Mutational analysis of the RAS/RAF/MEK/ERK signaling pathway in 260 Han Chinese patients with cervical carcinoma

Abstract

Abstract. Prevalent mutations in the mitogen-activated protein kinase 1 (MAPK1)/extracellular signal-regulated kinase 2 (ERK2) pathway have been identified in cervical squamous cell carcinoma in a large-scale genome sequencing effort. Furthermore, mutations in the rat sarcoma viral oncogene homolog (RAS)/Raf/Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway have also been revealed to have important roles in the pathogenesis of human cancer. However, whether the potential hotspot mutations in ERK2 and other components of the RAS/RAF/MEK/ERK signaling pathway also exist in Chinese patients with cervical carcinoma remains to be elucidated. In the present study, a total of 260 patients with cervical carcinoma of distinct subtypes were analyzed for the presence of potential hotspot mutations in the RAS/RAF/MEK/ERK signaling pathway. No ERK2 mutations were detected in these samples; however, Kirsten RAS (KRAS) p.G12D (c.35G>A) mutation was identified in 2/26 (7.7%) cervical adenocarcinoma cases, including 1/20 cervical mucinous adenocarcinoma and 1/6 cervical endometrioid carcinoma cases. In addition, no mutations in the ERK1, neuroblastoma RAS, Harvey RAS or B-Raf proto-oncogene serine/threonine kinase genes were detected in the present study. These results indicated that ethnic differences may be a primary reason for the discrepancy in ERK2 mutation frequencies between the current study and previous studies. Furthermore, mutation in the KRAS gene, but not other genes in the RAS/RAF/MEK/ERK signaling pathway, may have an active role in the pathogenesis of cervical carcinoma. IntroductionCervical carcinoma is the second most frequent type of gynecological malignancy (1). Despite the availability of Pap smear-based screening decreasing the incidence and mortality of cervical carcinoma, it remains a primary cause of cancer-associated mortality in females globally (2). It is well established that human papillomavirus infection has an important role in the development of cervical carcinoma, in addition to genetic alterations that have also been demonstrated to be required for the initiation and progression of this malignancy (3). Although there have been developments in the understanding of the molecular etiology of cervical carcinoma, the underlying mechanistic details remain to be elucidated, emphasizing the requirement for identifying novel molecular genetic alterations.The RAS/RAF/MEK/ERK cascade is an important signaling pathway that regulates diverse cellular functions, including cell proliferation, survival, differentiation and migration (4). A number of previous studies have demonstrated that mutations in the kinases of the RAS/RAF/MEK/ERK transduction pathway are frequently observed in human cancer, including cervical carcinoma (5-8). Of these, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS p.G12, p.G13 and p.Q61), neuroblastoma RAS (NRAS; p.G12, p.G13 and p.Q61), Harvey RAS (HRAS; p.G12, p.G13 and p.Q61) and B-Raf proto-oncogene serine/threoni...

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“…β-catenin functions as a powerful trans-activator of T-cell factor/lymphoid enhancer factor transcription factors, which regulate important downstream target genes that promote cell proliferation, differentiation and tissue development. The MEK signaling pathway comprises several key signaling components and phosphorylation events that have important roles in tumorigenesis ( 26 , 27 ). These activated kinases regulate cell growth, differentiation, proliferation and migration ( 28 ).…”

A systematic review and meta-analysis of the prevalence of therapeutic targets in cervical cancer

“…Twenty-three studies (31%) with 2,983 participants reported this mutation [ 6 , 13 , 15 , 30 , 31 , 35 , 37 , 42 , 43 , 62 , 63 , 70 , 72 , 73 , 75 – 77 , 79 , 84 , 86 , 87 , 89 , 91 ]. The combined positivity rate was 14% (95%CI: 8%–21%; I 2 = 95%, Figure 7, Appendix D ); however, considering the substantial, heterogeneity, the positivity rate ranged between 0% and 82%.…”

Molecular Differences Between Squamous Cell Carcinoma and Adenocarcinoma Cervical Cancer Subtypes: Potential Prognostic Biomarkers

“…Aberrant activation of this pathway is common in several cancers, including CC, which often results from the presence of mutations and ampli cations of KRAS. For instance, Zou Y. and collaborators, reported that the frequency of the KRAS mutation ranged from 8.0-17.5% in cervical ADC [35], to absent or rare in SCC, which suggested that KRAS mutations are frequent and might be a driving factor for the development of cervical ADC but not SCC [36], [37]. Although, in our study we observed that Ras pathway has a higher level of activation in SCC than ADC, which may be due to mutations or alterations in other elements of the pathway [35].…”