Publications by authors named "Alaa Abduljabbar"

32 Publications

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 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

Long-term outcomes after complete mesocolic excision for colon cancer at a tertiary care center in Saudi Arabia.

Ann Saudi Med 2020 May-Jun;40(3):207-211. Epub 2020 Jun 4.

From the Department of Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Background: Data on long-term survival and recurrence of cancer after complete mesocolic excision (CME) for colon cancer has not been reported from our center and related to international data.

Objective: Describe overall and disease-free survival, survival by surgery site and stage, and recurrence rates after curative surgery.

Design: Retrospective chart review.

Settings: Academic tertiary care center.

Patients And Methods: The study included all patients who underwent either laparoscopic or open surgery for colon cancer with curative intent between 2001 and 2011. The colorectal database was reviewed for the following: demographic data, comorbidities, radiologic investigations, clinical stage, type of operation, complications, pathologic assessment, adjuvant treatment, recurrence and survival. Survival and recurrence rates were calculated, and survival curves were generated.

Main Outcome Measures: 5-year overall survival, secondary endpoints were 5-year disease-free survival, survival by surgery site and stage, and recurrence rates.

Sample Size: 220.

Results: The mean (SD) age at diagnosis was 57 (13) years (CI 95%: 55-59 years). There were 112 males. Mean (SD) body mass index was 27.6 (5.7) kg/m (CI 95%: 27-28). Pathological assessment revealed R0 (microscopically margin-negative) resection in 207 (94%). The overall 5-year survival and disease-free survival was 77.9% and 70%, respectively. The 5-year disease-free survival was 69% for the sigmoid/left colon and 69% for the right colon (difference statistically nonsignificant). Stages at the time of resection were stage 0 for 2 (0.01%) patients, stage I for 18 (8%), stage II for 92 (42%), stage III for 100 (46%), and stage IV for 6 (3%). The 5-year overall survival by stages I, II, III and IV was 94%, 80%, 75% and 50%, respectively (difference statistically non-significant). The overall 5-year recurrence rate was 23.4%.

Conclusion: The outcomes of surgical treatment for colon cancer at our institution are equivalent to international sites. No difference was noted between left and right colon in terms of survival after CME.

Limitations: Single center, retrospective, small sample size.

Conflict Of Interest: None.
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http://dx.doi.org/10.5144/0256-4947.2020.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270623PMC
March 2021

A cutaneous metastasis of unresectable rectal adenocarcinoma: A case report and literature review.

Int J Surg Case Rep 2020 19;71:95-101. Epub 2020 May 19.

Department of Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Electronic address:

Background: Colorectal cancer is ranked third among the most commonly diagnosed malignancies and fourth among the leading causes of cancer death in the world. However, only a few case reports are found in the literature regarding skin metastasis originating from rectal cancer, which usually shows widespread disease and poor prognosis. Approximately, 0.8% of the patients will have skin lesion as the first indication of a silent internal malignancy, which is rare.

Case Report: We report a complicated case of a 45-year-old male patient who referred to our highly specialized governmental hospital for diversion loop colostomy as well as biopsies of rectal and inguinal skin areas followed by palliative radiation therapy to the pelvis. Histopathological exam of rectal biopsies revealed moderately differentiated rectal adenocarcinoma, while the skin of the right inguinal area showed metastatic cutaneous rectal adenocarcinoma. Unfortunately, palliative radiation therapy was not started as the patient passed away secondary to respiratory failure which ended by cardiopulmonary arrest.

Conclusion: A patient who is having new or evolving skin lesions with an oncology history should be well investigated as cutaneous metastasis is a strong possibility.
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http://dx.doi.org/10.1016/j.ijscr.2020.04.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243000PMC
May 2020

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

Survival and outcomes after laparoscopic versus open curative resection for colon cancer.

Ann Saudi Med 2019 May-Jun;39(3):137-142. Epub 2019 May 30.

From the Department of Surgery, College of Medicine, Princess Nourah bint Abdulrahman, Riyadh, Saudi Arabia.

Background: Many studies have shown that open and laparoscopicsurgery for resection of colonic cancers produce similar short- and long-term results, but no data have been reported from Saudi Arabia.

Objective: Compare 3-year disease-free and overall survival after laparoscopic versus open curative resection for potentially curable colon cancer.

Design: Multicenter retrospective cohort study.

Setting: Tertiary academic hospital.

Patients And Methods: We analyzed data of patients who underwent curative resection for potentially curable colon cancer using the laparoscopic or open approach at three tertiary care centers during the period 2000-2015.

Main Outcome Measures: Overall and disease-free 3-year survival were the primary endpoints. Secondary endpoints included conversion rate, duration of surgery, length of hospital stay, rate of wound infection, resumption of bowel function, number of lymph nodes retrieved, adequacy of resection and rate of recurrence. Risk factors for recurrence, including complete mesocolic excision, were assessed.

Sample Size: 721.

Results: Patient and tumor characteristics were similar in the two groups except for ASA class ( P<.01), weight ( P<.05) and tumor stage ( P<.05). Over a median follow-up of 46 months, the 3-year overall survival was 76.7% for open resection and 90.3% for laparoscopic colon resection ( P<.05). The 3-year disease-free survival was 55.3% for open colon resection and 64.9% for laparoscopic colon resection ( P=.0714).

Conclusion: Overall and disease-free survival after the laparoscopic approach for curative resection of colon cancer is comparable to the open approach.

Limitations: Retrospective design and the possibility of selection bias.

Conflict Of Interest: None.
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http://dx.doi.org/10.5144/0256-4947.2019.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832338PMC
December 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

Dose Escalation with Simultaneous Integrated Boost (SIB) Using Volumetric Modulated Arc Therapy (VMAT) in Rectal Cancer.

J Gastrointest Cancer 2018 Jul 14. Epub 2018 Jul 14.

Section of Colon and Rectal Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Purpose: Assess feasibility-rate of PCR, short-term toxicity after neoadjuvant concurrent chemoradiation (NACRT) delivered via simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT) technique for locally advanced rectal cancer.

Methods: Retrospective evaluation of patients with locally advanced rectal cancer treated with VMAT-SIB technique preoperatively at an academic tertiary care center in Riyadh, Saudi Arabia between February 2013 and March 2017.

Results: One hundred patients with depth of invasion staged as T3/T4 or T2 in 93 and seven patients, respectively. Lymph node metastasis was staged as N1/N2 or N0 in 87 and 13 patients, respectively. Circumferential radial margin (CRM) was involved radiologically prior to treatment in 50 patients. A dose of 55 or 50 Gy was given to 71 and 29 patients, respectively. All treatments were completed without interruption. Grade 3/4 toxicity was not observed. Low anterior resection and abdominoperineal resection were performed with negative proximal, distal, and radial margins in 72 and 28 patients, respectively. There were no immediate significant postoperative complications. Histologically, no residual tumor (grade 0) was noted in 20 patients (pCR). Regression grade 1, 2, and 3 were noted in 31, 34, and 15 patients. Average number of lymph nodes retrieved in the surgical specimen was 12 (range 6-22). Lymph nodes were negative for cancer in 80 patients.

Conclusion: Dose escalation with SIB-VMAT as NACRT for rectal cancer is feasible. Moreover, it can increase the rate of pathological complete response with a favorable toxicity profile. Clinical benefit of this approach needs to be validated in a larger cohort of patients with longer follow-up.
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http://dx.doi.org/10.1007/s12029-018-0133-0DOI Listing
July 2018

Cancer in an unexpected site post pouch surgery for familial adenomatous polyposis (FAP).

Int J Surg Case Rep 2018 28;42:266-268. Epub 2017 Dec 28.

Mayoclinic, Rochester, MN, United States. Electronic address:

Introduction: Familial Adenomatous Polyposis (FAP) is a hereditary condition characterized by multiple colorectal adenomatous polyps. FAP is the most common adenomatous polyposis syndrome. Restorative proctocolectomy is the most commonly performed surgical procedure performed for patients suffering from FAP with different options for anastomosis, namely ileorectal anastomosis (IRA) or ileal pouch anal anastomosis (IPAA). The occurrence of adenomas is a common finding during follow up and surveillance post surgery for these patients. Although there are a few cases of carcinoma that were namely at the anal transitional zone (ATZ), there are only a few cases of ileal pouch related adenocarcinoma reported. This work has been reported in line with the SCARE criteria (Agha et al., 2016) [1].

Presentation Of Case: We report a case of a 34-year-old man diagnosed with FAP who underwent proctocolectomy with IPAA, and subsequently referred to our center, who, despite appropriate measures and surveillance, developed adenocarcinoma in the ileal pouch.

Discussion: Restorative proctocolectomy for Familial Adenomatous Polyposis (FAP) is the mainstay of treatment. There are different surgical options, each with its own set of advantages and disadvantages. The most favored option is proctocolectomy with ileal pouch anal anastomosis (IPAA) due to because it involves resection of the rectum. Despite these interventions, adenomas and/or carcinomas have been reported on follow up post surgery.

Conclusion: Although the risk of developing adenomas or carcinomas in the ileal pouch post proctocolectomy with IPAA is low it should not be neglected as cancer occurrence or recurrence is unpredictable even with appropriate measures.
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http://dx.doi.org/10.1016/j.ijscr.2017.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766745PMC
December 2017

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

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

Pre-operative chemoradiotherapy using capecitabine and cetuximab followed by definitive surgery in patients with operable rectal cancer.

Hematol Oncol Stem Cell Ther 2016 Dec 2;9(4):147-153. Epub 2016 Sep 2.

Section of Anatomic Pathology, Department of pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background: Achieving a high rate of complete pathological response with pre-operative chemoradiotherapy in rectal cancer is an unmet need. We evaluated the efficacy and toxicity of the combination of cetuximab, capecitabine and radiation therapy in the pre-operative setting of localized rectal cancer.

Patients And Methods: Patients with clinically staged T3, T4 or nodepositive rectal cancer were treated with concurrent capecitabine and radiotherapy with weekly cetuximab starting one week before the start of radiation. This was followed by total mesorectal excision within 6-8 weeks. All patients achieving R0 resection received adjuvant capecitabine for 6 cycles.

Results: Fifteen patients were treated and all underwent surgery. Sphincter preservation was achieved in 11 patients (73.3%) and pathological complete response in two. With a median follow up of 48 months (range 8.4-57.5), 12 patients were relapse-free and 14 were alive with 4-year relapse free survival of 80%. Overall survival was 93%. Significant grade 3 and 4 toxicity was mainly cetuximab-induced skin reactions (33%), radiation-induced skin toxicity (13%) and diarrhea (20%).

Conclusions: Adding cetuximab to pre-operative concurrent capecitabine and radiotherapy provides modest efficacy with manageable toxicity.
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http://dx.doi.org/10.1016/j.hemonc.2016.08.004DOI Listing
December 2016

Colorectal cancer in Saudi Arabia: incidence, survival, demographics and implications for national policies.

Ann Saudi Med 2015 May-Jun;35(3):196-202

Nasser Alsanea, President of the Saudi Society of Colon & Rectal Surgery,, Head Section, Colon & Rectal Surgery,, King Faisal Specialist Hospital & Research Center- Riyadh,, (MBC-40) PO Box 3354 Riyadh 11211,, Saudi Arabia,

Background And Objectives: The national data on colorectal cancer in Saudi Arabia has not been analyzed. The objective of this study is to describe the demographics, incidence and survival rates for colorectal cancer in Saudi Arabia for the period 1994-2010.

Design: Retrospective analysis of the Saudi Cancer Registry data for the period 1994-2010.

Setting: Data from the Saudi Cancer Registry was analyzed by stage at presentation (local, regional, distal, unknown) and survival rates were calculated using the Kaplan-Meier method.

Patients: From 9889 colorectal cancer cases, a sample of 549 (5.6%) patients was selected and their living status ascertained to assess survival.

Results: Colorectal cancer has been the most common cancer among men and the third commonest among women since 2002 in Saudi Arabia. There has been a slight predominance among men with an average ratio of 116:100 over the years (range: 99:100-132:100). The overall age-standardized rate (ASR) approached a plateau of 9.6/100000 in 2010. The incidence of the disease has been highest in the capital, Riyadh, where it reached 14.5/100000 in 2010. Median age at presentation has been stable at around 60 years (95% confidence Interval (CI): 57-61 years) for men and 55 years (95% CI: 53-58 years) for women. Distant metastasis was diagnosed in 28.4% of patients at the time of presentation and rectal cancer represented 41% of all colorectal cancers diagnosed in 2010. The overall 5-year survival was 44.6% for the period 1994-2004. The ASR for all age groups below 45 years of age was lower than that for the United States.

Limitations: The study was retrospective with a possibility of bias from inaccurate staging of patients, and inaccurate survival information and patient demographics due to the underdeveloped census system prior to 2001. Survival data for the period 2005-2010 are lacking.

Conclusion: Colorectal cancer presents at a younger age in Saudis, especially in women. This has a major implication for decisions about the threshold age for screening. The ASR has increased, but is still much lower than in developed countries. The lower overall 5-year survival compared with developed countries is due to lack of screening, a higher proportion of advanced stage cancer at presentation, lack of specialized care outside the major cities and a higher proportion of rectal cancer cases.
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http://dx.doi.org/10.5144/0256-4947.2015.196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074461PMC
June 2016

National Guidelines for Colorectal Cancer Screening in Saudi Arabia with strength of recommendations and quality of evidence.

Ann Saudi Med 2015 May-Jun;35(3):189-95

Nasser Alsanea, MBBCh, President, Saudi Society of Colon & Rectal Surgery,, Head Section, Colon & Rectal Surgery,, King Faisal Specialist Hospital & Research Centre-Riyadh, (MBC-40), PO Box 3354, Riyadh 11211,, Saudi Arabia, T: 966-1-442 7754, F: 966-1-442.7772,

Background: Colorectal cancer is the most common cancer among Saudi men and the third commonest among Saudi women. Given the predominance of colorectal cancer compared with other cancers in Saudi Arabia, context-specific guidelines are needed for screening.

Methods: Experts from the Saudi Society of Colon and Rectal Surgery, Saudi Gastroenterology Association, Saudi Oncology Society, Saudi Chapter of Enterostomal Therapy, Family Medicine and Department of Public Health at the Saudi Arabian Ministry of Health and a patient advocate was assembled by the Saudi Centre for Evidence-Based Healthcare, a subsidiary of the Saudi Arabian Ministry of Health. The panel collaborated with a methodological team from McMaster University, Canada to develop national guidelines for colorectal cancer screening. After identifying key questions, the panel conducted a systematic review of all reports on the utility of screening, the cost of screening for colorectal cancer in Saudi Arabia and on the values and preferences of Saudi patients. Meta- analyses, when appropriate, were performed to generate pooled estimates of effect. Using the GRADE approach, the panel used the evidence-to-decision (EtD) framework to assess all domains important in determining the strength and direction of the recommendations (benefits and harms, values and preferences, resource implications, equity, acceptability, and feasibility). Judgments related to the EtD domains were resolved through consensus or voting, if consensus was not reached. The final recommendations were developed during a two-day meeting held in Riyadh, Saudi Arabia in March 2015. Conflicts of interests among the panel members were handled according to the World Health Organization rules.

Limitations: There is lack of national data on the incidence of adenomatous polyps or the age groups in which the incidence surges. There were no national clinical trials assessing the effectiveness of the different modalities of screening for colorectal cancer and their impact on mortality.

Conclusion: The panel recommends screening for colorectal cancer in Saudi Arabia in asymptomatic Saudi patients at average risk of colorectal cancer. An infrastructure should be built to achieve that goal.
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http://dx.doi.org/10.5144/0256-4947.2015.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074460PMC
June 2016

Risk Factors for Abdominal Incision Infection after Colorectal Surgery in a Saudi Arabian Population: The Method of Surveillance Matters.

Surg Infect (Larchmt) 2015 Jun 6;16(3):254-62. Epub 2015 Apr 6.

Background: Reported surgical site infection rates range from 2.1% to 40% after colorectal surgery and are believed to be underestimated depending on the method of surveillance. The study aims were to identify an accurate incidence and associated risk factors for abdominal incision surgical site infection after elective open colorectal surgery in a Saudi population.

Methods: This was a prospective observational longitudinal study of 300 consecutive adult patients, recruited upon admission to an 800-bed tertiary referral center. All consenting adults admitted for elective open colorectal surgery were included. Patients were followed for 36 d post-surgery by two certified and experienced wound care experts who diagnosed abdominal incision surgical site infections. The definition provided by the U.S. Centers for Disease Control and Prevention was used. Statistical analysis was performed using both univariate and multivariable logistic regression.

Results: Data were analyzed for 296 patients; the incidence of abdominal surgical site infection was 30%. Factors associated with surgical site infection by univariate analysis were pre-operative pre-albumin (p=0.04, odds ratio [OR] 0.81, 95% confidence interval [CI] 0.66-0.99); operative difficulty because of truncal obesity (p=0.006, OR 2.19, 95% CI 1.25-3.84) and obesity measured by body mass index (p=0.002, OR 4.00, 95% CI 1.95-8.20). Multivariable analysis identified only two significant risk factors: Pre-operative pre-albumin (p=0.02, OR 0.76, 95% CI 0.60-0.96), and obesity measured by body mass index (BMI; p=0.001, OR 4.71, 95% CI 2.20-10.10).

Conclusion: Obesity and nutritional status correlated with post-operative abdominal surgical site infection. The method of surveillance and length of follow-up impact the rate reported.
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http://dx.doi.org/10.1089/sur.2013.208DOI Listing
June 2015

Outcome after ileal pouch-anal anastomosis for familial adenomatous polyposis compared to mucosal ulcerative colitis in a Middle Eastern population.

Ann Saudi Med 2013 May-Jun;33(3):268-72

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

Background And Objectives: To compare the complications and outcome after ileal pouch-anal anastomosis (IPAA) for mucosal ulcerative colitis (MUC) and familial adenomatous polyposis (FAP).

Design And Settings: This is a retrospective study. The study was conducted at a single tertiary referral center.

Methods: All patients who underwent restorative proctocolectomy with IPAA at a tertiary center in Saudi Arabia from 2001 till 2009 were retrieved. Data was obtained regarding preoperative status, postoperative complications, and functional outcome.

Results: A total of 40 patients underwent IPAA, of which 21 cases were of FAP and 19 cases of MUC. Median age at operation for FAP and MUC was 31 (range: 16-45) and 43 (range: 15-65) years, respectively (P < .05). Median length of stay was 10 days (range: 6-42) for FAP and 12 days (range: 9-27) for MUC (P=.1). Postoperative morbidity was noted in 4 cases of FAP and 6 cases of MUC (P=.36). Specifically, wound infection was noted in 2 cases of FAP compared to 3 cases of MUC (P=.55); 1 MUC case had an anastomotic leak (P=.29). One mortality was recorded among the FAP cases (P=.35). The time between the creation of IPAA and the closure of ileostomy was 4.5 and 5 months for FAP and MUC, respectively (P=.87). Median follow-up was 36 months. Median bowel frequency per 24 hours was 6 (range: 3-24) for FAP and 7 (range 3-17) for MUC (P=.54). Intestinal obstruction was reported in 3 cases of FAP and 5 cases of MUC (P=.38). One pouch was excised in a FAP patient. One case of MUC developed pouchitis.

Conclusions: The outcome after IPAA was inferior for MUC compared to FAP, but it was not statistically significant due to the small sample size. The morbid status of the MUC cases and their older age contributed to the minor differences.
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http://dx.doi.org/10.5144/0256-4947.2013.268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078538PMC
February 2014

Laparoscopic ovarian transposition before pelvic radiation in rectal cancer patient: safety and feasibility.

Ann Surg Innov Res 2012 Sep 17;6(1). Epub 2012 Sep 17.

Department of colorectal surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Unlabelled:

Background: Infertility due to pelvic radiation for advanced rectal cancer treatment is a major concern particularly in young patients. Pre-radiation laparoscopic ovarian transposition may offer preservation of ovarian function during the treatment however its use is limited.

Aim: The study investigates the safety, feasibility and effectiveness of pre-radiation laparoscopic ovarian transposition and its effect on ovarian function in the treatment o locally advanced rectal cancer.

Methods: Charts review of all young female patients diagnosed with locally advanced rectal cancer, underwent laparoscopic ovarian transposition, then received preoperative radiotherapy at king Faisal Specialist Hospital and Research Centre between 2003-2007.

Results: During the period studied three single patients age between 21-27 years underwent pre-radiation laparoscopic ovarian transposition for advanced rectal cancer. All required pretreatment laparoscopic diversion stoma due to rectal stricture secondary to tumor that was performed at the same time. One patient died of metastatic disease during treatment. The ovarian hormonal levels (FSH and LH) were normal in two patients. One has had normal menstrual period and other had amenorrhoea after 4 months follow-up however her ovarian hormonal level were within normal limits.

Conclusions: Laparoscopic ovarian transposition before pelvic radiation in advanced rectal cancer treatment is an effective and feasible way of preservation of ovarian function in young patients at risk of radiotherapy induced ovarian failure. However, this procedure is still under used and it is advisable to discuss and propose it to suitable patients.
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http://dx.doi.org/10.1186/1750-1164-6-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499289PMC
September 2012

Coexpression of activated c-Met and death receptor 5 predicts better survival in colorectal carcinoma.

Am J Pathol 2011 Dec 5;179(6):3032-44. Epub 2011 Oct 5.

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

Dysregulated overexpression of hepatocyte growth factor and its receptor, c-Met, has been reported in various cancers, but its role in colorectal carcinoma (CRC) has not been elucidated. Therefore, we investigated the role of phosphorylated Met (p-Met) in Middle Eastern CRC patient samples and cell lines. The p-Met was overexpressed in 80.8% of CRCs and strongly associated with the expression of p-AKT, DR5, and Ki-67 by immunohistochemistry. Coexpression of p-Met and DR5 was seen in 53.1% of CRC cases and was associated with a less aggressive phenotype, characterized by a histological subtype of adenocarcinomas, well-differentiated tumors, and was an independent prognostic marker for better overall survival. PHA665752, a selective p-Met inhibitor, induced apoptosis in CRC cells via inactivation of c-Met and AKT. PHA665752 treatment also caused increased expression of DR5 via generation of reactive oxygen species, and combination treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and PHA665752 induced significant apoptosis. In vivo, cotreatment of a CRC xenograft with PHA665752 and TRAIL significantly reduced tumor volume and weight. These data demonstrate a significant correlation between p-Met and DR5 in patients with CRC. Furthermore, inhibition of p-Met signaling by PHA665752 in combination with TRAIL significantly inhibited cell growth and induced apoptosis in CRC cell lines, suggesting that this may have significant clinical implications as a therapeutic target in the treatment of CRC.
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http://dx.doi.org/10.1016/j.ajpath.2011.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260832PMC
December 2011

Bortezomib stabilizes mitotic cyclins and prevents cell cycle progression via inhibition of UBE2C in colorectal carcinoma.

Am J Pathol 2011 May;178(5):2109-20

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

Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention in CRC.
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http://dx.doi.org/10.1016/j.ajpath.2011.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081207PMC
May 2011

Genome-wide expression analysis of Middle Eastern colorectal cancer reveals FOXM1 as a novel target for cancer therapy.

Am J Pathol 2011 Feb;178(2):537-47

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

To identify genes potentially playing an important role in the progression of colorectal carcinoma (CRC), we screened global gene expression using cDNA expression array on 41 CRC tissue samples and 25 noncancerous colorectal tissue samples. Among the up-regulated genes, forkhead box M1 (FOXM1) has been shown to play a critical role in pathogenesis of various malignancies. Using immunohistochemistry on 448 Saudi CRC samples in tissue microarray format, FoxM1 protein overexpression was seen in 66% of CRC tissues and was significantly associated with poorly differentiated and highly proliferative tumors (P = 0.0200 and 0.0018, respectively). FoxM1 expression was also significantly associated with MMP-9 protein expression (P = 0.0002). In vitro data using CRC cell lines showed that inhibition of FoxM1 by thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Overexpression of FoxM1 potentiated cell proliferation, cell transformation, and migration/invasion of CRC cells via up-regulation of FoxM1 target genes MMP2 and MMP9 and protected these cells from thiostrepton-mediated antiproliferative effects. Finally, in vivo, overexpression of FoxM1 promoted growth of CRC-cell line xenograft tumors in nude mice. Altogether, our data indicate that FoxM1 signaling contributes to aggressiveness in a subset of CRC and that the FOXM1 gene may serve as a useful molecular biomarker and potential therapeutic target.
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http://dx.doi.org/10.1016/j.ajpath.2010.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070566PMC
February 2011

Laparoscopic ovarian transposition before pelvic irradiation: a Saudi tertiary center experience.

Int J Gynecol Cancer 2010 Aug;20(6):1082-6

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

Objective: To report the authors' experience with laparoscopic ovarian transposition and ovarian function preservation in women who require pelvic irradiation as part of their cancer therapy.

Design: Cohort study.

Setting: The gynecologic oncology service in a referral tertiary/quaternary medical center in Saudi Arabia.

Patients: Twenty-three premenopausal patients treated with radiotherapy for a pelvic malignancy.

Interventions: Laparoscopic ovarian transposition to paracolic gutters with uterine conservation.

Main Outcome Measures: Preservation of ovarian function assessed by patients' symptoms and serum follicle-stimulating hormone level.

Results: Bilateral laparoscopic ovarian transposition was performed in 23 patients: 15 with cervical cancer, 4 with rectal cancer, 3 with Ewing sarcoma, and 1 with Hodgkin lymphoma. No immediate intraoperative or postoperative complications were observed. Three patients were lost to follow-up. Ovarian preservation was achieved in 13 (65%) of 20 patients. Seven patients with low follicle-stimulating hormone levels had regular uterine bleeding at follow-up.

Conclusions: Laparoscopic ovarian transposition is a safe and effective procedure for preserving ovarian function. This procedure should be considered in all premenopausal women who need to undergo pelvic irradiation as part of their cancer treatment.
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http://dx.doi.org/10.1111/IGC.0b013e3181e2ace5DOI Listing
August 2010

Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations.

Mol Cancer 2010 Jul 30;9:203. Epub 2010 Jul 30.

Department of Human Cancer Genomic Research, MBC 98-16,Research Centre at KFNCCC, King Faisal Specialist Hospital and Research Centre,PO Box 3354, Riyadh 11211,Kingdom of Saudi Arabia.

Background: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells.

Methods: We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival.

Results: CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251) and a histology subtype of adenocarcinomas (p = 0.0355). Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p < 0.0001), histology subtype of adenocarcinomas (p = 0.0010) and tumors in left colon (p = 0.0009). Over expression of pro apoptotic markers: p27KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011). Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L) phenotype (p = 0.0003) and with absence of KRAS mutations (p = 0.0481).

Conclusion: TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.
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http://dx.doi.org/10.1186/1476-4598-9-203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922191PMC
July 2010

Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma.

J Pathol 2009 Dec;219(4):435-45

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

Somatic KRAS mutation is an early well-known event in colorectal carcinogenesis but a complete understanding of RAS function and dysfunction in colorectal cancer is still to come. Our aim was to study the incidence of KRAS mutation; KRAS splice variants: KRAS4A and KRAS4B; and their relationships with various clinico-pathological characteristics in colorectal cancer (CRC).In this study, 285 CRC cases were analysed for KRAS mutation by direct DNA sequencing followed by immunohistochemical analysis after validation with real-time PCR assay, to study the protein expression of KRAS4A and -4B isoforms. KRAS gene mutations were seen in 80/285 CRCs (28.1%) and of the mutated cases, the majority of the mutations were seen in codon 12 (81.2%) as opposed to codon 13 (18.8%). CRCs with KRAS mutations were associated with a poor overall survival (p = 0.0009). Furthermore, KRAS mutations at codon 12 were associated with a poor overall survival of 64.4% at 5 years compared with a 5-year overall survival of 75.8% and 78.2% with codon 13 mutation and absence of KRAS mutations, respectively (p = 0.0025). KRAS4A protein expression was predominantly seen in the cytoplasm, while KRAS4B protein was nuclear. KRAS4A overexpression was significantly associated with left colon, histology subtype of adenocarcinoma, p27kip1, and cleaved caspase3 expression. Interestingly, KRAS4A overexpression was associated with a better overall survival (p = 0.0053). On the other hand, KRAS4B overexpression (33.2%) was significantly associated with larger tumour size (p = 0.0234) and inversely correlated with p27kip1 protein (p = 0.0159). Both KRAS mutation and KRAS4A were independent prognostic markers in a multivariate analysis with age, gender, stage, differentiation, and MSI status. Our results highlight the differential role of KRAS isoforms in CRC, their utility as a prognostic biomarker, and underline the importance of KRAS alterations as a potential therapeutic target for CRC.
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http://dx.doi.org/10.1002/path.2625DOI Listing
December 2009

Frequent PIK3CA gene amplification and its clinical significance in colorectal cancer.

J Pathol 2009 Nov;219(3):337-46

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

Using a DNA microarray approach to screen for gene copy number changes in 20 colorectal (CR) carcinoma samples and filtering for high-level DNA copy number changes, we detected an amplicon at 3q26 containing the PIK3CA gene. Fluorescence in situ hybridization was employed for evaluation of PIK3CA amplification on a progression CR tissue microarray containing 448 CR carcinomas, normal mucosa, and adenomas with follow-up information. PIK3CA amplification (ratio PIK3CA/centromere 3 > or = 2.0) was found in 38% of cancers, while another 19% of tumours had PIK3CA gains (ratio >1.0 but <2.0). Both PIK3CA amplification and gains were associated with high levels of PIK3CA protein expression and no association was seen between PIK3CA amplification and PIK3CA mutation. In a subset of 220 patients who received adjuvant chemotherapy and/or radiotherapy, survival in patients with PIK3CA-amplified cancers was significantly longer compared with patients with cancers without amplification. This association was independent of stage, grade, histology subtype, gender, and age categories. Interestingly, PIK3CA amplification was also seen in CR adenomas, indicating an early genetic alteration, and was also a frequent event in colorectal carcinogenesis. Furthermore, PIK3CA amplification is an independent prognostic marker for better survival and may be one of the promising markers to define CRC subsets that may maximally benefit from adjuvant therapy.
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http://dx.doi.org/10.1002/path.2601DOI Listing
November 2009

Leptin receptor expression in Middle Eastern colorectal cancer and its potential clinical implication.

Carcinogenesis 2009 Nov 11;30(11):1832-40. Epub 2009 Jun 11.

Human Cancer Genomic Research, Research Centre, Saudi Arabia.

We investigated the role of leptin receptor (Ob-R) and its relationship with phosphatidylinositol 3-kinase (PI3K)/AKT activation in colorectal carcinomas (CRCs) tissues followed by in vitro studies using a panel of CRC cell lines. Obesity serves an important risk factor of several cancers including CRC that ranks as the second most common cancer in Saudi Arabia. High levels of adipokine leptin (Ob) and its Ob-R are seen in obesity and also in various carcinomas including CRC. We investigated the proliferative and antiapoptotic effect of Ob on human CRC cell lines Caco-2, HT-29 and SW-840 and the role of PI3K/AKT-signaling pathway in mediating these actions. Then the expression of Ob-R and its relationship with clinicopathological features was analyzed in 448 CRC, 229 normal colon mucosa and 24 colorectal adenomas using tissue microarray technology. Treatment with Ob resulted in increased proliferation of CRC cell lines and involved activation of PI3K/AKT-signaling pathway. Pretreatment with Ob-R small interfering RNA or PI3K inhibitor inhibited these responses. Ob-R was significantly overexpressed in primary CRC relative to adenomas and normal colonic mucosa. In primary CRC, Ob-R significantly correlated with Ob expression, early stage and well-differentiated tumors. Intriguingly, patient with Ob-R positive tumors showed significantly better overall survival (P = 0.0098). Ob plays a critical role in CRC carcinogenesis through PI3K/AKT pathway via Ob-R. Ob-R is a prognostic marker associated with better survival.
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http://dx.doi.org/10.1093/carcin/bgp145DOI Listing
November 2009

High prevalence of fatty acid synthase expression in colorectal cancers in Middle Eastern patients and its potential role as a therapeutic target.

Am J Gastroenterol 2009 Jul 2;104(7):1790-801. Epub 2009 Jun 2.

Department of Human Cancer Genomic Research, King Fahad National Center for Children's Cancer and Research, Research Center, Riyadh, Saudi Arabia.

Objectives: Many human epithelial cancers, particularly those with a poor prognosis, express high levels of fatty acid synthase (FASN), a key metabolic enzyme linked to synthesis of membrane phospholipids in cancer cells. Overexpression of FASN is linked with activation of the phosphatidylinositol-3'-kinase (PI3 K)/AKT pathway. However, the role of FASN in colorectal cancer (CRC) has not been fully elucidated. We investigated the expression of FASN and determined its functional association with the PI3/AKT pathway in CRC.

Methods: Expression of FASN and its associated targets were studied by immunohistochemistry on 448 CRC tumors in a tissue microarray (TMA) format. Analysis of apoptosis and cell cycle was evaluated in vitro using CRC cell lines by flow cytometry and DNA fragmentation assays. Protein expression was determined by immunohistochemistry and western blotting. In vivo xenograft studies were performed using CRC cell lines and NUDE mice.

Results: Correlation of FASN with various clinicopathological parameters on 448 CRC samples was assessed. Activated AKT was found in 294/409 (71.9%) of CRC and was associated with FASN overexpression. FASN expression was observed in 27.1% (109/403) of Middle Eastern CRC. Additionally, FASN expression was significantly more common in tumors characterized by microsatellite instability (MSI) than in those characterized by microsatellite stability (MSS) (P<0.01). Our in vitro data using HCT-15, an MSI CRC cell line, showed a better apoptotic response after inhibition of FASN activity as compared with Colo-320, an MSS CRC cell line. Finally, treatment of HCT-15 cell line xenografts with C-75 resulted in growth inhibition of tumors in NUDE mice via downregulation of FASN and AKT activity.

Conclusions: These data identify FASN as a potential biomarker and a novel therapeutic target in distinct molecular subtypes of CRC.
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http://dx.doi.org/10.1038/ajg.2009.230DOI Listing
July 2009

Morbidity and mortality rounds in a Saudi hospital.

Saudi Med J 2008 Dec;29(12):1833; author reply 1833-4

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December 2008

Bortezomib (Velcade) induces p27Kip1 expression through S-phase kinase protein 2 degradation in colorectal cancer.

Cancer Res 2008 May;68(9):3379-88

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

S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. We investigated the role of SKP2 and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and the NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. A colorectal cancer (CRC) subset with high level of SKP2 and low level of p27Kip1 showed a decreased overall survival (P = 0.0057). Treatment of CRC cell lines with bortezomib or expression of small interfering RNA of SKP2 causes down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of CRC cells with bortezomib causes apoptosis by involving the mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Finally, treatment of CRC cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice via down-regulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of CRC.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-6109DOI Listing
May 2008

Colorectal carcinomas from Middle East. Molecular and tissue microarray analysis of genomic instability pathways.

Saudi Med J 2008 Jan;29(1):75-80

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

Objective: To evaluate the overall incidence of microsatellite instability (MSI), hereditary non polyposis colorectal cancer, and tumor supressor gene (TP53) mutations in Saudi colorectal carcinomas.

Methods: We studied the MSI pathway in Saudi colorectal cancers (CRC) from 179 unselected patients using 2 methods: MSI by polymerase chain reaction, and immunohistochemistry detection of mutL homologs 1 and mutS homologs 2 proteins. The TP53 mutations were studied by sequencing exons 5, 6, 7, and 8.

Results: Of the 150 colorectal carcinomas analyzed for MSI, 16% of the tumors showed high level instability (MSI-H), 19.3% had low-level instability (MSI-L) and the remaining 64% tumors were stable. Survival of the MSI-H group was better as compared to the MSI-L or microsatellite stable group (p=0.0217). In the MSI-H group, 48% were familial MSI tumors, which could be attributable to the high incidence of consanguinity in the Saudi population. The TP53 mutations were found in 24% of the cases studied.

Conclusion: A high proportion of familial MSI cases and a lower incidence of TP53 mutations are some of the hallmarks of the Saudi colorectal carcinomas, which need to be explored further.
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January 2008