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.
Highlights
CDKN2A is located on chromosome 9p21.3 and encodes two proteins, p16 and p14ARF, that have different reading frames [1]. p14ARF inhibits p53 function and p16 inhibits the CDK4/6 complex acting as a negative cell cycle regulator suppressing the transition from the Gap1 to DNA synthesis (G1/S) phase and arresting the cell cycle in the G1 phase [2]
Our investigation showed that associations of p16 staining pattern with overall survival (OS) differ across ovarian carcinoma histotypes
Absence of p16 expression predicted shorter survival in low-grade serous carcinomas (LGSC) while no survival associations are observed for mucinous carcinomas (MC) and high-grade serous carcinomas (HGSC)
Summary
CDKN2A (cyclin-dependent kinase inhibitor 2A) is located on chromosome 9p21.3 and encodes two proteins, p16 and p14ARF, that have different reading frames [1]. p14ARF inhibits p53 function and p16 inhibits the CDK4/6 complex acting as a negative cell cycle regulator suppressing the transition from the Gap to DNA synthesis (G1/S) phase and arresting the cell cycle in the G1 phase [2]. Normal cells express variable amounts of p16 protein that can be detected by immunohistochemistry (IHC) in both nuclear and cytoplasmic localizations (heterogeneous p16 expression pattern) [3]. In keeping with its role as a tumor suppressor, absence of p16 expression can occur due to various mechanisms including homozygous deletion, loss of function mutations, promoter hypermethylation and translational suppression [5]. P16 block expression is classically observed in human papillomavirus (HPV)-associated uterine cervical neoplasms, in which viral proteins (E7) inactivate pRB and promote G1/S transition [9,10]. Ovarian carcinomas are not associated with HPV infections, but alterations promoting G1/S transition are common, e.g. RB1, CCNE1, CCND1, or MYC [6]
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