Predictive risk factors for distant metastasis in pediatric differentiated thyroid cancer from Saudi Arabia.

Background: Despite their excellent prognosis, children and young adults (CAYA) with differentiated thyroid cancer (DTC) tend to have more frequent occurrence of distant metastasis (DM) compared to adult DTC. Data about DM in CAYA from Middle Eastern ethnicity is limited. Methods: Medical records of 170 patients with DTC ≤18 years were retrospectively reviewed. Clinico-pathological factors associated with lung metastasis in CAYA, their clinical presentation and outcome were analyzed. Rick factors related to distant metastasis-free survival (DMFS) for the whole cohort were evaluated. Results: DM was observed in 27 patients and all were lung metastasis. Lung metastasis was significantly associated with younger age (≤15 years), extrathyroidal extension (ETE), multifocal tumors, bilaterality, presence of lymph node (LN) disease and high post-operative stimulated thyroglobulin (sTg). Highest negative predictive values were seen with low post-operative sTg (97.9%), absence of LN disease (93.8%), absence of ETE (92.2%) and age older than 15 years (92.9%). Post-therapy whole body scan (WBS) identified most of the lung metastasis (21 of 27; 77.8%). Upon evaluating patients response according to ATA guidelines, excellent response was seen in only one patient, while biochemical persistence and structural persistence were seen in 11.1% (3/27) and 77.8% (21/27), respectively. Elevated post-operative sTg (>10ng/ml) was the only risk factor found to be significantly associated with both biochemical persistence (with or without structural persistence (p = 0.0143)) and structural persistence (p = 0.0433). Cox regression analysis identified age and post-operative sTg as independent risk factors related to DMFS. Based on these two risk factors for DMFS, patients were divided into 3 groups: low risk (no risk factors), intermediate risk (1 risk factor) and high risk (both risk factors). 20-year DMFS rates in the low-, intermediate- and high-risk groups were 100.0%, 81.3% and 23.7% respectively (p < 0.0001). Conclusion: Higher suspicion for metastatic pediatric DTC should be considered in patients who are young, have LN disease, extrathyroidal extension and elevated post-operative sTg. Persistent disease, despite therapy, is very common and it appears to be related to post-operative sTg level. Hence, risk adaptive management is desirable in CAYA with DTC.

Loss of CDH16 expression is a strong independent predictor for lymph node metastasis in Middle Eastern papillary thyroid cancer.

Papillary Thyroid Cancer (PTC) is the most common type of thyroid cancer. The membrane-associated glycoprotein cadherin-16 (CDH16) plays a significant role in the embryonal development of thyroid follicles and cell adhesion. Previous studies have indicated a substantial downregulation of CDH16 in PTC. However, its role in Middle Eastern PTC has not been elucidated. We analyzed a tissue microarray comprising 1606 PTC and 240 normal thyroid tissues using immunohistochemistry to assess CDH16 expression and determine its clinico-pathological associations. We also conducted BRAF and TERT mutations analyses through Sanger sequencing. Disease-free survival (DFS) was assessed using Kaplan-Meier curves. CDH16 immunostaining was seen in 100% of normal thyroid tissues but only in 9.4% of PTC tissues (p < 0.0001). The loss of CDH16 expression was associated with aggressive PTC characteristics including bilaterality, multifocality, extrathyroidal extension, tall cell variant, lymph node metastasis (LNM) and distant metastasis. Additionally a correlation between loss of CDH16 expression and BRAF and TERT mutations was identified. Intriguingly, upon conducting multivariate logistic regression analysis, CDH16 was determined to be an independent predictor for LNM (Odds ratio = 2.46; 95% confidence interval = 1.60-3.79; p < 0.0001). Furthermore, CDH16 loss was associated with a shorter DFS (p = 0.0015). However, when we further subdivided CDH16 negative patients based on the co-existence of TERT and/or BRAF mutations, we found that patients with both CDH16 negative expression and TERT mutation exhibited the shortest DFS (p < 0.0001). In conclusion, our results suggest that CDH16 protein expression could serve as a valuable diagnostic tool for PTC. Furthermore, these findings demonstrate that the loss of CDH16 expression is an independent predictor of LNM and may contribute to the aggressiveness of PTC. Therefore, downregulation of CDH16 in PTC might be a potential target for designing novel therapeutic strategies to treat PTC.

X-linked inhibitor of apoptosis protein (XIAP) predicts disease-free survival in BRAFV600E mutant papillary thyroid carcinoma in middle eastern patients.

Background: X-linked inhibitor of apoptosis (XIAP) is the most potent caspase inhibitory IAP family member and its over-expression is implicated in aggressive behavior of various solid tumors, including papillary thyroid carcinoma (PTC). BRAFV600E mutation is the most common oncogenic event in PTC and is also known to be associated with aggressive clinico-pathological characteristics. In this study, we investigated the prevalence of XIAP expression in more than 1600 PTCs from Middle Eastern ethnicity and its prognostic value to predict disease-free survival (DFS), in combination with the BRAFV600E mutation. Methods: Clinical data, XIAP expression by immunohistochemistry and BRAF mutation status were analyzed in 1640 Saudi PTC patients seen at our institute between 1988 - 2020. Results: BRAFV600E mutation was found in 910 of 1640 patients (55.5%) and was significantly correlated with older age, extrathyroidal extension, bilaterality, multifocality and lymph node metastasis, but was not an independent predictor of DFS. XIAP was over-expressed in 758 of 1640 (46.2%) and was associated with aggressive clinico-pathological features. It was also found to be an independent prognostic marker for DFS (HR = 1.28, 95% CI = 1.02 - 1.60, P = 0.0342). XIAP overexpression was correlated with presence of BRAFV600E mutation in PTC patients. Interestingly, we found the ability to predict shorter DFS was 2.7-fold higher in PTCs with over-expression of XIAP and BRAFV600E mutation compared to patients with high XIAP and wild-type BRAFV600E status (HR = 2.74, 95% CI = 2.19 - 3.44, p < 0.0001). Conclusion: XIAP expression is an independent predictor of prognosis in Middle Eastern PTC patients. Combination of XIAP expression and BRAFV600E mutation can synergistically improve the DFS prediction in PTC patients, which may help clinicians to establish the most appropriate initial care and long-term surveillance strategies.

Lynch Syndrome Identification in Saudi Cohort of Endometrial Cancer Patients Screened by Universal Approach.

Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi Arabia, a total of 436 EC cases were screened utilizing immunohistochemistry (IHC), MLH1 promoter methylation analysis and next-generation sequencing technology. A total of 53 of 436 (12.2%) ECs were classified as DNA mismatch repair-deficient (dMMR). MLH1 promoter hypermethylation was detected in 30 ECs (6.9%). Three ECs (0.7%) were found to be LS harboring germline pathogenic variants (PVs)/likely pathogenic variants (LPVs): two in the MSH2 gene and one in the MSH6 gene. Three ECs (0.7%) were Lynch-like syndrome (LLS) carrying double somatic MSH2 PVs/LPVs. Seven cases were found to have variants of uncertain significance in cancer-related genes other than MMR genes. Our results indicate that LS prevalence is low among Saudi EC patients and LLS is as common as LS in this ethnicity. Our findings could help in better understanding of the prevalence and mutational spectrum of this syndrome in Saudi Arabia, which may help in defining best strategies for LS identification, prevention and genetic counseling for EC patients.

Tumor size is an independent negative prognostic factor for event free survival in children with differentiated thyroid cancer.

Background: The incidence of pediatric differentiated thyroid carcinoma (DTC) is increasing. Despite the advanced disease at presentation, the overall prognosis of DTC in children is excellent. The aim of this study is to investigate the risk stratifying factors for event free survival (EFS) of pediatric DTC from Middle Eastern ethnicity. Methods: Eighty-eight patients aged ≤18 years with diagnosis of primary DTC were retrospectively analyzed. Cox proportional hazards model were used to calculate Hazard Ratios (HR) and Kaplan-Meier analysis were conducted to investigate EFS. Results: Eighty-eight (23 males and 65 females) pediatric DTCs who underwent surgery and radioactive iodine therapy had been reported (median age at diagnosis 15 years; range 5.9-17.9), with lymph node metastasis (LNM) noted in 70.5% and distant metastasis in 13.6%. Mean follow-up was 8.4 years. Ten-year overall survival rate was 98.4% while 10-year EFS was 79.2%. EFS was negatively impacted by the presence of LNM, distant metastasis and tumor size >4cm. American Thyroid Association risk stratification did not impact EFS in our cohort. Multivariate analysis revealed tumor size >4cm (HR = 5.34; 95% confidence interval (CI) = 1.36 - 20.22; p = 0.0177) and distant metastasis (HR = 8.73; 95% CI = 1.48 - 60.05; p = 0.0154) as independent negative prognostic factors for EFS. Conclusions: Primary tumor size and the presence of distant metastasis at diagnosis are the only independent prognostic risk factors for EFS in pediatric DTC in Middle Eastern ethnicity. Children with tumor size over 4cm had poor EFS, which may justify the need of more aggressive treatment and frequent follow-up.

Risk Factors for Cervical Lymph Node Metastasis in Middle Eastern Papillary Thyroid Microcarcinoma.

Papillary thyroid microcarcinoma (PTMC) typically has an indolent course and excellent prognosis. Nonetheless, a subset of PTMC carries a risk of lymph node metastasis (LNM) and local recurrence. PTC from the Middle Eastern population is unique with respect to demographic and clinico-pathological characteristics as compared to other ethnicities of the world. The risk factors of LNM in PTMC patients of Middle Eastern ethnicity have not been fully explored. The present study aims to investigate the influencing factors of LNM in Middle Eastern PTMC patients and its predictive impact on patient's outcome. A total of 226 confirmed PTMC cases were selected in this retrospective study. The correlation between clinico-pathological, as well as molecular, characteristics and LNM was evaluated. Multivariate analysis was performed by logistic regression and Cox proportional hazards models. Among the 226 patients, the rate of LNM was 43.8% (99/226). Bilaterality, multifocality, gross extrathyroidal extension (ETE), and intermediate-to-high American Thyroid Association (ATA) risk tumors were significantly associated with LNM in PTMC. Multivariate logistic regression analysis showed that bilaterality and gross ETE were independent predictive factors for LNM in PTMC. The recurrence-free survival (RFS) was shorter in PTMC with LNM compared to those without LNM (p = 0.0051) and was significant on multivariate analysis. In conclusion, our study showed that bilaterality and gross ETE were independent influencing factors of LNM in Saudi patients with PTMC. LNM was also associated with shorter RFS. The identification of risk factors for LNM in patients of Middle Eastern ethnicity could help the individualization of clinical management for PTMC patients.

Male Sex Is an Independent Predictor of Recurrence-Free Survival in Middle Eastern Papillary Thyroid Carcinoma.

Background: Disparity between sexes with regard to incidence, disease aggressiveness, and prognosis has been documented in several cancers. Although various reports have documented the association between male sex and aggressive papillary thyroid carcinoma (PTC), the prognostic impact of sex on PTC has been inconsistent. The role of sex in PTC aggressiveness and outcome in Middle Eastern PTC remains unknown. Therefore, our study retrospectively analyzed the data of a large cohort of Middle Eastern PTC patients to address this issue. Methods: We compared men and women with respect to clinico-pathological characteristics, disease persistence, structural recurrence, risk stratification, and prognosis. We included 1,430 patients-1,085 (75.9%) women and 345 (24.1%) men. Results: The median follow-up was 9.3 years. At diagnosis, 27% (93/345) of men were ≥55 years, compared with 17.8% (193/1085) of women (p = 0.0003). Men had significantly more advanced disease at presentation: higher stage (p = 0.0074), larger tumor size (p = 0.0069), higher rates of lymphovascular invasion (p = 0.0129), extrathyroidal extension (p = 0.0086), regional lymph node metastasis (p = 0.0279), and distant metastasis (p = 0.0101). There was a higher rate of recurrence (p < 0.0001) and TERT mutations (p = 0.0003) in male PTC patients than in female patients. Additionally, radioiodine refractoriness was higher in male PTC patients (p = 0.0014). In multivariate analysis, male sex was an independent prognostic factor for poor recurrence-free survival (RFS) (hazard ratio = 1.58; 95% confidence interval = 1.20-2.06; p = 0.0011). Conclusions: Men with PTC are more likely to present with more advanced and aggressive disease. Importantly, male sex was an independent prognostic factor for RFS. Thus, men may benefit from more aggressive management and therapeutic interventions.

Bilateral multifocality is an independent predictor of patients' outcome in Middle Eastern papillary thyroid carcinoma.

Background: Tumor multifocality is frequently seen in Papillary thyroid carcinoma (PTC). However, few studies have analysed the impact of bilateral multifocality in PTC. The incidence of bilateral multifocality, its clinico-pathological associations and prognostic impact in PTC from Middle Eastern ethnicity remains unestablished. Methods: We retrospectively evaluated 1283 patients who underwent total thyroidectomy for PTC. Bilateral and unilateral multifocality were decided based on the final pathology result. Primary outcome was recurrence free survival (RFS). Risk factors for bilateral multifocality were analyzed by multivariate logistic regression analysis. Results: Multifocal PTC was found in 54.3% (697/1283) of patients. Among the 697 multifocal PTCs, 210 patients (30.1%) had unilateral multifocal PTC and 487 patients (69.9%) had bilateral multifocality. Bilateral multifocality was significantly associated with older age at diagnosis (p = 0.0263), male gender (p = 0.0201), gross extrathyroidal extension (p = 0.0332), larger primary tumor size (>4cm; p = 0.0002), lateral lymph node metastasis (p = 0.0008), distant metastasis at diagnosis (p = 0.0195) and recurrence (p = 0.0001). Bilateral multifocality was also found to be an independent predictor of RFS (Hazard ratio = 1.60; 95% Confidence Interval = 1.05 - 2.55; p = 0.0300). Multivariate logistic regression analysis demonstrated tumor diameter >4cm to be the only independent risk factors for bilaterality in multifocal PTC (Odds ratio = 1.86; 95% Confidence Interval = 1.13 - 3.07; p = 0.0155). Conclusions: Incidence of bilateral multifocality is high in Middle Eastern PTC. Tumor diameter >4cm can be considered as a predictive factor for bilateral multifocal PTC. Bilateral multifocality appears to be an important prognostic factor for PTC and an independent predictor of RFS. Therefore, patients with bilateral multifocal PTC may benefit from more frequent follow-up to identify recurrences earlier.

Loss of ZNF677 expression is a predictive biomarker for lymph node metastasis in Middle Eastern Colorectal Cancer.

Zinc-finger proteins are transcription factors with a "finger-like" domain that are widely involved in many biological processes. The zinc-finger protein 677 (ZNF677) belongs to the zinc-finger protein family. Previous reports have highlighted the tumor suppressive role of ZNF677 in thyroid and lung cancer. However, its role in colorectal cancer (CRC) has not been explored. ZNF677 protein expression was analyzed by immunohistochemistry in a large cohort of 1158 CRC patients. ZNF677 loss of expression was more frequent in CRC tissues (45.3%, 525/1158), when compared to that of normal tissue (5.1%, 11/214) (p < 0.0001) and was associated with mucinous histology (p = 0.0311), advanced pathological stage (p < 0.0001) and lymph node (LN) metastasis (p = 0.0374). Further analysis showed ZNF677 loss to be significantly enriched in LN metastatic CRC compared to overall cohort (p = 0.0258). More importantly, multivariate logistic regression analysis showed that ZNF677 loss is an independent predictor of LN metastasis in CRC (Odds ratio = 1.41; 95% confidence interval 1.05-1.87; p = 0.0203).The gain- and loss-of-function studies in CRC cell lines demonstrated that loss of ZNF677 protein expression prominently increased cell proliferation, progression of epithelial-mesenchymal transition and conferred chemoresistance, whereas its overexpression reversed the effect. In conclusion, loss of ZNF677 protein expression is common in Middle Eastern CRC and contributes to the prediction of biological aggressiveness of CRC. Therefore, ZNF677 could not only serve as a marker in predicting clinical prognosis in patient with CRC but also as a potential biomarker for personalized targeted therapy.

High Expression of Cyclin D1 is an Independent Marker for Favorable Prognosis in Middle Eastern Breast Cancer.

PURPOSE: The cyclin D1 protein regulates cell cycle progression which is mediated by its interactions with cyclin-dependent kinases. Over-expression of cyclin D1 has been observed in several human cancers. This study was conducted to evaluate cyclin D1 expression in a large cohort of Middle Eastern breast cancers and determine its prognostic significance. PATIENTS AND METHODS: Cyclin D1 expression was assessed immunohistochemically and its association with clinico-pathological parameters was analyzed in 1003 breast cancer patients. RESULTS: Cyclin D1 was over-expressed in 59.4% (596/1003) of cases and significantly associated with a subset of breast cancers having favorable prognostic features, such as low grade (p < 0.0001), low stage (p = 0.0276), estrogen receptor (p < 0.0001) and progesterone receptor positive (p < 0.0001) tumors. An inverse association was found with triple negative breast cancers (p < 0.0001). More importantly, cyclin D1 expression was an independent predictor of favorable overall survival in our cohort (hazard ratio = 0.70; 95% confidence interval = 0.50-0.98; p = 0.0395). Also, tumors that highly expressed cyclin D1 had a longer recurrence-free survival. However, this significant association was seen only in univariate analysis. We also found cyclin D1 to be associated with phospho-Rb in luminal subtype of breast cancer and co-expression of both these markers was an independent predictor of luminal A breast cancer. CONCLUSION: Our results reinforced the role of cyclin D1 in breast cancer pathology and revealed its expression as a valuable independent prognostic indicator for breast cancer from Middle Eastern ethnicity.

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

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 (p = 0.0005) and lymph node metastasis (p = 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; p = 0.0123). In conclusion, PD-L1 was strongly associated with non-endometrioid EC and was an independent prognostic marker of lymph node metastasis.

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

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.

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

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.

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

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.

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

BACKGROUND: Many Muslims believe that water from the Zamzam well is the cure for every disease. Zamzam water (ZW) is naturally alkaline water consumed by millions of people worldwide. The current study investigated the effect of ZW on cell viability and apoptosis in breast, colorectal and ovarian cancer cell lines and compared the effect with that of drinking water (DW). METHODS: Three different ZW samples collected from different sources at different periods were used. To balance the tonicity, ZW and DW were buffered using PBS and the pH was adjusted to 7.4. For the treatment, ZW and DW were diluted to 50% with RPMI medium (10% FBS). Cancer cell lines were treated with ZW or DW, with and without chemotherapeutic agents, for 24 h. Apoptosis was measured using flow cytometry whilst the level of protein expression was determined by Western blotting. RESULTS: The results showed that treatment with ZW significantly increased cell proliferation compared to DW control. Treatment with ZW significantly suppressed the effect of chemotherapeutic agents on decreasing cell viability and inducing apoptosis in all the cancer cell lines compared to chemotherapeutic agents alone treated in DW. Furthermore, ZW treatment increased the phosphorylation of CRAF, MEK1/2, ERK1/2 and P38 proteins in these cell lines. Notably, treatment with ZW suppressed the effect of chemotherapy-induced reduction of CRAF, MEK1/2, ERK1/2 and P38 phosphorylation in breast and ovarian cancer cell lines. We also showed that silencing of ERK1/2 significantly increased the chemotherapy-induced apoptosis in breast and colorectal cancer cell lines. These data suggest that MAPK proteins; especially activated ERK1/2 may play a role in ZW mediated suppression of chemotherapy-induced cell death. CONCLUSIONS: These findings clearly demonstrate that ZW protects cancer cells from chemotherapy-induced apoptosis through activation of the ERK1/2-MAPK signaling pathway.

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

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.