Search Results

You are looking at 1 - 6 of 6 items for

  • Author: Ali S Alzahrani x
  • Refine by access: All content x
Clear All Modify Search
Ali S Alzahrani Division of Endocrinology and Metabolism, Laboratory for Cellular and Molecular Thyroid Research, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287, USA

Search for other papers by Ali S Alzahrani in
Google Scholar
PubMed
Close
and
Mingzhao Xing Division of Endocrinology and Metabolism, Laboratory for Cellular and Molecular Thyroid Research, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287, USA

Search for other papers by Mingzhao Xing in
Google Scholar
PubMed
Close

The impact of metastasized cervical lymph nodes (CLN) identified on central neck dissection (CND) on the recurrence/persistence of papillary thyroid cancer (PTC) and the extent of CND needed to reduce recurrence/persistence have not been firmly established. To assess the impact of CLN metastasis and BRAF mutation on the recurrence/persistence of PTC and the potential of BRAF mutation in assisting CND. Analyses of 379 consecutive patients with PTC who underwent thyroidectomy with (n=243) or without CND (n=136) at a tertiary-care academic hospital during the period 2001–2010 for their clinicopathological outcomes and BRAF mutation status. Increasingly aggressive tumor characteristics were found as the extent of CND was advanced following conventional risk criteria from non-CND to limited CND to formal CND. Disease recurrence/persistence rate also sharply rose from 4.7% to 15.7% and 40.5% in these CND settings respectively (P<0.0001). CLN metastasis rate rose from 18.0 to 77.3% from limited CND to formal CND (P<0.0001). An increasing rate of BRAF mutation was also found from less to more extensive CND. A strong association of CLN metastasis and BRAF mutation with disease recurrence/persistence was revealed on Kaplan–Meier analysis and BRAF mutation strongly predicted CLN metastasis. CLN metastases found on CND are closely associated with disease recurrence/persistence of PTC, which are both strongly predicted by BRAF mutation. Current selection of PTC patients for CND is appropriate but higher extent of the procedure, once selected, is needed to reduce disease recurrence, which may be defined by combination use of preoperative BRAF mutation testing and conventional risk factors of PTC.

Free access
Avaniyapuram Kannan Murugan Division of Molecular Endocrinology, Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Search for other papers by Avaniyapuram Kannan Murugan in
Google Scholar
PubMed
Close
,
Arasambattu Kannan Munirajan Department of Genetics, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai, India

Search for other papers by Arasambattu Kannan Munirajan in
Google Scholar
PubMed
Close
, and
Ali S Alzahrani Division of Molecular Endocrinology, Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Search for other papers by Ali S Alzahrani in
Google Scholar
PubMed
Close

Thyroid cancer continues to be the most common malignancy of endocrine glands. The incidence of thyroid cancer has risen significantly over the past 4 decades and has emerged as a major health issue. In recent years, significant progress has been achieved in our understanding of the molecular mechanisms of thyroid carcinogenesis, resulting in significant diagnostic, prognostic and therapeutic implications; yet, it has not reached a satisfactory level. Identifying novel molecular therapeutic targets and molecules for diagnosis and prognosis is expected to advance the overall management of this common malignancy. Long noncoding RNAs (lncRNAs) are implicated in the regulation of various key cellular genes involved in cell differentiation, proliferation, cell cycle, apoptosis, migration and invasion mainly through modulation of gene expression. Recent studies have established that lncRNAs are deregulated in thyroid cancer. In this review, we discuss extensively the tumor-suppressive (for example, LINC00271, MEG3, NAMA, PTCSC1/2/3, etc.) and oncogenic (for example, ANRIL, FAL1, H19, PVT1, etc.) roles of various lncRNAs and their possible disease associations implicated in thyroid carcinogenesis. We briefly summarize the strategies and mechanisms of lncRNA-targeting agents. We also describe the potential role of lncRNAs as prospective novel therapeutic targets, and diagnostic and prognostic markers in thyroid cancer.

Free access
Avaniyapuram Kannan Murugan Division of Molecular Endocrinology, Department of Molecular Oncology, King Faisal, Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Avaniyapuram Kannan Murugan in
Google Scholar
PubMed
Close
,
Abeer Al-Amr Department of Microbiology, College of Science, Female Campus, King Saud University, Riyadh, Saudi Arabia

Search for other papers by Abeer Al-Amr in
Google Scholar
PubMed
Close
,
Mysoon M Al-Ansari Department of Microbiology, College of Science, Female Campus, King Saud University, Riyadh, Saudi Arabia
Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Mysoon M Al-Ansari in
Google Scholar
PubMed
Close
,
Pulicat S Manogaran Department of Stem Cell Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Pulicat S Manogaran in
Google Scholar
PubMed
Close
,
Hindi Al-Hindi Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Hindi Al-Hindi in
Google Scholar
PubMed
Close
, and
Ali S Alzahrani Division of Molecular Endocrinology, Department of Molecular Oncology, King Faisal, Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Ali S Alzahrani in
Google Scholar
PubMed
Close

Thyroid cancer is a common endocrine neoplasm. Despite its good prognosis, it can lead to significant morbidity and mortality due to metastasis and recurrence. However, the factors involved in metastasis are not well studied. Therefore, we selected matrix metalloproteinases 2 (MMP2) and determined whether it has any role in thyroid cancer. We sequenced the exons of MMP2 in 211 samples including 16 multi-nodular goiters and 195 differentiated thyroid cancers. We identified four non-synonymous single nucleotide polymorphisms (SNPs) of the MMP2 gene in 3.06% (6/195) thyroid cancers. Of the four tumors harboring MMP2 SNPs, three (75%) concomitantly had BRAF V600E. Hence, we speculated that the MMP2 SNPs may cooperate with BRAF V600E in promoting tumor aggressiveness. Overexpression of two MMP2 SNPs (P38L and T458I) exhibited markedly enhanced gelatinase activity with an intact dimerization and induced strong cortactin foci formation in HEK293T cells. Stable expression of the two MMP2 SNPs in BRAF V600E positive BCPAP cells dramatically enhanced cell proliferation, colony formation, and focus formation. Analysis of the morphology of MMP2 SNP bearing BCPAPV600E cells exhibited highly invasive phenotypes characterized by a high rate of wound healing and enhanced cell invasion compared with parental BCPAPV600E cells bearing vector. We also determined that BCPAPV600E cells stably transfected with MMP2 SNPs were highly sensitive to the treatment of BRAF inhibitor, PLX4720. Our study demonstrates that MMP2 SNPs could cooperate with BRAF V600E to promote oncogenicity, migration, and invasiveness of PTC cells. These results suggest that a subset of papillary thyroid cancer with this genetic makeup may benefit from BRAF-mediated therapeutic interventions.

Restricted access
Ebtesam Qasem Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Ebtesam Qasem in
Google Scholar
PubMed
Close
,
Avaniyapuram Kannan Murugan Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Avaniyapuram Kannan Murugan in
Google Scholar
PubMed
Close
,
Hindi Al-Hindi Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Hindi Al-Hindi in
Google Scholar
PubMed
Close
,
Mingzhao Xing Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Mingzhao Xing in
Google Scholar
PubMed
Close
,
Mai Almohanna Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Mai Almohanna in
Google Scholar
PubMed
Close
,
Meshael Alswailem Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Meshael Alswailem in
Google Scholar
PubMed
Close
, and
Ali S Alzahrani Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Department of Molecular Oncology, Department of Pathology and Laboratory Medicine, Department of Medicine, Division of Endocrinology and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Search for other papers by Ali S Alzahrani in
Google Scholar
PubMed
Close

Telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have recently been described in follicular cell-derived thyroid cancer (TC) in patients from North America and Europe. In this study, we explored whether these findings could be replicated in patients from a different ethnic group. We screened 17 benign thyroid adenomas and 265 TC samples from patients in the Middle East for these mutations by PCR and direct sequencing using DNA isolated from paraffin-embedded tumor tissues. None of the 17 benign adenomas harbored TERT promoter mutations. Of 265 TC, 34 (12.8%) harbored TERT promoter mutations, including 10/153 (6.5%) conventional papillary TC (CPTC), 8/57 (14.0%) follicular variant PTC, 9/30 (30%) tall cell variant PTC, 1/3 (30%) Hurthle cell thyroid cancer (HTC), 1/5 (20%) follicular TC, and 5/13 (38.5%) poorly differentiated TC. C250T mutation was present in only 6/265 (2.3%) cases, while C228T mutation was present in a total of 28/265 (10.6%) cases. These two mutations were mutually exclusive. TERT promoter mutations were significantly more common in older (≥45 years) than younger patients and were associated with larger tumour size, vascular invasion, higher TNM stage (stage III and IV), BRAF V600E mutation and persistent/recurrent disease at 6–12 months after initial treatment and at the last follow up. These associations were stronger in non-CPTC. Thus, this study on a large cohort of TC patients from Middle East demonstrates that TERT promoter mutations are relatively common, especially in the non-CPTC, and are associated with more aggressive histopathological features, BRAF V600E mutation, and disease persistence/recurrence than the WT TERT.

Free access
Ali S Alzahrani Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Search for other papers by Ali S Alzahrani in
Google Scholar
PubMed
Close
,
Meshael Alswailem Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Search for other papers by Meshael Alswailem in
Google Scholar
PubMed
Close
,
Alexandre Buffet Université Paris Cité, Inserm, Paris Centre de Recherche Cardiovasculaire (PARCC), Equipe Labellisée Ligue contre le Cancer, Paris, France
Département de Médecine Génomique des Tumeurs et des Cancers, Fédération de Génétique et de Médecine Génomique, Assistance Publique-Hôpitaux de Paris (AP-HP) Centre, Hôpital Européen Georges Pompidou, Paris, France

Search for other papers by Alexandre Buffet in
Google Scholar
PubMed
Close
,
Balgees Alghamdi Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Search for other papers by Balgees Alghamdi in
Google Scholar
PubMed
Close
,
Lulu Alobaid Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Search for other papers by Lulu Alobaid in
Google Scholar
PubMed
Close
,
Osamah Alsagheir Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Search for other papers by Osamah Alsagheir in
Google Scholar
PubMed
Close
,
Hindi Al-Hindi Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Search for other papers by Hindi Al-Hindi in
Google Scholar
PubMed
Close
, and
Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Karel Pacak in
Google Scholar
PubMed
Close

In 2012, somatic EPAS1 pathogenic variants were found to cause a triad of pheochromocytoma/paragangliomas (PPGLs), polycythemia, and somatostatinoma. Since then, a limited number of studies on this subject have been reported, and data on the long-term outcome of metastatic disease are not available on this rare syndrome. We comprehensively reviewed EPAS1-related PPGL and describe an unusual patient who has been living with an EPAS1-related metastatic PPGL for 47 years. The results of this work show that EPAS1 pathogenic variants are rare, more in females and patients without pathogenic variants in other PPGL susceptibility genes. PPGLs are the most common manifestation followed by polycythemia and somatostatinoma. The EPAS1 pathogenic variants are often postzygotic, and the timing of their acquirement during embryonic development seems to correlate with the number and timing of development of the disease manifestations. Although recurrent and multifocal disease is common in EPAS1-related PPGL, distant metastases are uncommon and usually indolent. This is illustrated by a case of a man who was diagnosed at the age of 9 years and is currently 56 years old, alive, and well for 47 years with these metastases. He was found to have a somatic EPAS1 pathogenic variant (c.1592C>A, p.Pro531His) in bilateral pheochomocytoma and a pancreatic NET (somatostatinoma) but not in genomic DNA isolated from peripheral leukocytes. This and previous reports suggest that distant metastases are uncommon and less aggressive in EPAS1-related PPGLs compared to those found in other hereditary PPGLs.

Restricted access
Shahab Uddin Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Shahab Uddin in
Google Scholar
PubMed
Close
,
Prashant Bavi Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Prashant Bavi in
Google Scholar
PubMed
Close
,
Abdul K Siraj Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Abdul K Siraj in
Google Scholar
PubMed
Close
,
Maqbool Ahmed Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Maqbool Ahmed in
Google Scholar
PubMed
Close
,
Maha Al-Rasheed Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Maha Al-Rasheed in
Google Scholar
PubMed
Close
,
Azhar R Hussain Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Azhar R Hussain in
Google Scholar
PubMed
Close
,
Mohammed Ahmed Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Mohammed Ahmed in
Google Scholar
PubMed
Close
,
Tarek Amin Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Tarek Amin in
Google Scholar
PubMed
Close
,
Ali Alzahrani Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Ali Alzahrani in
Google Scholar
PubMed
Close
,
Fouad Al-Dayel Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Fouad Al-Dayel in
Google Scholar
PubMed
Close
,
Jehad Abubaker Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Jehad Abubaker in
Google Scholar
PubMed
Close
,
Rong Bu Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Rong Bu in
Google Scholar
PubMed
Close
, and
Khawla S Al-Kuraya Human Cancer Genomic Research, Pathology, Departments of

Search for other papers by Khawla S Al-Kuraya in
Google Scholar
PubMed
Close

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 (P=0.0235). 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 (P=0.0005, P=0.0006, P=0.0398, P=0.0004, P=0.0111, P=0.0003, and P=0.0235 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′ 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 disease-free survival.

Free access