Clinicopathological Analysis of Papillary Thyroid Cancer with<i>PIK3CA</i>Alterations in a Middle Eastern Population

Abubaker, Jehad; Jehan, Zeenath; Bavi, Prashant; Sultana, Mehar; Al-harbi, Sayer; Ibrahim, Muna; Al-Nuaim, Abdulrahman; Ahmed, Mohammed; Amin, Tarek; Al-Fehaily, Maha; Al-Sanea, Osama; Al‐Dayel, Fouad; Uddin, Shahab; Al‐Kuraya, Khawla S.

doi:10.1210/jc.2007-1717

Cited by 167 publications

(166 citation statements)

References 29 publications

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“…18,19 splice junctions, were amplified and sequenced using primers and DNA samples from formalin-fixed paraffin-embedded blocks as described previously. 20 Primer 3 software was used to design the primers for exon 15 of BRAF (Table 2).…”

Section: Dna Isolationmentioning

confidence: 99%

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

Siraj

Prabhakaran

Bavi

et al. 2015

Cancer

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BACKGROUND: Lynch syndrome (LS; hereditary nonpolyposis colorectal cancer) is a common cause of hereditary colorectal cancer (CRC). CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC. There currently are no clear guidelines for the selection criteria for these patients to screen for LS. METHODS: A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction. BRAF mutation screening, high CpG island methylator phenotype, and analysis for germline mutations were performed in 425 CRC samples. These were all high microsatellite instability (MSI-H) samples (91 cases), all low MSI samples (143 cases), and selected cases from the microsatellite stable group (191 cases) that met revised Bethesda guidelines. RESULTS: Polymerase chain reaction identified 91 MSI-H cases (11.3%) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only. Of the total of 807 CRC cases, these 8 cases (0.99%) were MSI-H, met the revised Bethesda guidelines, and did not harbor BRAF mutations. CONCLUSIONS: The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations. This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives. Cancer 2015;121:1762-71.

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Section: Dna Isolationmentioning

confidence: 99%

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

Siraj

Prabhakaran

Bavi

et al. 2015

Cancer

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“…28 For the study of UBE2C amplification, we used the bacterial artificial chromosome clone RP3-447F3, from Children's Hospital Oakland Research Institute (Oakland, CA). A UBE2C/centromere 20 ratio of 1.0 was considered normal, a ratio between 1.0 and 2.0 was considered as having UBE2C gains, and a ratio of Ͼ2.0 was considered as amplified.…”

Section: Fishmentioning

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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“…According to the current knowledge, leptin signaling pathway is mainly transduced by Janus activated kinase/signal transducers and activators of transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinisitol-3 0 -kinase (PI3K) signaling pathways (Hegyi et al 2004). Previously, we have shown that aberrant PI3K/AKT signaling activation plays a role in Middle Eastern PTC pathogenesis (Abubaker et al 2008b). However, the expression of leptin receptors and the potential correlation between leptin receptors and PI3K/AKT activation have yet to be studied in the Middle Eastern population.…”

Section: Introductionmentioning

confidence: 99%

Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma

Uddin¹,

Bavi²,

Siraj³

et al. 2010

Endocrine-Related Cancer

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The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease-free survival (PZ0.0235). PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage, tall cell variant histological subtype, and a poor disease-free survival (PZ0.0005, PZ0.0006, PZ0.0398, PZ0.0004, PZ0.0111, PZ0.0003, and PZ0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of XIAP (P!0.0001) and Bcl-XL (P!0.0001). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3 0 kinase (PI3K)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor diseasefree survival.

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Clinicopathological Analysis of Papillary Thyroid Cancer withPIK3CAAlterations in a Middle Eastern Population

Cited by 167 publications

References 29 publications

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer

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

Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma

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