Inverse correlation between RASSF1A hypermethylation, KRAS and BRAF mutations in cervical adenocarcinoma

Kang, Sokbom; Kim, Hy Sook; Seo, Sang Soo; Park, Soo‐Jin; Sidransky, David; Dong, Seung Myung

doi:10.1016/j.ygyno.2007.01.045

Cited by 61 publications

(41 citation statements)

References 29 publications

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“…Amongst these, a KRAS p.G12D mutation was identified at a high frequency (7.7%, 2/26) in cervical adenocarcinoma, but was absent in the 207 cases of squamous cell carcinoma and in the 27 of adenosquamous carcinoma. The frequency of the KRAS mutation observed in the tissue samples analyzed in the present study was similar to that identified in numerous previous studies, where the frequency of the KRAS mutation ranged from 8.0-17.5% in cervical adenocarcinoma, to absent or rare in cervical squamous cell carcinoma (11,20,21). Taken together, these results further support the hypothesis that KRAS mutations are frequent and may be a driving factor for the development of cervical adenocarcinoma (20,21), but not for squamous cell carcinoma or adenosquamous carcinoma.…”

Section: Discussionsupporting

confidence: 91%

“…However, it was noted that each tissue sample analyzed in the present study contained >40% of tumor cells; this is beyond the detection sensitivity of Sanger sequencing, which has a detection threshold of 6.6-20% of the mutated allele in a background of the wild-type allele (15)(16)(17)(18)(19). Furthermore, a high frequency of KRAS mutations were detected in the cervical adenocarcinoma tissues using Sanger sequencing, which is comparable to that observed by numerous previous studies wherein the analyzed patient tissue samples contained high proportions of cancerous cells (≥40% malignant cells), comparable to the proportion of malignant cells in the present study (11,20,21). Therefore, a possible explanation for the discrepancy in mutation frequencies is the difference in ethnic background, as the prior study (11) focused on European females whilst the current sample cohort was Chinese in origin, suggesting that the ERK2 mutations may be specific to certain populations.…”

Section: Discussionsupporting

confidence: 88%

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

Zou

Liu

et al. 2017

Oncology Letters

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

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

Zou

Liu

et al. 2017

Oncology Letters

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“…Further, CIMP-high was associated with HPV positivity and methylation frequencies of most of the genes/loci were higher in HPV associated cases except RASSF1. This inverse association of HPV and RASSF1 corroborates previous findings that HPV infection inversely correlates with RASSF1A methylation in human cervical squamous cell carcinomas [45]. The role of HPV in promoting aberrant host DNA methylation is evident in both clinical as well as cell culture studies.…”

Section: Discussionsupporting

confidence: 89%

Association of HPV with genetic and epigenetic alterations in colorectal adenocarcinoma from Indian population

et al. 2015

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Several studies from developing countries have shown human papillomavirus to be associated with colorectal cancers, but the molecular characteristics of such cancers are poorly known. We studied the various genetic variations like microsatellite instability (MSI), oncogenic mutations and epigenetic deregulations like CpG island methylation in HPV associated and nonassociated colorectal cancer patients from Indian population. HPV DNA was detected by PCR using My09/My11 and Gp5+/Gp6+ consensus primers and typed using HPV16 and HPV18 specific primers. MSI was detected using BAT 25 and BAT 26 markers, and mutation of KRAS, TP53 and BRAF V600E were detected by direct sequencing. Methyl specific polymerase chain reaction (MSP) was used to determine promoter methylation of the classical CIMP panel markers (P16, hMLH1, MINT1, MINT2 and MINT31) and other tumour-related genes (DAPK, RASSF1, BRCA1 and GSTP1). HPV DNA was detected in 34/93 (36.5 %) colorectal tumour tissues, HPV 18 being the predominant high-risk type. MSI was detected in 7.5 % cases; KRAS codon 12, 13, BRAF V600E and TP53 mutations were detected in 36.5, 3.2 and 37.6 % of the cases, respectively. CIMP-high was observed in 44.08 % cases. HPV presence was not associated with age, stage or grade of tumours, MSI or mutations in KRAS, TP53 or BRAF genes. Higher methylation frequencies of all genes/loci under study except RASSF1, as well as significantly higher CIMP-high characteristics were observed in HPV positive tumours as compared to negative cases. HPV in association with genetic and epigenetic features might be a potent risk factor for colorectal cancer in Indian population.

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“…The prevalence of RASSF1A promoter methylation in cervical adenocarcinoma is around 20%, and there is an inverse correlation between RASSF1A inactivation and the presence of HPV-transforming gene products (65,66). It may suggest that RASSF1A promoter methylation plays an important role in the development of cervical adenocarcinoma, independently of HPV infection status.…”

Section: Intracellular Signaling Kinasesmentioning

confidence: 99%

Molecular targets for therapeutic interventions in human papillomavirus-related cancers (Review)

Ramalho

Lopes²,

Talans³

et al. 2010

Oncol Rep

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Abstract. The infection by the human papillomavirus (HPV)is the origin of several cancers around the world. In some areas of Brazil, cervical carcinoma is still the cancer with the highest incidence among women. After epithelial cell transformation by HPV, several molecular events are observed, resulting in the malignant phenotype. In this review we discuss potential molecular targets for therapeutic interventions in human HPV-related carcinomas, with emphasis on cervical cancer, based on the alterations observed in the signaling transduction pathways caused by HPV infection. With a special attention to tyrosine kinase receptors, and other kinases involved in signal transduction and angiogenesis, these pathological alterations are evaluated as novel targets for anticancer therapies in HPV-related carcinomas.

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Inverse correlation between RASSF1A hypermethylation, KRAS and BRAF mutations in cervical adenocarcinoma

Cited by 61 publications

References 29 publications

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

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

Association of HPV with genetic and epigenetic alterations in colorectal adenocarcinoma from Indian population

Molecular targets for therapeutic interventions in human papillomavirus-related cancers (Review)

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