Mismatch repair deficiency and aberrations in the Notch and Hedgehog pathways are of prognostic value in patients with endometrial cancer

Abstract

The aim of this study was to investigate the prognostic value of the Hedgehog (Gli, Patched-1, Shh, Smo) and Notch (Jag1, Notch2, Notch3) pathway members, in comparison to a panel of proteins (ER, PgR, HER2/neu, Ki67, p53, p16, PTEN and MMR) previously suggested to be involved in the pathogenesis of endometrial cancer, in association with clinical outcome and standard clinicopathological characteristics. A total of 204 patients with histological diagnosis of endometrial cancer treated from 2004 to 2013 were included. The evaluation of protein expression was assessed by immunohistochemistry. Univariate analysis showed that higher Ki67 labeling, expression of PTEN, p16, Notch2 and Notch3 proteins, as well as MMR proficiency were associated with increased relapse and mortality rate. Additionally, Patched-1 protein expression was associated with worse DFS, while p53 overexpression was associated with worse OS. In multivariate analyses, patients with MMR proficient tumors had more than double risk for death than patients with MMR deficient (MMRd) tumors (adjusted HR = 2.19, 95% CI 1.05–4.58, p = 0.036). Jag1 positivity conferred reduced mortality risk (HR = 0.48, 95% CI 0.23–0.97, p = 0.042). However, as shown by hierarchical clustering, patients fared better when their tumors expressed high Jag1 protein in the absence of Notch2 and Notch3, while they fared worse when all three proteins were highly expressed. Patched-1 positivity conferred higher risk for relapse (HR = 2.04, 95% CI 1.05–3.96, p = 0.036).Aberrant expression of key components of the Notch and Hedgehog signaling pathways, as well as MMRd may serve as independent prognostic factors for recurrence and survival in patients with endometrial cancer.

Prognostic implications of mismatch repair deficiency in patients with nonmetastatic colorectal and endometrial cancer

“…Patients with colorectal cancer had received adjuvant chemotherapy at HeCOG-affiliated institutions 3 28–32. Patients with endometrial cancer had been treated at a tertiary hospital, with surgery followed by adjuvant treatment where appropriate, as previously described 33. Patient clinical demographics, tumour histopathological, treatment and outcome data were retrieved from the HeCOG electronic clinical database.…”

Prognostic Biomarkers in Endometrial Cancer: A Systematic Review and Meta-Analysis

“…Its labeling index is low in low-grade squamous areas of EC [43]. Its expression has been related to the early stages of the disease, as well as worse OS [45]. Besides its potential to predict lymph node metastasis with an AUC of 0.604 [46].…”

CD133 Expression in the Nucleus Is Associated with Endometrial Carcinoma Staging and Tumor Angioinvasion

“…Abnormal activation of this pathway was previously described to be involved in the proliferation of endometrial carcinoma cells [ 30 ]. Moreover, the aberrant expression of key components of the SHH signaling pathway may serve as a prognostic factor for recurrence and survival in patients with endometrial cancer [ 31 ]. Nevertheless, the unexpected function of nuclear CD133 expression in endometrial carcinoma requires future study.…”