Somatic Mutation Screening: Identification of Individuals Harboring K-ras Mutations With the Use of Plasma DNA

Kopreski, Michael S.; Benko, Floyd A.; Borys, David J.; Khan, Amin; McGarrity, Thomas J.; Gocke, Christopher D.

doi:10.1093/jnci/92.11.918

Cited by 116 publications

(81 citation statements)

References 25 publications

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“…The phospho-ERK activation is in addition to the constitutive levels stimulated by oncogenic RAS in these cells (Fig. 4), as FET colon cancer cells contain a mutated K-RAS gene (codon 12 mutation: GGT>GCT) [6], making K-RAS constitutively active. BMP2 activation of phospho-ERK may act as a "brake" on BMP-induced growth suppression by regulating or limiting this response in the correct setting.…”

Section: Bmp-smad Signaling and Growth Suppression Is Modulated By K-mentioning

confidence: 99%

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BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Beck

Jung

Rosario

et al. 2007

Cellular Signalling

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Bone morphogenetic proteins (BMPs) regulate cell differentiation, proliferation, and apoptosis through a canonical SMAD signaling cascade. Absence of BMP signaling causes the formation of intestinal juvenile polyps in the colon cancer-prone syndrome familial juvenile polyposis. As sporadic colon cancers appear to have intact BMP signaling, we evaluated if K-RAS, driving a mitogenic pathway frequently activated in colon cancer, negatively affects BMP growth suppression. We treated non-tumorigenic but activated RAS/ERK FET cells with BMP2, and in combination with pharmacological or genetic inhibition of RAS/ERK, examined BMP-SMAD signaling, transcriptional activity, and cell growth, and also assessed p21 WAF1 mRNA, transcriptional activation, and protein levels. BMP2 increased nuclear phospho-SMAD1 2-fold, which increased another 2-3 fold when RAS/ERK was inhibited. BMP2 increased BMP-specific SMAD transcriptional activity 2-fold over control and decreased cell growth, but inhibition of RAS/ERK further enhanced BMP-specific transcriptional activity by an additional 1.5-2 fold and enhanced growth suppression by 20%. BMP-induced growth suppression is mediated in part by p21 WAF1 , not by transcriptional upregulation but by improved p21 protein stability, which is inhibited by RAS/ERK. In colon cancer cells, BMP-SMAD signaling and growth suppression is facilitated by p21 WAF1 but modulated by oncogenic K-RAS to reduce the growth suppression directed by this pathway.

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Section: Bmp-smad Signaling and Growth Suppression Is Modulated By K-mentioning

confidence: 99%

“…A common finding in colonic neoplasms is activation of RAS and its downstream effectors [6,7]. RAS proteins are proto-oncogenes involved in a variety of signal transduction pathways that normally regulate cellular proliferation, differentiation and death.…”

Section: Introductionmentioning

confidence: 99%

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Beck

Jung

Rosario

et al. 2007

Cellular Signalling

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“…5,6 The same somatic mutations in oncogenes or tumor suppressor genes such as K-ras or p53 that are present in primary tumors were also detected in the circulating cell-free DNA samples of patients with cancer. [7][8][9] Additionally, the cancer-specific hypermethylation of the p16INK4A, CDH1, and DAPK1 promoter regions in plasma DNA isolated from patients with cancer suggested that circulating methylated DNA could be used as a diagnostic and prognostic marker for the disease. 10 -12 While the quantification of plasma DNA has been proposed as a diagnostic tool for cancer, current results suggest that additional controlled studies are required to establish this possibility.…”

mentioning

confidence: 99%

Comparison of Circulating Plasma DNA Levels between Lung Cancer Patients and Healthy Controls

Yoon

Park

Lee

et al. 2009

The Journal of Molecular Diagnostics

105

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Although the biological functions of tumor-originated cell-free DNA have not been previously clarified , such molecular characteristics as mutations , hypermethylation , and microsatellite instability have confirmed its tumor origin. Therefore , to investigate the use of plasma DNA level as a biomarker of lung cancer, we compared plasma DNA concentrations in 102 patients with lung cancer and 105 healthy individuals using quantitative PCR analyses. The median plasma DNA concentrations for the healthy and cancer groups were 10.4 and 22.6 ng/ml , respectively (P < 0.0001), and elevated plasma DNA levels were also detected in patients with either stage I or II disease. Neither smoking status nor the number of packs per year had an effect on the level of circulating cell-free DNA. Increased concentrations of circulating cell-free DNA showed the potential power to discriminate lung cancer (area under the receiver operating characteristic curve ‫؍‬ 0.86 , 95% CI ‫؍‬ 0.81 to 0.91). When subjects were classified into three groups based on their plasma DNA concentrations, subjects in the upper tertile (ie, those with the highest concentration) had a significantly increased risk of lung cancer as compared with those in the lowest tertile (adjusted odds ratio ‫؍‬ 50.6, P < 0.001). These results suggest that elevated circulating plasma DNA levels may serve as a potential diagnostic indicator and be an important risk factor for lung cancer. Lung cancer is the leading cause of cancer-related death in Korea and across the globe. Despite the development of several advanced technologies with enhanced sensitivity for detecting cancer, current screening methods for the diagnosis of lung cancer at an early stage are insufficient. Recently, circulating cell-free DNA was detected in blood fractions from patients with cancer. Since then, efforts have been made to use circulating cell-free DNA as a diagnostic or prognostic factor for lung cancer.

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“…При пороговом значении уровня опухолевой цДНК в 4,86 нг/мл чувствительность и специфичность метода составили 78,52 и 86,08 % соответственно [29]. Аналогичные результаты получены и другими исследо-вательскими группами [14,[30][31][32].…”

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“…При этом в 1-м исследова-нии совпадение по мутационному статусу гена и пер-вичной опухоли отмечено в 83 %, «дикий» же тип гена в первичной опухоли в 93 % случаев сопровождался и отсутствием мутации в цДНК. Во 2-м исследовании чувствительность метода оказалась низкой: если в цДНК мутация в гене KRAS была выявлена у 8,5 % больных, то в первичной опухоли она выявлялась уже у 41,0 % [32,52]. В других исследованиях, проведенных в конце 90-х годов прошлого века, частота соответствия мута-ционного статуса гена KRAS в цДНК и опухолевом ма-териале варьирует от 19 до 86 % [4,53,54].…”

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Definition and scope of the surgical treatment in patients with pulmonary metastases from colorectal cancer

Ахмедов¹,

Давыдов²,

Аллахвердиев³

et al. 2016

Onkol. koloproktol.

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Somatic Mutation Screening: Identification of Individuals Harboring K-ras Mutations With the Use of Plasma DNA

Abstract: Plasma DNA assays for the detection of mutations in K-ras codon 12 may provide a feasible method to screen populations for somatic mutations frequently found in neoplasms. The clinical utility of using this test in screening populations requires further study.

Cited by 116 publications

References 25 publications

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Comparison of Circulating Plasma DNA Levels between Lung Cancer Patients and Healthy Controls

Definition and scope of the surgical treatment in patients with pulmonary metastases from colorectal cancer

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