Activation of telomerase induced by telomerase reverse transcriptase (TERT) promoter mutations has been implicated in human carcinogenesis. The two mutations termed C228T and C250T in TERT promoter region have been reported in various human tumor entities with different frequencies in Western populations. However, the contribution of these mutations to cancer progression in the Middle Eastern region remains poorly understood. In this study we investigated the frequency of TERT promoter mutations and TERT protein expression with their association to clinicopathological characteristics in 2113 samples from 13 different types of cancers. The TERT promoter mutations were most frequently present in bladder cancers (68.6%), followed by anaplastic thyroid cancers (50%), Hurthle cell carcinomas (40%), central nervous system (CNS) tumors (28.7%) and follicular thyroid cancers (19%). The low frequency of these mutations was found in medullary thyroid cancers (10%), prostate cancers (9.3%), endometrial carcinomas (3.7%), rhabdomyosarcomas (1.4%), colorectal cancers (CRC) (1%), epithelial ovarian carcinomas (EOC) (0.7%) and breast cancers (0.7%). No mutations were observed in gastric cancers, lung cancers, diffuse large B-cell lymphomas (DLBCL) and acute lymphoblastic leukemias (ALL). In CNS tumors the TERT promoter mutations were significantly associated with older age (p<0.0001), histological subtype (p<0.0001), high grade (p<0.0001) and poor 5 years overall survival (p<0.0001). In gliomas, TERT promoter mutations were more frequently present in cases with old age (p=0.003), high grade (p<0.0001) and poor 5 years overall survival (p<0.0001). Furthermore it was also revealed that co-occurrence of TERT promoter mutations and IDH1 wildtype predicted worst survival (p=0.0001) in gliomas. Our results demonstrate that mutations in TERT promoter is a frequently occurring event in several types of cancers and may be utilized for prognostic prediction in CNS tumors from Middle Eastern Region.Citation Format: Rong Bu, Abdul K. Siraj, Kaleem Iqbal, Sandeep Parvathareddy, Mark Diaz, Dionne Rala, Ingrid G. Victoria, Khadija Al-Obaisi, Wael Al-Haqawi, Nabil Siraj, Allianah Benito, Khawla S. Al-Kuraya. Telomerase reverse transcriptase (TERT) promoter mutations in cancers derived from multiple organ sites among Middle Eastern population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1577.
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.
Abstract Colorectal carcinoma is the fourth most common cancer in men and the third in women worldwide, accounting for 8% of all cancer deaths. NF-κB gene plays a role in tumorgenesis through the transcriptional activation of genes associated with cell proliferation, angiogenesis, metastasis, tumor promotion, inflammation and suppression of apoptosis. NF-κB protein activation, defined as nuclear expression of NF-κB by immunohistochemistry was an independent prognostic marker for poor survival. CARD10 gene is known positive regulator of the NF-κB activation pathway and can activate the NF-κB activity. CARD10 is an enzyme that is encoded by the CARD10 gene and it associates with IKK complex resulting in NF-κB activation. Considering the potential therapeutic utility of targeting NF-κB and its key modulators, we previously studied CARD10 genetic alterations and immunohistochemical expression of CARD10 in a large cohort cases1. CARD10 protein expression associated significantly with NF-κB activation, and CARD10 amplification was significantly associated with CARD10 protein expression and presence of distance metastasis. To extend and confirm our clinical finding, we performed in vitro studies using a panel of CRC cell lines to investigate the biological role of CARD10 alterations in CRC carcinogenesis. Our data showed that TNF-α treatment caused efficient translocation of p56 in CARD 10 muatation harboring cell line -DLD-1 cells to nucleus as compared to HCT-15 cells. Furthermore, the luciferase activity was significantly higher in CARD 10 amplified HCT-116 cells as compared to DLD1 and HCT-15 cells which carry normal CRAD10 gene copy number after 48 hours of transfection with an NF-κB reporter. In addition, it was also observed that the formation of colonies was significantly higher in HCT-116 as compared to DLD-1 and HCT-15. Finally CARD 10 siRNA transfection knocked down the expression of CARD10 and abrogated the expression of NF-κB, and resulted in apoptosis through activation of caspase-3. These data suggest that CARD10 mutation and amplification mediated NFκB activation play an important role in cellular transformation of CRC cells. Thus, the study raises the possibility that inhibition of CARD10 might have significant therapeutic value in CRC. Reference: 1: Jehad Abubaker, Prashant Bavi, Zeenath Jehan, Maqbool Ahmed, Wael Al-Haqawi, Mehar Sultana, Sarita Prabhakaran, Nasser Al-Sanea, Alaa Abduljabbar, Luai H Ashari, Samar Alhomoud, Fouad Al-Dayel, Shahab Uddin, Khawla S. Al-Kuraya. Clinicopathological significance of CARD10 alterations in Middle Eastern colorectal cancer. 102nd AACR Annual Meeting, April2-6, 2011, Orlando, Florida. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 110. doi:1538-7445.AM2012-110
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.
Abstract Purpose The aim of this study was evaluate biochemical incomplete response (BIR) in Middle Eastern differentiated thyroid cancer (DTC), identify factors that could predict BIR before radioactive iodine (RAI) ablation and to investigate the long-term clinical outcome of DTC patient exhibiting BIR to initial therapy. Methods We retrospectively evaluated 1286 DTCs from Middle Eastern ethnicity who underwent total thyroidectomy and RAI therapy. Demograpic and clinico-pathological factors predicting BIR were evaluated. The outcome of these patients was analyzed using primary outcome of structural disease and disease-free survival (DFS). Results With a median follow-up of 10 years, 266 (20.7%) patients had BIR. High pre-ablation stimulated thyroglobulin (presTg), presence of lymph node metastasis, male gender and delayed initial RAI therapy (≥3 months) after thyroidectomy were significant independent predictors of BIR. Upon evaluating long-term clinical outcomes in 266 patients with BIR, we found 36.8% of patients developed structural disease. Male sex (OR = 1.56; 95% CI = 1.05–2.30; p = 0.0272) and increasing Tg after initial therapy (OR = 4.25; 95% CI = 1.93–10.82; p = 0.0001) were independent risk factors for structural disease in patients with BIR. DFS was significantly worse if both these risk factors existed concomitantly ( p < 0.0001). Conclusion To achieve the fair efficacy of RAI therapy, early prediction of BIR before RAI ablation is desirable. Our finding of the clinico-pathological factors (high presTg level, LNM, delayed RAI therapy and male gender) could serve as easy and robust early predictors of BIR. In addition, DTC patients exhibiting BIR had a high risk of structural disease and hence personalized management approach would be preferable for BIR patients to ensure best clinical outcome.
Mutation-induced activation of Wnt-β Catenin signaling pathway is frequent in CRC. The E3 ubiquitin ligase, RNF43, has been reported to negatively regulate the Wnt signaling pathway and RNF43 mutations are frequently seen in CRC. However, its role in Middle Eastern CRC remains unclear. Therefore, we employed Exome and Sanger sequencing technology to assess the frequency of RNF43 mutations and its association with other clinico-pathological features in Middle Eastern CRC. RNF43 mutations were found in 5.9% (13/220) of CRC cases and was inversely correlated to APC and TP53 mutations. A strong association of RNF43 mutations with right sided and sporadic microsatellite instable (MSI) CRC was observed. No association was identified between RNF43 mutation and other clinico-pathological features including BRAF mutation, age, tumor histological subtype, tumor grade or patients' prognosis. Multivariate logistic regression analysis revealed that MSI status and wild type APC were independent predictor of RNF43 mutation. We conclude that RNF43 mutations occur in Middle Eastern CRC at comparable frequencies with BRAF mutations and represent a distinct molecular subtype which further enhances our understanding of how different mutational subsets of Wnt tumor suppressor genes link to distinct tumor characteristics, which might be considered for treatment strategies for CRC patients.
To characterize the prevalence and effect of BRCA1 and BRCA2 mutations in Middle Eastern EOC patients.
Methods
BRCA mutation screening was performed in 407 unselected ovarian cancer patients using targeted capture and/or Sanger sequencing.
Results
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_4137 delCT and c.1140 dupG) sharing the same haplotypes thus representing founder mutations in the Middle Eastern population.
Conclusions
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.
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.
Abstract A20, also known as TNF alpha induced protein3 (TNFAIP3), is a tumor suppressor gene and a well-known negative regulator of the NF-kB pathway in hematolymphoid neoplasms. In colorectal carcinoma (CRC), aberrant NF-kB regulation has been associated with poor prognosis and resistance to therapy. However, role of A20 gene in CRC is unknown. Therefore, we sought to elucidate the biological role of A20, mechanism of its inactivation and its prognostic role in colorectal carcinoma. We investigated the genetic and epigenetic abnormalities of A20 gene in CRC. In a tissue microarray cohort of 434 CRC, we studied loss of A20 protein expression by immunohistochemistry and A20 deletions by FISH. We also screened 116 random CRC and 14 CRC cell lines for mutations in A20 gene and A20 promoter methylation. Of the 116 CRC samples, A20 deletions were seen in 15.3% and incidence of A20 mutation was 2.5%; most of the mutations (4/5) were missense mutations. A20 promoter hyper-methylation was seen in 50.8% and was correlated with loss of protein expression (p=0.0079). A20 inactivation, defined as loss or reduced expression of protein was observed in 63% of CRC and A20 inactivation was an independent prognostic marker for poor survival in all CRC. In addition A20 expression retained its prognostic value in the following subgroups: Stage III; Stage II and III; and Stage III and IV. A20 was inactivated in majority of the CRC due to promoter methylation and can be targeted to modulate NF-κb expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2104. doi:10.1158/1538-7445.AM2011-2104
