Publications by authors named "Abdul K Siraj"

66 Publications

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

Differential expression of PD-L1 between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation.

Sci Rep 2021 Feb 12;11(1):3750. Epub 2021 Feb 12.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Ovarian cancer (OC) is one of the most common gynecologic cancer, which has the worst prognosis and highest mortality rate. The lack of curative treatment and the high relapse rate, especially in advanced OC, continues to present a clinical challenge, highlighting the need for new therapeutic strategies. This study was performed to compare the expression of PD-L1 in primary epithelial ovarian cancer (EOC) and their corresponding peritoneal metastases, as well as to evaluate its correlation with clinico-pathological parameters. In total, 194 treatment naïve paired EOC and peritoneal metastasis were analyzed by immunohistochemistry for PD-L1 expression. Clinico-pathological information was available for all patients. Significant differences in PD-L1 expression were found between primary EOC and peritoneal metastasis (p < 0.0001). We found discordant tumor cell PD-L1 expression between primary tumors and corresponding peritoneal metastasis in 34% (66/194) of cases. Furthermore, PD-L1 expression in peritoneal metastasis samples was significantly associated with adverse prognostic factors, such as high proliferative index (Ki67) (p = 0.0039) and high histologic grade (p = 0.0330). In conclusion, the discordance of PD-L1 expression between primary EOC and corresponding peritoneal metastases suggests that its assessment as a potential biomarker for predicting response to anti-PD-L1 therapy may require analysis of metastatic lesions.
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http://dx.doi.org/10.1038/s41598-021-83276-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881132PMC
February 2021

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

PD-L1 Expression Is Associated with Deficient Mismatch Repair and Poor Prognosis in Middle Eastern Colorectal Cancers.

J Pers Med 2021 Jan 26;11(2). Epub 2021 Jan 26.

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

Several clinical trials are investigating the use of immune-targeted therapy with Programmed death ligand-1 (PD-L1) inhibitors for colorectal cancer (CRC), with promising results for patients with mismatch repair (MMR) deficiency or metastatic CRC. However, the prognostic significance of PD-L1 expression in CRC is controversial and such data are lacking in CRC from Middle Eastern ethnicity. We carried out this large retrospective study to investigate the prognostic and clinico-pathological impact of PD-L1 expression in Middle Eastern CRC using immunohistochemistry. A total of 1148 CRC were analyzed for PD-L1 expression. High PD-L1 expression was noted in 37.3% (428/1148) cases and was correlated with aggressive clinico-pathological features such as high malignancy grade ( < 0.0001), larger tumor size ( = 0.0007) and mucinous histology ( = 0.0005). Interestingly, PD-L1 expression was significantly higher in patients exhibiting MMR deficiency ( = 0.0169) and mutation ( = 0.0008). Furthermore, the expression of PD-L1 was found to be an independent marker for overall survival (HR = 1.45; 95% CI = 1.06 - 1.99; = 0.0200). In conclusion, the results of this study indicate that PD-L1 expression could be a valid biomarker for poor prognosis in Middle Eastern CRC patients. This information can help in decision-making for anti-PD-L1 therapy in Middle Eastern CRC, especially for patients with MMR deficient tumors.
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http://dx.doi.org/10.3390/jpm11020073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911042PMC
January 2021

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

Eur J Endocrinol 2021 Apr;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

PD-L1 Protein Expression in Middle Eastern Breast Cancer Predicts Favorable Outcome in Triple-Negative Breast Cancer.

Cells 2021 Jan 25;10(2). Epub 2021 Jan 25.

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

Programmed cell-death ligand 1 (PD-L1) has been shown to induce potent T-cell mediated anti-tumoral immunity. The significance of PD-L1 expression in the prognosis of breast cancer (BC) remains controversial and its prevalence and prognostic value in breast cancer from Middle Eastern ethnicity is lacking. A total of 1003 unselected Middle Eastern breast cancers were analyzed for PD-L1 expression using immunohistochemistry. PD-L1 expression, seen in 32.8% (329/1003) of cases, was significantly associated with poor prognostic indicators such as younger patients, high-grade tumors, estrogen-receptor (ER)-negative, progesterone-receptor (PR)-negative, and triple-negative breast cancers (TNBC) as well as high Ki-67 index. We also found a significant association between PD-L1 expression and deficient mismatch repair protein expression. No association was found between PD-L1 expression and clinical outcome. However, on further subgroup analysis, PD-L1 expression was found to be an independent marker for favorable overall survival and recurrence-free survival in TNBC. In conclusion, we demonstrated strong association between PD-L1 and mismatch repair deficiency in Middle Eastern BC patients and that PD-L1 overexpression in tumor cells was an independent prognostic marker in TNBCs from Middle Eastern ethnicity. Overall, these findings might help in the development of more appropriate treatment strategies for BC in Middle Eastern population.
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http://dx.doi.org/10.3390/cells10020229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910988PMC
January 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

Krupple-Like Factor 5 is a Potential Therapeutic Target and Prognostic Marker in Epithelial Ovarian Cancer.

Front Pharmacol 2020 3;11:598880. Epub 2020 Dec 3.

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

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite current therapeutic and surgical options, advanced EOC shows poor prognosis. Identifying novel molecular therapeutic targets is highly needed in the management of EOC. Krupple-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in a variety of cancer types. However, its role and expression in EOC is not fully illustrated. Immunohistochemical analysis was performed to assess KLF5 protein expression in 425 primary EOC samples using tissue microarray. We also addressed the function of KLF5 in EOC and its interaction with signal transducer and activator of transcription 3 (STAT3) signaling pathway. We found that KLF5 overexpressed in 53% (229/425) of EOC samples, and is associated with aggressive markers. Forced expression of KLF5 enhanced cell growth in low expressing EOC cell line, MDAH2774. Conversely, knockdown of KLF5 reduced cell growth, migration, invasion and progression of epithelial to mesenchymal transition in KLF5 expressing cell lines, OVISE and OVSAHO. Importantly, silencing of KLF5 decreased the self-renewal ability of spheroids generated from OVISE and OVSAHO cell lines. In addition, downregulation of KLF5 potentiated the effect of cisplatin to induce apoptosis in these cell lines. These data reveals the pro-tumorigenic role of KLF5 in EOC and uncover its role in activation of STAT3 signaling pathway, suggesting the importance of KLF5 as a potential therapeutic target for EOC therapy.
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http://dx.doi.org/10.3389/fphar.2020.598880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793801PMC
December 2020

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

Clonal Evolution and Timing of Metastatic Colorectal Cancer.

Cancers (Basel) 2020 Oct 12;12(10). Epub 2020 Oct 12.

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

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. Multi-region whole-exome sequencing was performed on 191 sampled tumour regions of patient-matched therapy-naïve and treated CRC primary tumours ( = 92 tumour regions) and metastases ( = 99 tumour regions), in 30 patients. Somatic variants were analysed to define the origin, composition, and timing of seeding in the metastatic progression of therapy-naïve and treated metastatic CRC. High concordance, with few genomic differences, was observed between primary CRC and metastases. Most cases supported a late dissemination model, via either monoclonal or polyclonal seeding. Polyclonal seeding appeared more common in therapy-naïve metastases than in treated metastases. Whereby, treatment prompted for the selection of distinct resistant clones, through monoclonal seeding to distant metastatic sites. Overall, this study reinforces the importance of early clinical detection and surgical excision of the CRC tumour, whilst further highlighting the clinical challenges for metastatic CRC with increased intratumour heterogeneity (either due to early dissemination or polyclonal metastatic spread) and the underlying risk of future therapeutic resistance in treated patients.
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http://dx.doi.org/10.3390/cancers12102938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601934PMC
October 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

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

Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases.

Br J Cancer 2020 04 26;122(8):1219-1230. Epub 2020 Feb 26.

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

Background: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated.

Methods: Multi-region whole-exome sequencing was performed on HGSOC primary tumours and their metastases (n = 33 tumour regions) from six patients. The resulting somatic variants were analysed to delineate tumour evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis.

Results: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination, in which the metastatic tumour mostly acquires the same mutational process active in primary tumour, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic-specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway, and identified potential clinically actionable events in individual patients of the metastatic HGSOC cohort.

Conclusions: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.
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http://dx.doi.org/10.1038/s41416-020-0763-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156387PMC
April 2020

Germline and proofreading domain mutations in endometrial carcinoma from Middle Eastern region.

Cancer Cell Int 2019 11;19:334. Epub 2019 Dec 11.

1Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211 Saudi Arabia.

Background: Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. Although most ECs are sporadic, 2-5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. In this study, we attempted to uncover the frequency, spectrum and phenotype of germline mutations in the proofreading domain of and genes in a large cohort of ECs from Middle Eastern region.

Methods: We performed Capture sequencing and Sanger sequencing to screen for proofreading domains of and genes in 432 EC cases, followed by evaluation of protein expression using immunohistochemistry. Variant interpretation was performed using PolyPhen-2, MutationAssessor, SIFT, CADD and Mutation Taster.

Results: In our cohort, four mutations (0.93%) were identified in 432 EC cases, two each in and proofreading domains. Furthermore, low expression of POLE and POLD1 was noted in 41.1% (170/1414) and 59.9% (251/419) of cases, respectively. Both the cases harboring mutation showed high nuclear expression of POLE protein, whereas, of the two mutant cases, one case showed high expression and another case showed low expression of POLD1 protein.

Conclusions: Our study shows that germline mutations in and proofreading region are a rare cause of EC in Middle Eastern population. However, it is still feasible to screen multiple cancer related genes in EC patients from Middle Eastern region using multigene panels including and .
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http://dx.doi.org/10.1186/s12935-019-1058-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907229PMC
December 2019

APC truncating mutations in Middle Eastern Population: Tankyrase inhibitor is an effective strategy to sensitize APC mutant CRC To 5-FU chemotherapy.

Biomed Pharmacother 2020 Jan 5;121:109572. Epub 2019 Nov 5.

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

Colorectal Cancer (CRC) is highly heterogeneous for which prognosis is dependent mainly on clinical staging. There is a need to stratify subpopulations of CRC on molecular basis to better predict outcome and therapy response. Truncating mutations in adenomatous polyposis coli (APC) are well-described events in CRC carcinogenesis. Clinical and genotypic characterization of Middle Eastern CRC based on presence and type of APC was determined in 412 CRC tumors using modern next generation sequencing. APC truncating mutations were identified in 58.2% (240/412) of CRCs. Overall, mutation was significant predictor of superior overall survival. Further, the type of APC mutations (short or long) did not have impact on clinical outcome. However, in vitro analysis showed difference between CRC cell lines carrying short truncating APC vs CRC cells that carry long truncating APC mutation in response to 5-flourouracil (5-FU). Importantly, we were able to overcome the resistance to 5-FU seen in CRC cells carrying short APC by tankyrase inhibitor, XAV939, thereby inhibiting Wnt/β-catenin signaling cascade. Overall, our results showed that APC mutation status plays an important role in predicting overall survival in Middle Eastern population. Furthermore, in vitro data showed that selective targeting of APC mutated CRC by tankyrase inhibitor can be an effective strategy to overcome 5-FU resistance in CRC cells.
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http://dx.doi.org/10.1016/j.biopha.2019.109572DOI Listing
January 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

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

TGFβ-induced SMAD4-dependent Apoptosis Proceeded by EMT in CRC.

Mol Cancer Ther 2019 07 3;18(7):1312-1322. Epub 2019 May 3.

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

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. In Saudi Arabia, colorectal cancer is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFβ/Smad4 signaling pathway in initiation and progression of colorectal cancer is well documented. This study examined the role of TGFβ/Smad4 signaling pathway in a large cohort of Saudi patients with colorectal cancer, followed by analysis to dissect the dual role of TGFβ on inducing epithelial-to-mesenchymal transition (EMT) and apoptosis. Our study demonstrated high frequency of alterations with low expression of Smad4 protein identifying a subgroup of aggressive colorectal cancer to be an independent marker for poor prognosis. Functional studies using colorectal cancer cells show that TGFβ induces Smad4-dependent EMT followed by apoptosis. Induction of mesenchymal transcriptional factors, Snail1 and Zeb1, was essential for TGFβ-induced apoptosis. Our results indicate that KLF5 acts as an oncogene in colorectal cancer cells regardless of Smad4 expression and inhibition of KLF5 is requisite for TGFβ-induced apoptosis. Furthermore, TGFβ/Smad4 signal inhibits the transcription of KLF5 that in turn switches Sox4 from tumor promoter to suppressor. A high incidence of alterations were found in the Saudi patients with colorectal cancer. Functional study results indicate that TGFβ induces Smad4-dependent EMT followed by apoptosis in colorectal cancer cells.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1378DOI Listing
July 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

FoxM1 and β-catenin predicts aggressiveness in Middle Eastern ovarian cancer and their co-targeting impairs the growth of ovarian cancer cells.

Oncotarget 2018 Jan 16;9(3):3590-3604. Epub 2017 Dec 16.

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

Epithelial ovarian cancer (EOC) is a highly lethal disease with poor prognosis especially in advanced stage tumor. Emerging evidence has reported that aberrant upregulation of FoxM1 and β-catenin are closely associated with aggressiveness of human cancer. However, interplay between these factors in the aggressiveness of EOC is not fully illustrated. In this study, we show that FoxM1 is frequently increased in Middle Eastern EOC and associated with high proliferative index ( = 0.0007) and high grade tumor ( = 0.0024). Interestingly, FoxM1 is significantly associated with elevated nuclear β-catenin and the concomitant increase of FoxM1 and β-catenin is associated with advanced stage of EOC by immunohistochemical analysis of 261 samples of Saudi patients with EOC. Functional analysis showed that β-catenin is a direct transcriptional target of FoxM1 in EOC cell lines. FoxM1 inhibition either by specific inhibitor, thiostrepton or siRNA suppressed β-catenin expression, whereas overexpression of FoxM1 increased nuclear β-catenin expression. We identified two FoxM1 binding sites in the β-catenin promoter that specifically bound to FoxM1 protein. Down-regulation of FoxM1 using thiostrepton induced apoptosis and inhibited cell migration/invasion in EOC cells. Moreover, co-inhibition of FoxM1 by thiostrepton and β-catenin by FH535 significantly and synergistically inhibited EOC cell growth and . Collectively, our findings confer that co-targeting FoxM1/β-catenin signaling cascade may be a promising molecular therapeutic choice in advanced EOC.
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http://dx.doi.org/10.18632/oncotarget.23338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790485PMC
January 2018

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

Response to Yehia et al.

Am J Hum Genet 2017 03;100(3):564-565

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

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http://dx.doi.org/10.1016/j.ajhg.2017.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339109PMC
March 2017

is recurrently mutated in Middle Eastern colorectal cancer.

Gut 2018 Apr 9;67(4):663-671. Epub 2017 Feb 9.

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

Objective: Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognising the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients.

Design: In the discovery phase of the study, we conducted whole genome sequencing of tumour and corresponding germline DNA in 27 patients with CRC. In addition to known driver mutations, we identified three somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence and other candidate genes in a larger sample of 400 patients with CRC and confirmed the enrichment for recurrent mutations.

Results: In order to gain insight into a plausible biological mechanism for the potential role of mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of , and found the latter to be correlated inversely with transforming growth factor (TGF)-β signalling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when expression was experimentally manipulated.

Conclusions: Our data expand the recently described role of as a tumour suppressor in other cancers to include CRC, and suggest TGF-β signalling as a potential mediator of this effect.
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http://dx.doi.org/10.1136/gutjnl-2016-313334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868237PMC
April 2018