Publications by authors named "Nabil Siraj"

6 Publications

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PD-L1 Expression Is an Independent Marker for Lymph Node Metastasis in Middle Eastern Endometrial Cancer.

Diagnostics (Basel) 2021 Feb 25;11(3). Epub 2021 Feb 25.

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

Programmed death ligand 1 (PD-L1) expression in endometrial cancer (EC) tumor cells have been reported in several studies with inconsistent results. Furthermore, there is scarcity of data on the prevalence and prognostic significance of PD-L1 expression in EC from Middle Eastern ethnicity. We aimed to assess PD-L1 expression in a large cohort of Middle Eastern EC and to correlate this with clinico-pathological factors, as well as mismatch repair (MMR) protein status and patients' outcome. PD-L1 expression was investigated using immunohistochemistry on tissue microarray in an unselected cohort of 440 EC. Kaplan-Meier and logistic regression analysis were used to compare the outcome and prognostic factors. PD-L1 expression in tumor tissue was detected in 18.9% (83/440) EC cases with no impact on survival. When stratified for MMR protein status, PD-L1 expression was similar for both MMR deficient and MMR proficient ECs. However, the expression of PD-L1 in tumor cells was significantly associated with type II (non-endometrioid) histology ( = 0.0005) and lymph node metastasis ( = 0.0172). Multivariate analysis showed PD-L1 expression to be an independent risk factor for lymph node metastasis (odds ratio: 2.94; 95% CI: 1.26-6.84; = 0.0123). In conclusion, PD-L1 was strongly associated with non-endometrioid EC and was an independent prognostic marker of lymph node metastasis.
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http://dx.doi.org/10.3390/diagnostics11030394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996603PMC
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

POLE and POLD1 germline exonuclease domain pathogenic variants, a rare event in colorectal cancer from the Middle East.

Mol Genet Genomic Med 2020 08 22;8(8):e1368. Epub 2020 Jun 22.

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

Background: Colorectal cancer (CRC) is a major contributor to morbidity and mortality related to cancer. Only ~5% of all CRCs occur as a result of pathogenic variants in well-defined CRC predisposing genes. The frequency and effect of exonuclease domain pathogenic variants of POLE and POLD1 genes in Middle Eastern CRCs is still unknown.

Methods: Targeted capture sequencing and Sanger sequencing technologies were employed to investigate the germline exonuclease domain pathogenic variants of POLE and POLD1 in Middle Eastern CRCs. Immunohistochemical analysis of POLE and POLD1 was performed to look for associations between protein expression and clinico-pathological characteristics.

Results: Five damaging or possibly damaging variants (0.44%) were detected in 1,135 CRC cases, four in POLE gene (0.35%, 4/1,135) and one (0.1%, 1/1,135) in POLD1 gene. Furthermore, low POLE protein expression was identified in 38.9% (417/1071) cases and a significant association with lymph node involvement (p = .0184) and grade 3 tumors (p = .0139) was observed. Whereas, low POLD1 expression was observed in 51.9% (555/1069) of cases and was significantly associated with adenocarcinoma histology (p = .0164), larger tumor size (T3 and T4 tumors; p = .0012), and stage III tumors (p = .0341).

Conclusion: POLE and POLD1 exonuclease domain pathogenic variants frequency in CRC cases was very low and these exonuclease domain pathogenic variants might be rare causative events of CRC in the Middle East. POLE and POLD1 can be included in multi-gene panels to screen CRC patients.
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http://dx.doi.org/10.1002/mgg3.1368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434734PMC
August 2020

Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population.

Genomics 2020 03 31;112(2):1746-1753. Epub 2019 Oct 31.

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

Sanger Sequencing and immunohistochemistry was employed to investigate the TERT promoter mutations and TERT protein expression with their association to clinicopathological characteristics in over 2200 samples of Middle Eastern origin from 13 different types of cancers. The TERT promoter mutations were most frequently present in bladder cancer (68.6%), followed by central nervous system tumors (28.7%), thyroid cancer (15.4%), prostate cancer (9.3%), endometrial carcinoma (3.7%), rhabdomyosarcoma (1.4%), colorectal cancer (1%), epithelial ovarian carcinoma (0.7%) and breast cancer (0.7%). No mutations were observed in other types of cancers. In bladder cancer, we found significant inverse association with metastasis and a trend to good survival in patients with TERT mutations. In gliomas, TERT promoter mutations predicted poor prognosis. In thyroid cancer, high frequency of TERT mutation was observed in poorly differentiated carcinoma. In addition, TERT promoter mutations were associated with aggressive markers and poor outcome in follicular thyroid carcinomas.
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http://dx.doi.org/10.1016/j.ygeno.2019.09.017DOI Listing
March 2020

Zamzam water protects cancer cells from chemotherapy-induced apoptosis via mitogen-activated protein kinase-dependent pathway.

Biomed Pharmacother 2019 Oct 28;118:109376. Epub 2019 Aug 28.

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

Background: Many Muslims believe that water from the Zamzam well is the cure for every disease. Zamzam water (ZW) is naturally alkaline water consumed by millions of people worldwide. The current study investigated the effect of ZW on cell viability and apoptosis in breast, colorectal and ovarian cancer cell lines and compared the effect with that of drinking water (DW).

Methods: Three different ZW samples collected from different sources at different periods were used. To balance the tonicity, ZW and DW were buffered using PBS and the pH was adjusted to 7.4. For the treatment, ZW and DW were diluted to 50% with RPMI medium (10% FBS). Cancer cell lines were treated with ZW or DW, with and without chemotherapeutic agents, for 24 h. Apoptosis was measured using flow cytometry whilst the level of protein expression was determined by Western blotting.

Results: The results showed that treatment with ZW significantly increased cell proliferation compared to DW control. Treatment with ZW significantly suppressed the effect of chemotherapeutic agents on decreasing cell viability and inducing apoptosis in all the cancer cell lines compared to chemotherapeutic agents alone treated in DW. Furthermore, ZW treatment increased the phosphorylation of CRAF, MEK1/2, ERK1/2 and P38 proteins in these cell lines. Notably, treatment with ZW suppressed the effect of chemotherapy-induced reduction of CRAF, MEK1/2, ERK1/2 and P38 phosphorylation in breast and ovarian cancer cell lines. We also showed that silencing of ERK1/2 significantly increased the chemotherapy-induced apoptosis in breast and colorectal cancer cell lines. These data suggest that MAPK proteins; especially activated ERK1/2 may play a role in ZW mediated suppression of chemotherapy-induced cell death.

Conclusions: These findings clearly demonstrate that ZW protects cancer cells from chemotherapy-induced apoptosis through activation of the ERK1/2-MAPK signaling pathway.
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http://dx.doi.org/10.1016/j.biopha.2019.109376DOI Listing
October 2019

Prevalence, spectrum, and founder effect of BRCA1 and BRCA2 mutations in epithelial ovarian cancer from the Middle East.

Hum Mutat 2019 06 18;40(6):729-733. Epub 2019 Mar 18.

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

Germline mutations in breast cancer susceptibility gene 1 and 2 have previously been estimated to contribute to 13-18% of all epithelial ovarian cancer (EOC). To characterize the prevalence and effect of BRCA1 and BRCA2 mutations in Middle Eastern EOC patients, BRCA mutation screening was performed in 407 unselected ovarian cancer patients using targeted capture and/or Sanger sequencing. A total of 19 different pathogenic variants (PVs) were identified in 50 (12.3%) women. Nine PVs were recurrent accounting for 80% of cases with PVs (40/50) in the entire cohort. Founder mutation analysis revealed only two mutations (c.4136_4137delCT and c.1140dupG) sharing the same haplotypes thus representing founder mutations in the Middle Eastern population. Identification of the mutation spectrum, prevalence, and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment, and development of a cost-effective screening strategy.
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http://dx.doi.org/10.1002/humu.23736DOI Listing
June 2019