Predicting factors and clinical outcome of biochemical incomplete response in middle eastern differentiated thyroid carcinoma.

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.

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.

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.

Exome sequencing revealed comparable frequencies of RNF43 and BRAF mutations in Middle Eastern colorectal cancer.

Mutation-induced activation of Wnt-ß 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.

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.

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.

Role of nuclear factor-κB regulators TNFAIP3 and CARD11 in Middle Eastern diffuse large B-cell lymphoma.

Aberrant nuclear factor-κB (NF-κB) regulation has been observed in many hematopoietic malignancies including diffuse large B-cell lymphoma (DLBCL). Considering the potential therapeutic utility of targeting NF-κB and its key modulators, we studied genetic alterations (mutations and amplifications) in TNFAIP3 and CARD11 genes in DLBCL samples. The incidence of CARD11 and TNFAIP3 mutations was 10.7% and 4.6%, respectively. Interestingly, CARD11 amplification was seen in a significant proportion of cases of DLBCL (23%) and was linked to NF-κB activation (p = 0.0142). Immunohistochemical analysis of DLBCL samples showed CARD11 overexpression and loss of TNFAIP3 in 17.7% (32/181) and 13.5% (24/178), respectively. Poor overall survival was noted in DLBCL harboring CARD11 gene amplification (p = 0.0491). Our study reports the incidence of TNFAIP3 and CARD11 alterations in Saudi DLBCL, a potentially unique ethnic group, and highlights for the first time the role of CARD11 gene amplification as a novel mechanism for NF-κB activation in Middle Eastern DLBCL.

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

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.

PIK3CA alterations in Middle Eastern ovarian cancers.

BACKGROUND: PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer (EOC). Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs. RESULTS: Fluorescence in situ hybridization (FISH) technique and DNA sequencing were used to analyze PIK3CA amplification and mutation respectively. Expression of PIK3CA protein expression (p110 alpha), PTEN, p-AKT and Ki-67 was analyzed by immunohistochemistry. PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 alpha overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67. CONCLUSION: Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently. High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.