Prognostic significance of alterations in KRAS isoforms KRAS‐4A/4B and <i>KRAS</i> mutations in colorectal carcinoma

Abubaker, Jehad; Bavi, Prashant; Al‐Haqawi, Wael; Sultana, Mehar; Al-harbi, Sayer; Al‐Sanea, Nasser; Abduljabbar, Alaa; Ashari, Luai H.; Alhomoud, Samar; Al‐Dayel, Fouad; Uddin, Shahab; Al‐Kuraya, Khawla S.

doi:10.1002/path.2625

Cited by 83 publications

(82 citation statements)

References 49 publications

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“…Often, results were not statistically significant, possibly due to lack of power. Eighteen studies were included in an analysis on KRAS status in MC and NMC and KRAS mutations were found in MC more frequently (RR 1.27, 95% CI 1.14-1.41; Figure 1) [6,33,[47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62].…”

Section: Krasmentioning

confidence: 99%

The molecular background of mucinous carcinoma beyond MUC2

Hugen

Simons²,

Halilović³

et al. 2014

Clin J Pathol

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The increasing interest of the oncology community in tumour classification and prediction of outcome to targeted therapies has put emphasis on an improved identification of tumour types. Colorectal mucinous adenocarcinoma (MC) is a subtype that is characterized by the presence of abundant extracellular mucin that comprises at least 50% of the tumour volume and is found in 10-15% of colorectal cancer patients. MC development is poorly understood, however, the distinct clinical and pathological presentation of MC suggests a deviant development and molecular background. In this review we identify common molecular and genetic alterations in colorectal MC. MC is characterized by a high rate of MUC2 expression. Mutation rates in the therapeutically important RAS/RAF/MAPK and PI3K/AKT pathways are significantly higher in MC compared with non-mucinous adenocarcinoma. Furthermore, mucinous adenocarcinoma shows higher rates of microsatellite instability and is more frequently of the CpG island methylator phenotype. Although the majority of MCs arise from the large intestine, this subtype also develops in other organs, such as the stomach, pancreas, biliary tract, ovary, breast and lung. We compared findings from colorectal MC with tumour characteristics of MCs from other organs. In these organs, MCs show different mutation rates in the RAS/RAF/MAPK and PI3K/ AKT pathways as well, but a common mucinous pathway cannot be identified. Identification of conditions and molecular aberrations that are associated with MC generates insight into the aetiology of this subtype and improves understanding of resistance to therapies.

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Section: Krasmentioning

confidence: 99%

The molecular background of mucinous carcinoma beyond MUC2

Hugen

Simons²,

Halilović³

et al. 2014

Clin J Pathol

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“…X-tile plots were constructed for assessment of biomarker and optimization of cutoff points based on outcome as has been described earlier. [25][26][27] CRCs were grouped into two groups based on X-tile plots: one with complete absence or reduced staining (H score ϭ 0 to 40) and the other with UBE2C expression (H score Ͼ110), depending on the H score. Similarly, X-tile plots were used to stratify the CRC cases into two groups for cyclin A and cyclin B1.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

Bavi

Uddin

Ahmed

et al. 2011

The American Journal of Pathology

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Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiq- Although colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide, various therapeutic modalities followed in clinical practice are not life saving. More recently, advances in understanding of tumor biology have led to the development of targeted therapies, 1 allowing progress in the treatment of CRC. 2 The ubiquitin proteasome system is important for the orchestration of several important cell cycle events, such as proteolysis of cyclin-dependent kinase and their inhibitors. 3,4 Proper cell cycle progression is orchestrated by the controlled oscillation of a series of cell cycle events. Deregulation of appropriate cell cycle control often results in chromosomal instability, which is a potential trigger for the initiation of cancer. 5 In this system, substrate molecules are regulated for degradation by ubiquitinactivating enzyme (E1), ubiquitin-conjugating enzyme (E2), and E3 ligase. The ubiquitin-conjugating enzyme E2C (UBE2C), also known as UBCH10, along with the E3 ligase of the anaphase-promoting complex catalyze the ubiquitination of mitotic cyclins A and B1, as well as securin. 3,6 UBE2C is essential for cell cycle progression, and mutation of its active site cysteine confers a dominant-negative phenotype. 3,6 Overexpression of UBE2C at the mRNA level has been reported in a number of cancer cell lines and primary tumors, whereas only low levels were found in normal tissues. 7 The oncogenic role of UBE2C is also reported in thyroid, 8 ovarian, 9 esopha-

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“…29,30 CRCs were grouped into two groups based on X-tile plots for p-Met, DR5, cleaved caspase-3, and KRAS4A. [31][32][33] …”

Section: Ihc Assessmentmentioning

confidence: 99%

Coexpression of Activated c-Met and Death Receptor 5 Predicts Better Survival in Colorectal Carcinoma

Uddin

Hussain

Ahmed

et al. 2011

The American Journal of Pathology

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Prognostic significance of alterations in KRAS isoforms KRAS‐4A/4B and KRAS mutations in colorectal carcinoma

Cited by 83 publications

References 49 publications

The molecular background of mucinous carcinoma beyond MUC2

The molecular background of mucinous carcinoma beyond MUC2

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

Coexpression of Activated c-Met and Death Receptor 5 Predicts Better Survival in Colorectal Carcinoma

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