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Immunohistochemical characterisation of molecular subtypes in endometrial cancer.

ABSTRACT: Four molecular subtypes have lately been established in endometrial cancer basing on estrogen receptor (ER), progesterone receptor (PR) and HER2 status: ER+/PR+/HER2+, ER+/PR+/HER2-, ER-/PR-/HER2+ and ER-/PR-/HER2-. The subtypes have shown diversity in terms of prognosis, clinicopathological and molecular characteristics, with ER+/PR+/HER2- and ER-/PR-/HER2+ group exhibiting exceptionally benign and aggressive behavior, respectively. We have further characterized the subtypes in the context of pathways known to drive endometrial carcinogenesis: phosphatidylinositol 3-kinase (PI3K)-AKT pathway (ERBB/PI3K pathway), TP53 system, and the mismatch repair (MMR) mechanism. Analysis of tumor heterogeneity was also included. ER+/PR+/HER2+ was characterized by active ERBB/PI3K pathway occurring in 58% of cases. Subtype ER-/PR-/HER2+ was characterized by the most frequent TP53 mutations (83% of cases). Triple negative phenotype utterly lacked active ERBB/PI3K pathway. Analyzed major pathways rarely correlated with clinicopathologial data but mutated TP53 and retained MMR did correlate with shorter overall survival (both P<0.01). The presence of tumor heterogeneity was most frequent in ER-/PR-/HER2+ subtype (53% of all cases). The presented results further emphasize that the molecular subtype distinction, along with MMR and TP53 status, could be a useful diagnostic tool in guiding individualized therapy.

SUBMITTER: Lapinska-Szumczyk SM

PROVIDER: S-EPMC4724016 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Immunohistochemical characterisation of molecular subtypes in endometrial cancer.

Łapińska-Szumczyk Sylwia M SM Supernat Anna M AM Majewska Hanna I HI Gulczyński Jacek J Biernat Wojciech W Wydra Dariusz D Żaczek Anna J AJ

International journal of clinical and experimental medicine 20151115 11

Four molecular subtypes have lately been established in endometrial cancer basing on estrogen receptor (ER), progesterone receptor (PR) and HER2 status: ER+/PR+/HER2+, ER+/PR+/HER2-, ER-/PR-/HER2+ and ER-/PR-/HER2-. The subtypes have shown diversity in terms of prognosis, clinicopathological and molecular characteristics, with ER+/PR+/HER2- and ER-/PR-/HER2+ group exhibiting exceptionally benign and aggressive behavior, respectively. We have further characterized the subtypes in the context of p ...[more]

PMID: 26885170

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Project description:Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal - p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple-classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd-p53abn), 31 with POLEmut (POLEmut-p53abn), and 12 with all three aberrations (MMRd-POLEmut-p53abn). MMRd-p53abn ECs and POLEmut-p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd-p53abn ECs and 7/15 (46.7%) POLEmut-p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd-p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut-p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd-p53abn and POLEmut-p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd-p53abn EC as MMRd and POLEmut-p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Project description:ObjectiveThe aim of this study is to explore the consistency of P53 immunohistochemical expression between preoperative biopsy and final pathology in endometrial cancer (EC), and to predict the prognosis of patients based on the 4-tier P53 expression and classic clinicopathological parameters.MethodsThe medical data of patients with stage I-III EC who received preoperative biopsy and initial surgical treatment in two medical centers was retrospectively collected. The consistency of P53 immunohistochemistry expression between preoperative biopsy and final pathology was compared using Cohen's kappa coefficient and Sankey diagram, then 4-tier P53 expression was defined (P53wt/P53wt, P53abn/P53wt, P53wt/P53abn, and P53abn/P53abn). Univariate and multivariate Cox regression analysis was used to determine the correlation between 4-tier P53 expression and the prognosis of patients. On this basis, the nomogram models were established to predict the prognosis of patients by combining 4-layer P53 expression and classic clinicopathological parameters, then risk stratification was performed on patients.ResultsA total of 1186 patients were ultimately included in this study through inclusion and exclusion criteria. Overall, the consistency of P53 expression between preoperative biopsy and final pathology was 83.8%, with a kappa coefficient of 0.624. ROC curve suggested that the AUC of 4-tier P53 expression to predict the prognosis of patients was better than AUC of P53 expression in preoperative biopsy or final pathology alone. Univariate and multivariate Cox regression analysis suggested that 4-tier P53 expression was an independent influencing factor for recurrence and death. On this basis, the nomogram models based on 4-tier P53 expression and classical clinicopathological factors were successfully established. ROC curve suggested that the AUC (AUC for recurrence and death was 0.856 and 0.838, respectively) of the models was superior to the single 4-tier P53 expression or the single classical clinicopathological parameters, which could provide a better risk stratification for patients.ConclusionThe expression of P53 immunohistochemistry had relatively good consistency between preoperative biopsy and final pathology of EC. Due to the discrepancy of P53 immunohistochemistry between preoperative biopsy and final pathology, the prognosis of patients can be better evaluated based on the 4-layer P53 expression and classic clinical pathological parameters.

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Immunohistochemical characterisation of molecular subtypes in endometrial cancer.

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Immunohistochemical characterisation of molecular subtypes in endometrial cancer.

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