The Role of KRAS in Endometrial Cancer: A Mini-Review

Abstract

Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from oestrogen-related proliferative endometrium (type I, endometrioid), or from atrophic endometrium (type II, non-endometrioid). Each type of EC is characterized by different molecular profile alterations. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a signalling protein which moderates response to various extracellular signals via down-regulation of the mitogenactivated protein kinase (MAPK) or phosphoinositide-3-kinase/vakt murine thymoma viral oncogene (PI3K/AKT) pathways. This article reviews the role of KRAS in predicting transition from hyperplastic endometrium to early-stage well-differentiated EC, as well as further invasive proliferation of the tumour to advanced-stage disease. KRAS seems to be directly associated with type I EC, and most studies support its early involvement in carcinogenesis. Current evidence correlates KRAS mutations with increased cell proliferation and apoptosis, as well as upregulation of endometrial cell oestrogen receptors. Tumours positive for KRAS mutation can harbour hypermethylation-related changes in genome expression, and this can be the cause of concurrent loss of DNA repair proteins. Despite some evidence that KRAS mutation status affects cancer progression, a consensus is yet to be reached. Based on the available evidence, we suggest that screening for KRAS mutations in patients with hyperplastic endometrium or early-stage type I EC, may provide important information for prognosis stratification, and further provision of personalised treatment options. Endometrial cancer (EC) is the most common cancer of the female genital tract in developed countries (1). Each year 319,500 women are diagnosed with EC resulting in 76,000 deaths worldwide (2). EC develops from the inner lining of the uterine corpus (3), and it is currently divided into two types as firstly described by Llobet et al. (4). Type I tumours tend to be low or intermediate tumour grade; they overlap considerably (80%) with oestrogen-related endometrioid carcinomas. Contrary to type I, type II EC results from a sequence of genetic alterations occurring in atrophic endometrium; this can occasionally reflect a progression from polyps or pre-cancerous lesions to EC. Type II EC is mostly considered as non-endometrioid serous carcinomas (4); it tends to be high grade, deeply invasive into the myometrium, and of more advanced stage at presentation (4, 5). The estimated 5-year overall survival for patients with any type of EC is 81.5% (any stage) (6). Current Staging EC staging consensus keeps with the 2009 International Federation of Gynaecology and Obstetrics (FIGO) revised classification. Revised FIGO staging defines four stages 533 This article is freely accessible online.

Clinical Relevance of Oncogenic Driver Mutations Identified in Endometrial Carcinoma

“…Sideris et al reported that a consensus on the exact way that KRAS overall affects EC prognosis has yet to be achieved [30]. In the present study, no signi cant correlation between KRAS mutation and OS was observed, so the prognostic signi cance of KRAS mutation remains controversial.…”

Atypical Mesonephric Hyperplasia of the Uterus Harbors Pathogenic Mutation of Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) and Gain of Chromosome 1q

“…Mutations of KRAS result in constitutive activation of mitogen-activated protein kinase, which subsequently activates various downstream targets, leading to expression of genes involved in cellular proliferation, differentiation, and survival (10,30,31). Activating KRAS mutations have been detected in many human malignancies, particularly in pancreatic, colorectal, and pulmonary carcinomas, but also in endometrial and endocervical adenocarcinomas (32)(33)(34)(35)(36). At the early stage of carcinogenesis, the precancerous cells require KRAS for survival.…”

Applications of CRISPR‐Cas9 in gynecological cancer research

“…Pathological changes in these genes can cause anomalistic transduction of signal pathways such as AKT‐/‐PI3K, NF‐κB, MARK, and Wnt‐/‐β‐catenin, or abnormal expression of P53 and P16 proteins, leading to uncontrolled cell proliferation and tumorigenesis. Given its extensive study in tumors and obvious therapeutic effect, the CRISPR‐Cas9 technology has been used in related research and treatment of endometrial cancer (summarized in Table ).…”