Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Abstract

Purpose: Advanced stage MOC have poor chemotherapy response and prognosis and lack biomarkers to aid Stage I adjuvant treatment. Differentiating primary mucinous ovarian carcinoma (MOC) from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathological and gene expression data were analysed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n=333), mucinous borderline ovarian tumors (MBOT, n=151), upper GI (n=65), and lower GI tumors (n=55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2-years from diagnosis, compared with expansile pattern in Stage I MOC (hazard ratio HR 2.77 (1.04-7.41, p=0.042). Increased expression of THBS2 and TAGLN were associated with shorter OS in MOC patients, (HR 1.25 (95% CI 1.04-1.51, p=0.016)) and (1.21 (1.01-1.45, p=0.043)) respectively. ERBB2 (HER2)-amplification or high mRNA expression was evident in 64/243 (26%) of MOCs, but only 8/243 (3%) were also infiltrative (4/39, 10%) or Stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2-years from diagnosis and may help select Stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confer an adverse prognosis and is upregulated in the infiltrative subtype which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Molecular characteristics and clinical behaviour of epithelial ovarian cancers

“…Some retrospective analyses have suggested improvement in outcomes with gastrointestinal regimens [67], though these are no substitute for prospective randomised studies. While ERBB2 has been identified as a potential target for therapeutic interventions, recent analysis suggests this event most frequently occurs in early stage MOC, with an amplification rate of only ~15% in stage III/IV MOC [64]. This study also identified higher ERBB2 expression in expansile versus infiltrative MOC.…”

“…These Mullerian type cases were reclassified as a distinct entity termed 'seromucinous' over the last decade, displaying a distinct PAX8-positive and ER-positive immunoprofile (true MOC are PAX8 negative and almost always ER negative), and have since been further reclassified to reflect their recent recognition as variants of EnOC [63]. Recently, subclassification of MOC into expansile (~80% of cases) versus infiltrative invasive types (~20% of cases) has revealed poorer survival within the infiltrative invasive type [64,65].…”

“…Higher genomic complexity may be associated with poorer survival, independent of other clinicopathological features. The transcriptomic landscape of MOC has only recently begun to be unravelled, though contemporary data have identified potential transcriptomic markers of poor prognosis (high THBS2 expression, high TAGLN2 expression) [64]. Recent data also suggest MOC are immunogenically cold, with low numbers of tumour-infiltrating immune cells [66].…”

Ciliated Cells in Ovarian Cancer Decrease with Increasing Tumor Grade and Disease Progression

“…There may be a difference between subtypes of mucinous cancer such as endocervical or gastrointestinal which contribute to these findings, although these data were not available for our cases [ 29 , 30 ]. Our study adds to the scant literature on the relationship between ciliated cells and the origin of mucinous EOC in contrast to the origin of other EOC histologic subtypes [ 31 ].…”

Profiling the immune landscape in mucinous ovarian carcinoma

“…Similarly tumors with an infiltrative pattern of invasion had higher tumor epithelial PD-1+ cells, and higher stromal FOXP3+ Tregs. An infiltrative pattern of invasion is associated with a poorer prognosis [13], potentially involving an environment of T cell exhaustion/suppression. We showed on univariate analysis only that high epithelial density of FOXP3+ cells was associated with poorer overall survival.…”