Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Abstract

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

Immunohistochemistry and Next Generation Sequencing are Complementary Tests in Identifying PTEN Abnormality in Endometrial Carcinoma Biopsies

“…IHC discordant cases were revaluated at a multiheaded microscope for consensus. The following patterns recorded: 1) retained for similar PTEN IHC staining intensity in tumor cell cytoplasm compared to the internal control; 2) complete absence of PTEN staining in tumor cells with retained internal control (intervening stroma and inflammatory cells); 3) subclonal loss with a clearly recognizable zone of complete absence of PTEN staining in tumor cells with retained internal control in this zone and other areas with unequivocal expression (retained or reduced), 4) reduced for unequivocal PTEN staining in tumor cytoplasm but less staining intensity compared to the internal control; 5) and a new equivocal category for cases with just weak cytoplasmic blush of PTEN staining in tumor cells, which remained difficult to classify even after consensus assessment (12). Discordant cases between the observers were finalized by consensus assessment at a multiheaded microscope.…”

“…Specimens were collected from five pathology departments and included cases with a diagnosis of endometrial carcinoma serous:non-serous high grade:G1-2 endometrioid EC in an approximately 2:1:1 ratio with the goal of identifying 200 cases with >50% prevalence of TP53 mutation for the purpose of a previous study (13). PTEN IHC was carried out centrally using a DAKO Omnis protocol (H30-R10- (12). Discordant cases between the observers were finalized by consensus assessment at a multiheaded microscope.…”

“…Another “Reduced/Attenuated” pattern shows a lower intensity of PTEN expression in tumor cells compared to the internal controls. Both sub-clonal loss and reduced staining have been previously interpreted as abnormal PTEN expression (2,9,12), however, the correlation of the latter two staining patterns with mutational analysis has not been well characterized.…”

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

“…Significantly higher levels of p-p70S6K levels were detected in patients who did not respond to chemotherapy [58] . Immunohistochemical staining of tissue microarrays (TMA) of different ovarian cancer subtypes showed significantly increased staining of p-4EBP1, p-p70S6K and p-S6, in particular p-4EBP1 expression correlated with high-grade tumors and poor prognosis [64] . A multi-center study from the Ovarian Tumor Tissue Analysis Consortium of over 5400 patient tumors investigated PTEN loss as a putative driver in different histological subtypes of ovarian cancer [65] .…”

How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development

“…For example, PIK3CA mutation is found in 40–51% of CCCs and 27–43% of ECs. PTEN is also mutated in 5% of CCCs and 29% of ECs ( Table 1 ), and loss of PTEN expression has been detected in 12–40% of CCCs [ 24 , 25 , 26 ] and 35–38% of ECs [ 26 , 27 ]. The correlation between loss of ARID1A expression and activation of the PI3K/AKT pathway in CCC has been reported [ 25 , 28 ].…”