding of the biological mechanisms of endometrial cancer and may ultimately result in improvement of treatment options and patient prognosis.
Highlights
Endometrial cancer is the sixth most common cancer diagnosed among women with approximately 320,000 new cases and 76,000 deaths worldwide each year (Ferlay et al, 2013)
Clinical specimens used in this study were collected from patients who were treated at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC)
Our study showed that PIK3CA mutations were comparable between both estrogen receptor (ER) subtypes with more events occurring in the ER negative subtype compared to ER positive subtype
Summary
Endometrial cancer is the sixth most common cancer diagnosed among women with approximately 320,000 new cases and 76,000 deaths worldwide each year (Ferlay et al, 2013). The less common Type II non-endometrioid endometrial cancer (NEEC), which accounts for 10–20% of all cases, follows the estrogen unrelated pathway and arise in background of atrophic endometrium (Doll et al, 2008). This type has a poorer prognosis and usually presents at the advanced stage, especially in older postmenopausal women (Amant et al, 2005). NEEC is associated with a high mortality, reduced survival rates, and tendency to recur This dualistic categorization has been incorporated into clinical decision-making algorithms to define high-risk patients, yet its prognostic value remains limited because one-fifth of EEC (i.e., Type I) will eventually relapse, whereas half of NEEC (i.e., Type II) do not (Bokhman, 1983). 15–20% of EEC are high-grade lesions, and it is unclear where they fit into the dualistic model (Zannoni et al, 2013)
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