CHAPTER 1 16 Molecular biomarkers Recently, The Cancer Genome Atlas (TCGA) defined four important prognostic molecular subgroups in EC based on integrated genomic data: I) ultramutated tumors with polymerase epsilon (POLE) mutations, II) hypermutated tumors with microsatellite instability (MSI), III) copy-number-high (CNH) with frequent tumor protein (TP53) mutations and, IV) copy-number-low (CNL) (also known as no-specific molecular profile (NSMP)). These four subgroups increase insight in biological tumor behavior based on molecular signature beyond the histological morphological classification of type 1 and 2 EC.7, 51 Several studies have shown that patients with POLE mutation have an excellent outcome in EC. Patients within the MSI or NSMP subgroup are known with intermediate outcome, and patients with TP53-mutant tumors have the worst outcome, the latter representing 15% of all EC diagnosis and responsible for 50-70% of all EC-related mortality.51-54 The diagnostic algorithm and prognostic relevance of these subgroups are shown in Figure 3A-B. These molecular subgroups have shown to improve prognostication mainly in patients with high-grade EC, probably due to poor interobserver reproducibility of morphological classification and the prognostic and intratumoral heterogeneity of high-grade ECs.53, 55, 56 Specifically in patients with low-grade EC, the prognostic relevance of molecular classification so far is lacking. Clinical biomarkers In addition to the tumor histology and immunohistochemical and/or molecular biomarkers, clinical biomarkers may contribute to an improved risk stratification by reflecting the tumor macro-environment. Endometrial carcinogenesis is characterized by chronic inflammation with elevated pro-inflammatory cytokines and acute phase proteins.57 Overexpression of inflammatory cytokines could contribute to the development of cancer-related anemia, thrombocytosis and leukocytosis, thus generating a pro-tumorigenic environment.58-61 Preoperative anemia, thrombocytosis and leukocytosis, as clinical hematological parameters, may contribute to the identification of patients with extended disease and/or aggressive tumor behavior.46, 62-64 Indeed, they have been associated with advanced-stage (FIGO stage III-IV) and therefore prognostic relevant, however results remain conflicting.59, 60, 65-70 If these often routinely obtained preoperative hematological parameters may also influence the response to adjuvant therapy still remains to be elucidated.46, 62, 63
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