Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Abstract

We aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

Nuclear β‐catenin and CDX2 expression in ovarian endometrioid carcinoma identify patients with favourable outcome

“…Among these studies, oestrogen receptor (ER)‐positive and progesterone receptor (PR)‐positive expression was shown to demonstrate survival advantage, but the subset of stage IC/II patients with expression of any of these two markers failed to reach the 5‐year survival threshold of 95% required for withholding adjuvant chemotherapy . Conversely, p16 identifies a subset of EC with unfavourable outcome …”

“…6,7 Conversely, p16 identifies a subset of EC with unfavourable outcome. 8 The most common molecular alteration in EC occurs in CTNNB1. 9,10 CTNNB1 encodes b-catenin, a membrane-associated protein involved in the regulation of cellular adhesion and a key mediator in the Wnt signalling pathway.…”

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

“…LGSOC cell lines were characterized by a strong enrichment of C>T and C>A nucleotide substitution mutations, a predominance of KRAS mutations, and CNA's that are characteristic of those described in previous reports of LGSOC [10,11]. Both LGSOC cell lines and tumors were characterized by a lower tumor mutation burden than other ovarian cancer subtypes.…”

“…However, in the last 5-10 years investigators have elucidated many key genomic aberrations, leading to major advancements in the molecular characterization and classification of LGSOC [3,4]. In contrast to other ovarian cancer subtypes, LGSOC are genetically characterized by high frequency of oncogenic mutations in KRAS, NRAS, and BRAF (20-40%, 7-26%, 5-33%, respectively) [5-7], a very low prevalence of TP53 mutations (<8%) [8,9], frequent copy-number deletion of CDKN2A resulting in loss of tumor suppressor protein p16 (15-53%) [10,11], and high expression of estrogen receptor (ER) and progesterone receptor (PR) (>90% and >50%, respectively) [12][13][14]. More recently, less frequent mutations in USP9X (15%) and EIF1AX (8%) have been described in a small proportion of LGSOC tumors [10,15].Traditionally, the therapeutic management of different ovarian cancer histotypes has been similar as it is now appreciated that different ovarian histological subtypes represent different diseases [16].Consequently, the most common treatment for LGSOC is based on cytoreductive surgery followed by platinum/paclitaxel chemotherapy.…”

Validation of Novel Prognostic Biomarkers for Early-Stage Clear-Cell, Endometrioid and Mucinous Ovarian Carcinomas Using Immunohistochemistry

“…The prognostic role of p16 was examined in a large cohort of ovarian carcinoma patients (n = 6,525), wherein differences in prognosis were demonstrated across the five main histotypes of varying FIGO stages. Block expression (overexpression >90% of tumor cells are stained) of p16 was associated with shorter overall survival (OS) in CCC and EC, absence of p16 in LGSC correlated with shorter OS, while no prognostic significance was found for HGSC-or MC-patients (2). A further study showed an association between favorable outcome and ARID1A-and p53-expression, as well as negative nuclear/positive membrane expression for β-Catenin, in 97 ovarian [CCC (n = 11), EC (n = 21)] and endometrial [clearcell (n = 6) and endometrioid uterine (n = 59)] carcinomas.…”