Publications by authors named "Saif S Al-Sobhi"

17 Publications

  • Page 1 of 1

PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by Mutation.

Cancers (Basel) 2021 Feb 1;13(3). Epub 2021 Feb 1.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating in PTC cell lines. PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with aggressive clinico-pathological parameters. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with mutation and patients with co-existing PD-L1 over-expression and mutation had a poor disease-free survival compared to patients with mutation alone. In vitro analysis showed high expression of PD-L1 in -mutated PTC cell lines compared to a wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in -mutated cell lines without affecting cell growth. Knockdown of PD-L1 in -mutated cell lines significantly decreased the cell growth and induced apoptosis. Our data suggest that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as the tall cell variant, mutation-positive patients that are unresponsive to standard treatment.
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http://dx.doi.org/10.3390/cancers13030555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867170PMC
February 2021

NTRK fusion analysis reveals enrichment in Middle Eastern BRAF wild-type PTC.

Eur J Endocrinol 2021 04;184(4):503-511

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Objective: Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known oncogenic drivers in a broad range of tumor types. It recently gained attention as a predictor of targeted therapy since selective NTRK inhibitors are now approved in the US and Europe for patients with solid tumors harboring gene fusions. However, estimation of NTRK gene fusion/alteration frequency and its clinicopathological characteristics in papillary thyroid cancer (PTC) is limited, especially in a population with high incidence for PTC like Middle Eastern population. This study aims to characterize the NTRK gene fusion frequency and investigate the utility of pan-Trk immunohistochemistry (IHC) as predictor of NTRK fusion in a large cohort of Middle Eastern PTC.

Methods: FISH analysis for NTRK gene fusions and pan-Trk IHC was performed on 315 Middle Eastern PTCs. Correlation of NTRK gene fusion and protein expression with clinicopathological markers and patient outcome were determined.

Results: In our cohort, 6.0% (19/315) patients showed NTRK gene fusions and were significantly associated with pediatric PTC (P = 0.0143), lymph node metastasis (P = 0.0428) and BRAF WT tumors (P < 0.0001). Pan-Trk IHC was positive in 9.2% (29/315) of cases and significantly associated with NTRK fusions, with a sensitivity of 73.7% and specificity of 94.9% in this cohort.

Conclusions: This study confirms the presence of NTRK fusions in Middle Eastern PTC which is significantly enriched in BRAF WT as well as pediatric age group and proposes the usefulness of IHC to screen for PTC patients with NTRK fusion that might benefit from TRK inhibitors.
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http://dx.doi.org/10.1530/EJE-20-1345DOI Listing
April 2021

Prognostic Value and Function of KLF5 in Papillary Thyroid Cancer.

Cancers (Basel) 2021 Jan 7;13(2). Epub 2021 Jan 7.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

The Krüppel-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in several solid tumors, but its role in PTC remains unclear. We investigated the expression of KLF5 protein in a large cohort of PTC patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. KLF5 overexpression was observed in 65.1% of all PTC cases and it was significantly associated with aggressive clinico-pathological parameters and poor outcome. Given the significant association between KLF5 and HIF-1α overexpression in PTC patients, we investigated the functional correlation between KLF5 and HIF-1α in PTC cells. Indeed, the analysis revealed the co-immunoprecipitation of KLF5 with HIF-1α in PTC cells. We also identified KLF5-binding sites in the HIF-1α promoter that specifically bound to KLF5 protein. Mechanistically, KLF5 promoted PTC cell growth, invasion, migration, and angiogenesis, while KLF5 downregulation via specific inhibitor or siRNA reverses its action in vitro. Importantly, the silencing of KLF5 decreases the self-renewal ability of spheroids generated from PTC cells. In addition, the depletion of KLF5 reduces PTC xenograft growth in vivo. These findings suggest KLF5 can be a possible new molecular therapeutic target for a subset of PTC.
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http://dx.doi.org/10.3390/cancers13020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825749PMC
January 2021

CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells.

Int J Mol Sci 2021 Jan 6;22(2). Epub 2021 Jan 6.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Chromodomain-helicase-DNA-binding protein 4 (CHD4), a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex is highly expressed in several cancers. However, its role in the pathogenesis and progression of papillary thyroid carcinoma (PTC) has not been investigated. We investigated the prognostic significance of CHD4 in a large cohort of Middle Eastern PTC patients and explored the functional role of CHD4 in regulating cancer stemness and EMT in PTC cells. CHD4 overexpression was observed in 45.3% (650/1436) of PTCs, and was associated with aggressive clinico-pathological parameters and worse outcome. Functional analysis using PTC cell lines showed that forced expression of CHD4 promoted cell proliferation, spheroid growth, migration, invasion and progression of epithelial to mesenchymal transition (EMT) in PTC cells whereas its knockdown reversed the effect. Methylation of E-cadherin was associated with loss of expression in CHD4 expressing cells, while CHD4 depletion reactivated E-cadherin expression. Most importantly, knockdown of mesenchymal transcriptional factors, Snail1 or Zeb1, attenuated the spheroid growth in CHD4 expressing PTC cells, showing a potential link between EMT activation and stemness maintenance in PTC. These findings suggest that CHD4 might be a promising therapeutic target in the treatment of patients with an aggressive subtype of PTC.
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http://dx.doi.org/10.3390/ijms22020504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825451PMC
January 2021

Prognostic Significance of COX-2 Overexpression in -Mutated Middle Eastern Papillary Thyroid Carcinoma.

Int J Mol Sci 2020 Dec 14;21(24). Epub 2020 Dec 14.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

The cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) pathway has been implicated in carcinogenesis, with mutation shown to promote PGE2 synthesis. This study was conducted to evaluate COX-2 expression in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC), and further evaluate the prognostic significance of COX-2 expression in strata of mutation status. mutation analysis was performed using Sanger sequencing, and COX-2 expression was evaluated immunohistochemically using tissue microarray (TMA). COX-2 overexpression, noted in 43.2% (567/1314) of cases, was significantly associated with poor prognostic markers such as extra-thyroidal extension, lymph-node metastasis, and higher tumor stage. COX-2 was also an independent predictor of poor disease-free survival (DFS). Most notably, the association of COX-2 expression with DFS differed by mutation status. COX-2 overexpression was associated with poor DFS in -mutant but not wild-type PTCs, with a multivariate-adjusted hazard ratio of 2.10 (95% CI = 1.52-2.92; < 0.0001) for COX-2 overexpressed tumors in -mutant PTC. In conclusion, the current study shows that COX-2 plays a key role in prognosis of PTC patients, especially in mutated tumors. Our data suggest the potential therapeutic role of COX-2 inhibition in patients with -mutated PTC.
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http://dx.doi.org/10.3390/ijms21249498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764962PMC
December 2020

Annual Hazard Rate of Recurrence in Middle Eastern Papillary Thyroid Cancer over a Long-Term Follow-Up.

Cancers (Basel) 2020 Dec 3;12(12). Epub 2020 Dec 3.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Predicting the pattern of recurrence in papillary thyroid cancer (PTC) is necessary to establish optimal surveillance and treatment strategies. We analyzed changes in hazard rate (HR) for tumor recurrence over time in 1201 unselected Middle Eastern PTC patients. The changes in risk were further analyzed according to clinical variables predictive of early (≤5 years) and late (>5 years) recurrence using Cox regression analysis to identify patient populations that remain at risk. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 and 2 years (3.7%), with a second smaller peak between 13 and 14 years (3.2%). Patients receiving radioactive iodine (RAI) therapy had lower recurrence hazard compared to those who did not (1.5% vs. 2.7%, = 0.0001). Importantly, this difference was significant even in intermediate-risk PTC patients (0.7% vs. 2.3%; = 0.0001). Interestingly, patients aged ≥55 years and having lymph node metastasis were at persistent risk for late recurrence. In conclusion, we confirmed the validity of the double-peaked time-varying pattern for recurrence risk in Middle Eastern PTC patients and our findings could help in formulating individualized treatment and surveillance plans.
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http://dx.doi.org/10.3390/cancers12123624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761718PMC
December 2020

POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer.

Endocr Connect 2020 Oct;9(9):923-932

Human Cancer Genomic Research, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Thyroid cancer is the most frequent endocrine cancer with an increasing incidence rate worldwide and is the second most common malignancy among females in Saudi Arabia. Papillary thyroid cancer (PTC) is the most common subtype. Germline pathogenic variants in the proofreading domain of the POLE and POLD1 genes predispose to several types of cancers. However, the role of pathogenic variants of these two genes in PTC remains unknown. Capture sequencing, Sanger sequencing and immunohistochemistry were performed on 300 PTC cases from the Middle Eastern region. One germline pathogenic variant each of POLE (1/300, 0.33%) and POLD1 (1/300, 0.33%) genes was identified. Low expression of POLD1 was detected in 46.5% (133/286) of cases and was significantly associated with the follicular variant of PTC (P = 0.0006), distant metastasis (P = 0.0033) and stage IV tumours (P = 0.0081). However, no somatic pathogenic variant was detected in POLE gene. Furthermore, low expression of POLE was noted in 61.7% (175/284) of cases with no significant clinicopathological associations. Our study shows that pathogenic variant in the POLE and POLD1 proofreading domain is a cause of PTC and low expression of POLD1 is associated with poor prognostic markers in the Middle Eastern population. Further studies from different geographic populations are needed to determine the frequency and spectrum of proofreading domain pathogenic variants in POLE and POLD1 genes and in PTC from different ethnicities.
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http://dx.doi.org/10.1530/EC-20-0258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583138PMC
October 2020

Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer.

Am J Hum Genet 2019 11 24;105(5):959-973. Epub 2019 Oct 24.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia. Electronic address:

Unlike many cancers, the pattern of tumor evolution in papillary thyroid cancer (PTC) and its potential role in relapse have not been elucidated. In this study, multi-region whole-exome sequencing (WES) was performed on early-stage PTC tumors (n = 257 tumor regions) from 79 individuals, including 17 who had developed relapse, to understand the temporal and spatial framework within which subclonal mutations catalyze tumor evolution and its potential clinical relevance. Paired primary-relapse tumor tissues were also available for a subset of individuals. The resulting catalog of variants was analyzed to explore evolutionary histories, define clonal and subclonal events, and assess the relationship between intra-tumor heterogeneity and relapse-free survival. The multi-region WES approach was key in correctly classifying subclonal mutations, 40% of which would have otherwise been erroneously considered clonal. We observed both linear and branching evolution patterns in our PTC cohort. A higher burden of subclonal mutations was significantly associated with increased risk of relapse. We conclude that relapse in PTC, while generally rare, does not follow a predictable evolutionary path and that subclonal mutation burden may serve as a prognostic factor. Larger studies utilizing multi-region sequencing in relapsed PTC case subjects with matching primary tissues are needed to confirm these observations.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849094PMC
November 2019

Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer.

Thyroid 2020 01 4;30(1):42-56. Epub 2019 Dec 4.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Distant metastasis is a rare occurrence in thyroid cancer, and it can be associated with poor prognosis. The genomic repertoires of various solid malignancies have previously been reported but remain underexplored in metastatic papillary thyroid cancer (PTC). Furthermore, whether distant metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing on 14 matched distant metastases, primary PTC tumors, and normal tissues. Point mutations, copy number alterations, cancer cell fractions, and mutational signatures were defined using the state-of-the-art bioinformatics methods. All likely deleterious variants were validated by orthogonal methods. Genomic differences were observed between primary and distant metastatic deposits, with a median of 62% (range 21-92%) of somatic mutations detected in metastatic tissues, but absent from the corresponding primary tumor sample. Mutations in known driver genes including , , and were shared and preferentially clonal in both sites. However, likely deleterious variants affecting DNA methylation and transcriptional repression signaling genes including , , and were found to be restricted in the metastatic lesions. Moreover, a mutational signature shift was observed between the mutations that are specific or enriched in the metastatic and primary lesions. Primary PTC and distant metastases differ in their range of somatic alterations. Genomic analysis of distant metastases provides an opportunity to identify potentially clinically informative alterations not detected in primary tumors, which might influence decisions for personalized therapy in PTC patients with distant metastasis.
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http://dx.doi.org/10.1089/thy.2019.0052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983753PMC
January 2020

Prognostic significance of DNMT3A alterations in Middle Eastern papillary thyroid carcinoma.

Eur J Cancer 2019 08 4;117:133-144. Epub 2019 Jul 4.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia. Electronic address:

Background: Thyroid cancer is the second most common cancer affecting Saudi women after breast cancer, with papillary thyroid carcinoma (PTC) accounting for 80-90% of thyroid cancers. DNA methyltransferases affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers.

Methods: We sought to evaluate the frequency of DNA methyltransferase 3A (DNMT3A) alterations in a large cohort of >1000 PTC cases using exome sequencing, capture sequencing, immunohistochemistry and methylation-specific polymerase chain reaction. We also performed in vitro analysis to investigate the role of DNMT3A methylation in PTC cell lines.

Results: DNMT3A pathogenic mutations were noted in 1.2% (12/1013) of PTC cases. Reduced/loss of DNMT3A expression was seen in 59.8% (579/968) of PTC cases and was significantly associated with the DNMT3A mutation (p = 0.0120). DNMT3A alterations (mutation and/or loss of expression) were associated with aggressive clinical parameters and a poor outcome. The promoter region of the DNMT3A gene was methylated in 57.1% of PTC cases tested and was significantly associated with reduced DNMT3A protein expression (p = 0.0253). Treatment of the methylated PTC cell line with 5-aza-2'-deoxycytidine resulted in demethylation of the DNMT3A gene, leading to restoration of its expression. Demethylation significantly potentiated the TRAIL-mediated apoptosis in PTC cells. Interestingly, silencing of DNMT3A using siRNA suppressed TRAIL-mediated apoptosis.

Conclusion: These findings suggest that DNMT3A alterations play an important role in PTC pathogenesis and demethylation agents can be used to restore the function of DNMT3A in a subset of patients with PTC.
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http://dx.doi.org/10.1016/j.ejca.2019.05.025DOI Listing
August 2019

Downregulation of SKP2 in Papillary Thyroid Cancer Acts Synergistically With TRAIL on Inducing Apoptosis via ROS.

J Clin Endocrinol Metab 2018 04;103(4):1530-1544

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Context And Objective: S-phase kinase protein 2 (SKP2) is an F-box protein with proteasomal properties and has been found to be overexpressed in a variety of cancers. However, its role in papillary thyroid cancer (PTC) has not been fully elucidated.

Experimental Design: SKP2 expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of >1000 PTC samples. In vitro and in vivo studies were performed using proteasome inhibitor bortezomib and proapoptopic death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) either alone or in combination on PTC cell lines.

Results: SKP2 was overexpressed in 45.5% of PTC cases and was significantly associated with extrathyroidal extension (P = 0.0451), distant metastasis (P = 0.0435), and tall cell variant (P = 0.0271). SKP2 overexpression was also directly associated with X-linked inhibitor of apoptosis protein overexpression (P < 0.0001) and Bcl-xL overexpression (P = 0.0005) and inversely associated with death receptor 5 (P < 0.0001). The cotreatment of bortezomib and TRAIL synergistically induced apoptosis via mitochondrial apoptotic pathway in PTC cell lines. Furthermore, bortezomib and TRAIL synergistically induced reactive oxygen species (ROS) generation and caused death receptor 5 upregulation through activation of the extracellular signal-regulated kinase-C/EBP homologous protein signaling cascade. Finally, bortezomib treatment augmented the TRAIL-mediated anticancer effect on PTC xenograft tumor growth in nude mice.

Conclusion: These data suggest that SKP2 is a potential therapeutic target in PTC and that a combination of bortezomib and TRAIL might be a viable therapeutic option for the treatment of patients with aggressive PTC.
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http://dx.doi.org/10.1210/jc.2017-02178DOI Listing
April 2018

Telomerase reverse transcriptase mutations are independent predictor of disease-free survival in Middle Eastern papillary thyroid cancer.

Int J Cancer 2018 05 29;142(10):2028-2039. Epub 2017 Dec 29.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, , Riyadh, 11211, Saudi Arabia.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in ∼20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation to cancer progression in PTC patients is still not fully understood. In this study, we investigated the incidence of TERT promoter mutations and TERT protein expression and their association with clinicopathological outcomes in a large cohort of PTC samples using direct sequencing technology and immunohistochemistry. Furthermore, two PTC cell lines were utilized to investigate role of TERT mutations in mediating metastasis. Two promoter hotspot mutations C228T and C250T were identified in 18.0% (167/927) of our cohort and were significantly associated with poor 5 years disease-free survival and distant metastasis of PTC. TERT protein overexpression was noted in 20.1% of our PTC cohort and was significantly associated with poor prognostic markers such as older age, extrathyroidal extension and Stage IV tumors. A significant association was also found between TERT overexpression and epithelial-mesenchymal transition (EMT) markers. Functional analysis showed that TERT inhibition reduced cell growth, invasion, migration and angiogenesis in PTC via suppression of EMT in PTC cells. Our results suggest that TERT promoter mutation is an independent predictor of disease-free survival and might drive the metastasis, and downregulation of TERT could potentiate antitumor and antimetastatic activities in PTC.
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http://dx.doi.org/10.1002/ijc.31225DOI Listing
May 2018

Expanding the spectrum of germline variants in cancer.

Hum Genet 2017 11 3;136(11-12):1431-1444. Epub 2017 Oct 3.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.
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http://dx.doi.org/10.1007/s00439-017-1845-0DOI Listing
November 2017

Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis.

Am J Hum Genet 2016 06 26;98(6):1170-1180. Epub 2016 May 26.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia. Electronic address:

Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p < 0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908175PMC
June 2016

High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma.

Carcinogenesis 2014 Jul 28;35(7):1564-72. Epub 2014 Feb 28.

Human Cancer Genomic Research, Department of Life Science, College of Science and College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia

The mammalian target of rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of messenger RNA in mammalian cells. Although dysregulation of mTOR signaling has been reported earlier in cancers, there is paucity of data about mTOR expression in papillary thyroid carcinoma (PTC). Therefore, in this study, we investigated the presence of mTORC2 and mTORC1 complexes in a large cohort of >500 PTC samples. Our clinical data showed the presence of active mTORC1 and mTORC2 in 81 and 39% of PTC samples, respectively. Interestingly, coexpression of mTORC1 and mTORC2 activity was seen in a 32.5% (164/504) of the PTC studied and this association was statistically significant (P = 0.0244). mTOR signaling complex was also found to be associated with activated AKT and 4E-BP1. In vitro, using Torin2, a second-generation mTOR inhibitor or gene silencing of mTOR expression prevented mTORC1 and mTORC2 activity leading to inactivation of P70S6, 4E-BP1, AKT and Bad. Inhibition of mTOR activity led to downregulation of cyclin D1, a gene regulated by messenger RNA translation via phosphorylation of 4E-BP1. Torin2 treatment also inhibited cell viability and induced caspase-dependent apoptosis via activation of mitochondrial apoptotic pathway in PTC cells. Finally, Torin2 treatment induces anticancer effect on PTC xenograft tumor growth in nude mice via inhibition of mTORC1 and mTORC2 and its associated pathways. Our results suggest that coexpression of mTORC1 and mTORC2 is seen frequently in the clinical PTC samples and dual targeting of mTORC1 and mTORC2 activity may be an attractive therapeutic target for treatment of PTC.
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http://dx.doi.org/10.1093/carcin/bgu051DOI Listing
July 2014

Preoperative neck ultrasonographic mapping for persistent/recurrent papillary thyroid cancer.

World J Surg 2004 Nov;28(11):1110-4

Department of Surgery, King Faisal Specialist Hospital & Research Centre, 11211 Riyadh, Saudi Arabia.

Surgical resection of persistent/recurrent (P/R) papillary thyroid cancer (PTC), when localized to the neck, is generally recommended; however, its impact on the course of the disease is not clear. We introduced a new technique in the form of preoperative neck ultrasonographic mapping (US-M) to improve the outcome of the surgical resection of P/R PTC. A total of 19 patients had undergone regional (central, lateral, or both) neck dissection before introducing the current technique (group 1, or G1), and 26 patients (group 2, or G2) had limited lymph node resection guided by US-M with findings accurately plotted on a standard diagram. All of the operations were performed by a single surgeon. The surgical outcomes of the two groups were compared. The resected lesions were positive for PTC in 17 patients (89.5%) in G1 and in 25 patients (96.2%) in G2. In G2, the intraoperative findings exactly matched the US-M in 23 patients (88.5%). Postoperatively, neck US became negative in 50% in G1 and in 83.3% in G2 (p = 0.02). Thyroglobulin (Tg) became undetectable in 37.5% in G1 and 52.3% in G2 (p = 0.37). Whole-body iodine scans (WBS) became negative in one of six patients (16.7%) in G1, and in three of four patients (75%) in G2, (p = 0.06). After a mean follow-up of 23.8+/-7.1 months in G1 and 9.8+/-4.7 months in G2, 6 patients (31.6%) in G1 and 15 patients (62.5%) in G2 were in remission (p = 0.04), whereas the disease persisted in 13 cases (68.4%) in G1 and 9 (37.5%) in G2 (p = 0.04). In conclusion, US-M improved the surgical outcome, as evidenced by the postoperative US, Tg, and WBS findings and the higher remission rate for the G2 patients than for the G1 patients.
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http://dx.doi.org/10.1007/s00268-004-7636-5DOI Listing
November 2004

Decreased axillary lymph node retrieval in patients after neoadjuvant chemotherapy.

Am J Surg 2002 Oct;184(4):299-301

Department of Surgery, King Fahad Hospital, Jeddah, Saudi Arabia.

Background: The purpose of this study was to assess our clinical impression that fewer lymph nodes are retrieved after level I and II axillary dissection after neoadjuvant chemotherapy and whether there is a positive correlation between the total number of lymph nodes retrieved and the number of diseased lymph nodes.

Methods: Patients included those with stage IIB, IIIA, and IIIB breast cancer of whom 77 had neoadjuvant chemotherapy and 58 had initial surgery only. All had modified radical mastectomy with in continuity level I and II axillary dissection.

Results: Patients after neoadjuvant chemotherapy had 14.3 +/- 6.7 lymph nodes detected versus 16.9 +/- 8.8 (mean +/- SD; P <0.057) for those with initial surgery only. The number of positive nodes were 3.7 +/- 4.7 versus 6.6 +/- 8.7 (mean +/- SD; P <0.033) respectively and the number of negative nodes were 10.6 +/- 7.5 versus 10.4 +/- 8 (mean +/- SD; P <0.9). The correlation between the number of positive lymph nodes and the total number of lymph nodes was r = 0.58; P <0.001.

Conclusions: It appears that fewer lymph nodes are retrieved after level I and II axillary dissection after neoadjuvant chemotherapy. The total number of lymph nodes retrieved increases directly with the number of positive lymph nodes in patients not treated with chemotherapy.
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http://dx.doi.org/10.1016/s0002-9610(02)00959-5DOI Listing
October 2002