Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

Abstract

Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (Po0.001), preserved ARID1A immunoreactivity (P ¼ 0.017) and infrequent PIK3CA mutation (P ¼ 0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age 445 (P ¼ 0.045) and preserved ARID1A expression (P ¼ 0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P ¼ 0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P ¼ 0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy. Modern Pathology (2015) 28, 303-311; doi:10.1038/modpathol.2014 published online 1 August 2014 Ovarian clear cell carcinoma represents 5-25% of all epithelial ovarian carcinomas with geographic variation. 1 Compared with high-grade serous adenocarcinomas, ovarian clear cell carcinomas are characterized by a higher incidence among Asians, younger patient age and early tumor staging at presentation, association with endometriosis, higher frequencies of AT-rich interactive domain 1 A (ARID1A) mutation and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, and higher resistance to first-line platinum and taxane-based chemotherapy.

A novel truncated form of HMGA2 in tumors of the ovaries

“…Notably, TERT C228T appears to be recurrent in ovarian fibromas, but further studies of a larger cohort are necessary to more reliably evaluate the frequency of this mutation. The present study did not find any TERT mutations in the clear cell samples, however, Huang et al (25) found the mutation in 16% of tumors (9/56 tumors) of this carcinoma subtype. The discrepancy between the present data and previous data may be due to the low number of clear cell carcinomas analyzed in the present cohort (n=12).…”

Are clear cell carcinomas of the ovary and endometrium phenotypically identical? A proteomic analysis

“…However, if any differences are present, they may be highly significant. For example, recent studies indicate that mutations of telomerase reverse transcriptase promoter are similarly prevalent in ECCCs and OCCCs but that mutations at −124CNT are less frequent in ECCCs (33%) than in OCCCs (89%) [24]. Importantly, telomerase reverse transcriptase promoter mutation is an independently negative prognostic factor in early stage OCCCs but is not associated with clinicopathologic factors in ECCCs [24].…”

“…For example, recent studies indicate that mutations of telomerase reverse transcriptase promoter are similarly prevalent in ECCCs and OCCCs but that mutations at −124CNT are less frequent in ECCCs (33%) than in OCCCs (89%) [24]. Importantly, telomerase reverse transcriptase promoter mutation is an independently negative prognostic factor in early stage OCCCs but is not associated with clinicopathologic factors in ECCCs [24]. Similarly, several groups have shown that p53 alterations, which are uncommon in OCCCs, are present in up to 37.5% of ECCCs [14,17,18] and may define a more clinically aggressive, "serous-like" subset [ 14,25].…”

“…The primary antibodies that were ultimately used included annexin A4 (AnxA4, dilution 1:500, clone 1D3; Novus Biologicals, Littleton, CO), vimentin (prediluted, clone SLR33; Leica), and 14-3-3 protein beta/alpha (dilution 1:800, polyclonal; Novus Biologicals). Immunohistochemical scoring was performed by 2 authors (C. R. F. and O. F.) using the histoscore system, wherein a score is generated for each case that encompasses the extent of immunoreactive cells as well as the intensity of staining [24]. The histoscore is determined on a scale of 0 to 300 using the following formula: (3 × percentage of strongly staining cells) + (2 × percentage of moderately staining cells) + (1 × percentage of weakly staining cell).…”

Genetic landscape of clear cell endometrial cancer and the era of precision medicine

“…ARID1A loss by immunohistochemistry was observed in 25% of cases, higher than the mutational frequency (15.9%) reported by Le Gallo et al Another small study of 14 cases of CCEC reported mutations of telomerase reverse transcriptase promoter in 21% of cases. 4 …”