Abstract
BackgroundUterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma. Large-scale comprehensive efforts have resulted in an improved molecular understanding of its pathogenesis, and the p53 pathway has been proposed as a key player and is potentially targetable. Here we attempt to further portray the p53 pathway in USC by assessing p53 isoform expression.MethodsWe applied quantitative Real-Time PCRs (RT-qPCR) for expression analyses of total p53 mRNA as well as quantitative distinction of p53β, p53γ, and the total mRNA of amino-terminal truncated Δ40p53 and Δ133p53 in a retrospective cohort of 37 patients with USC. TP53 mutation status was assessed by targeted massive parallel sequencing. Findings were correlated with clinical data.ResultsThe p53 isoform expression landscape in USCs was heterogeneous and dominated by total Δ133p53, while the distinct p53β and p53γ variants were found at much lower levels. The isoform expression profiles varied between samples, while their expression was independent of TP53 mutation status. We found high relative p53γ expression to be associated with reduced progression-free survival (PFS).ConclusionsThis is the first indication that elevated p53γ expression is associated with reduced PFS in USC. This single-center study may offer some insight in the landscape of p53 isoform expression in USC, but further validation studies are crucial to understand the context-dependent and tissue-specific role of the p53 isoform network in gynecological cancer.
Highlights
Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma
We present the mRNA expression analysis of the main p53 isoforms in combination with Tumor protein p53 (TP53) mutational status in serous endometrial cancers
A substantial number of patients were diagnosed in the early stages of the disease as 41% (15 of 37) and 8% (3 of 37) of the women presented with The International Federation of Gynecology and Obstetrics (FIGO) stage I and stage II, respectively
Summary
Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma. Largescale comprehensive efforts have resulted in an improved molecular understanding of its pathogenesis, and the p53 pathway has been proposed as a key player and is potentially targetable. Endometrial cancer is the most common gynecological malignancy in the Western world [1, 2], with the incidence increasing in recent years [3]. Through large-scale comprehensive molecular characterization, endometrial carcinomas have recently been classified into four specific subgroups and we have gained a new understanding of the biology of USC [7]. In USC, somatic mutations in the TP53 gene are a common characteristic and seen in more than 90% of cases, resulting in genetic instability and widespread copy-number alterations. Other subtype-specific molecular features are present, including increased transcriptional activity of genes such as CCNE1 or MYC, that are involved in cell cycle regulation
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