Publications by authors named "Shaham Beg"

23 Publications

  • Page 1 of 1

Integration of whole-exome and anchored PCR-based next generation sequencing significantly increases detection of actionable alterations in precision oncology.

Transl Oncol 2021 Jan 12;14(1):100944. Epub 2020 Nov 12.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY, United States. Electronic address:

Background: Frequency of clinically relevant mutations in solid tumors by targeted and whole-exome sequencing is ∼30%. Transcriptome analysis complements detection of actionable gene fusions in advanced cancer patients. Goal of this study was to determine the added value of anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) assay to identify further potential drug targets, when coupled with whole-exome sequencing (WES).

Methods: Selected series of fifty-six samples from 55 patients enrolled in our precision medicine study were interrogated by WES and AMP-based NGS. RNA-seq was performed in 19 cases. Clinically relevant and actionable alterations detected by three methods were integrated and analyzed.

Results: AMP-based NGS detected 48 fusions in 31 samples (55.4%); 31.25% (15/48) were classified as targetable based on published literature. WES revealed 29 samples (51.8%) harbored targetable alterations. TMB-high and MSI-high status were observed in 12.7% and 1.8% of cases. RNA-seq from 19 samples identified 8 targetable fusions (42.1%), also captured by AMP-based NGS. When number of actionable fusions detected by AMP-based NGS were added to WES targetable alterations, 66.1% of samples had potential drug targets. When both WES and RNA-seq were analyzed, 57.8% of samples had targetable alterations.

Conclusions: This study highlights importance of an integrative genomic approach for precision oncology, including use of different NGS platforms with complementary features. Integrating RNA data (whole transcriptome or AMP-based NGS) significantly enhances detection of potential targets in cancer patients. In absence of fresh frozen tissue, AMP-based NGS is a robust method to detect actionable fusions using low-input RNA from archival tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tranon.2020.100944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674614PMC
January 2021

Fusions involving BCOR and CREBBP are rare events in infiltrating glioma.

Acta Neuropathol Commun 2020 06 3;8(1):80. Epub 2020 Jun 3.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.

BCOR has been recognized as a recurrently altered gene in a subset of pediatric tumors of the central nervous system (CNS). Here, we describe a novel BCOR-CREBBP fusion event in a case of pediatric infiltrating astrocytoma and further probe the frequency of related fusion events in CNS tumors. We analyzed biopsy samples taken from a 15-year-old male with an aggressive, unresectable and multifocal infiltrating astrocytoma. We performed RNA sequencing (RNA-seq) and targeted DNA sequencing. In the index case, the fused BCOR-CREBBP transcript comprises exons 1-4 of BCOR and exon 31 of CREBBP. The fused gene thus retains the Bcl6 interaction domain of BCOR while eliminating the domain that has been shown to interact with the polycomb group protein PCGF1. The fusion event was validated by FISH and reverse transcriptase PCR. An additional set of 177 pediatric and adult primary CNS tumors were assessed via FISH for BCOR break apart events, all of which were negative. An additional 509 adult lower grade infiltrating gliomas from the publicly available TCGA dataset were screened for BCOR or CREBBP fusions. In this set, one case was found to harbor a CREBBP-GOLGA6L2 fusion and one case a CREBBP-SRRM2 fusion. In a third patient, both BCOR-L3MBTL2 and EP300-BCOR fusions were seen. Of particular interest to this study, EP300 is a paralog of CREBBP and the breakpoint seen involves a similar region of the gene to that of the index case; however, the resultant transcript is predicted to be completely distinct. While this gene fusion may play an oncogenic role through the loss of tumor suppressor functions of BCOR and CREBBP, further screening over larger cohorts and functional validation is needed to determine the degree to which this or similar fusions are recurrent and to elucidate their oncogenic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-020-00951-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271411PMC
June 2020

Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

JCO Precis Oncol 2019 20;3. Epub 2019 Sep 20.

Weill Cornell Medicine, New York, NY.

Purpose: We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis.

Patients And Methods: Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated.

Results: Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were (33%), (11%), (10%), (8%), (8%), and (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently (1.9%), (1.5%), (1.5%), and (1.4%). Novel gene fusions were identified, including a fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant.

Conclusion: Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778956PMC
September 2019

Cancer-Specific Thresholds Adjust for Whole Exome Sequencing-based Tumor Mutational Burden Distribution.

JCO Precis Oncol 2019 31;3. Epub 2019 Jul 31.

Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, New York.

Purpose: To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold.

Materials And Methods: Using whole exome sequencing (WES) data from primary tumors in The Cancer Genome Atlas (TCGA) (n=3,534) and advanced/metastatic tumors from Weill Cornell Medicine (WCM Advanced) (n=696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds.

Results: The distribution of TMB varied dramatically between cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, while the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared to the static pan-cancer threshold. Additionally, no significant difference in survival outcomes was found with the cancer-specific threshold compared to the pan-cancer one. Further, the cancer-specific threshold maintains higher predicted neoantigen load for the TMB high samples compared to the TMB low samples, even when the threshold is lower than the pan-cancer threshold.

Conclusion: TMB is relative to the context of cancer type, metastatic state, and disease stage. Compared to a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that were not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Due to the potential impact in cancer patient care, TMB status should be determined in a cancer-specific manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.18.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716608PMC
July 2019

Bone biopsy protocol for advanced prostate cancer in the era of precision medicine.

Cancer 2018 03 19;124(5):1008-1015. Epub 2017 Dec 19.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

Background: Metastatic biopsies are increasingly being performed in patients with advanced prostate cancer to search for actionable targets and/or to identify emerging resistance mechanisms. Due to a predominance of bone metastases and their sclerotic nature, obtaining sufficient tissue for clinical and genomic studies is challenging.

Methods: Patients with prostate cancer bone metastases were enrolled between February 2013 and March 2017 on an institutional review board-approved protocol for prospective image-guided bone biopsy. Bone biopsies and blood clots were collected fresh. Compact bone was subjected to formalin with a decalcifying agent for diagnosis; bone marrow and blood clots were frozen in optimum cutting temperature formulation for next-generation sequencing. Frozen slides were cut from optimum cutting temperature cryomolds and evaluated for tumor histology and purity. Tissue was macrodissected for DNA and RNA extraction, and whole-exome sequencing and RNA sequencing were performed.

Results: Seventy bone biopsies from 64 patients were performed. Diagnostic material confirming prostate cancer was successful in 60 of 70 cases (85.7%). The median DNA/RNA yield was 25.5 ng/μL and 16.2 ng/μL, respectively. Whole-exome sequencing was performed successfully in 49 of 60 cases (81.7%), with additional RNA sequencing performed in 20 of 60 cases (33.3%). Recurrent alterations were as expected, including those involving the AR, PTEN, TP53, BRCA2, and SPOP genes.

Conclusions: This prostate cancer bone biopsy protocol ensures a valuable source for high-quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. © 2017 American Cancer Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.31173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821525PMC
March 2018

XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis.

BMC Cancer 2017 Sep 11;17(1):640. Epub 2017 Sep 11.

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

Background: Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored.

Methods: We examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors.

Results: XIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo.

Conclusion: These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-017-3627-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594504PMC
September 2017

Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis.

Am J Hum Genet 2016 06 26;98(6):1170-1180. Epub 2016 May 26.

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

Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p < 0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908175PMC
June 2016

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

Int J Cancer 2016 09 3;139(5):1091-7. Epub 2016 May 3.

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

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.30143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111783PMC
September 2016

Reply to specific gene patterns and molecular pathways related to human carcinogenesis in different populations among various geographic locations.

Cancer 2016 Apr 5;122(7):1135-7. Epub 2016 Feb 5.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.29904DOI Listing
April 2016

ALK alteration is a frequent event in aggressive breast cancers.

Breast Cancer Res 2015 Sep 17;17:127. Epub 2015 Sep 17.

Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia.

Introduction: Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Anaplastic lymphoma kinase (ALK) gene has been found to be altered in several solid and hematologic tumors. We aimed to comprehensively study the prevalence of ALK expression, and changes in copy number and translocation in a large cohort of breast cancer cases in a Middle Eastern population.

Methods: ALK protein expression was investigated by immunohistochemistry and numerical and structural variations of the ALK gene were analyzed by fluorescence in situ hybridization (FISH) in a tissue microarray format in a cohort of more than 1000 Middle Eastern breast cancers. The data were correlated with clinicopathologic parameters and other important molecular biomarkers.

Results: Immunohistochemical analysis showed ALK overexpression in 36.0 % of the breast cancer patients and gene amplification was present in 13.3 % of cases, seen by FISH analyses. ALK overexpression was significantly associated with ALK gene amplification (p = 0.0031). ALK-overexpressing tumors showed significant association with high-grade tumors (p = 0.0039), ductal histologic subtype (p = 0.0076), triple-negative phenotype (p = 0.0034), and high Ki-67 (p = 0.0001) and p-AKT (p <0.0001).

Conclusions: Immunohistochemical analysis showed ALK is overexpressed in a substantial proportion of breast cancers and possibly plays a significant role in the aggressive behavior of this cancer. Gene amplification is hypothesized to be a possible cause for a significant proportion of this overexpression. Based on these findings, a potential role for an ALK inhibitor, as a therapeutic agent targeting aggressive subtypes of breast cancer, merits further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13058-015-0610-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588266PMC
September 2015

Molecular markers and pathway analysis of colorectal carcinoma in the Middle East.

Cancer 2015 Nov 28;121(21):3799-808. Epub 2015 Jul 28.

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

Background: Colorectal cancer (CRC) is one of the most common cancers in the world. A newly proposed integrated pathway comprising traditional, alternate, and serrated pathways by genetic and epigenetic factors was defined recently and hypothesized to play a role in the pathogenesis of CRC; however, to the authors' knowledge, there is a paucity of information regarding these proposed molecular pathways in different ethnic groups.

Methods: Molecular characterization of 770 CRC specimens was performed for microsatellite instability, BRAF, and KRAS by polymerase chain reaction and 500 cases for CpG island methylator phenotype (CIMP) high phenotype by MethyLight technology. Tumors were assigned to different molecular pathways and examined for clinicopathological correlation and survival analysis.

Results: The traditional pathway constituted 33.4% of CRC cases, the alternate pathway comprised 11.6%, and the serrated molecular pathway accounted for only 0.8% of Middle Eastern CRC cases. Approximately 54.2% of CRC cases did not qualify to fit into any pathway and thus were designated as an unassigned group. Molecular pathways were found to be significantly associated with tumor site and grade. A subset of cases with an uncategorized pathway demonstrated a significant survival difference (P = .0079).

Conclusions: The serrated pathway was found to account for a very low percentage of the CRC patient cohort in the current study. The unassigned group accounted for the majority of Middle Eastern CRC cases, and therefore methods of CRC pathway analysis might not be applicable to this ethnic group. The current study demonstrates the need to unravel the molecular genetic basis of this disease to further subcategorize these CRC cases. It also identifies a need for further studies on different populations for a better understanding of their exact role and incidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.29580DOI Listing
November 2015

Co-targeting of Cyclooxygenase-2 and FoxM1 is a viable strategy in inducing anticancer effects in colorectal cancer cells.

Mol Cancer 2015 Jul 10;14:131. Epub 2015 Jul 10.

Human Cancer Genomic Research, Research Center, Riyadh, Saudi Arabia.

Background: Cross-talk between deregulated signaling pathways in cancer cells causes uncontrolled growth and proliferation. These cancers cells become more aggressive and quickly develop resistance to therapy. Therefore targeting of these deregulated pathways simultaneously can result in efficient cell death of cancer cells. In this study we investigated co-expression of Cox-2 and FoxM1 in a cohort of colorectal carcinoma (CRC) samples and also examined whether inhibition of Cox-2 and FoxM1 simultaneously can lead to inhibition of cell viability and induction of apoptosis in colorectal cancer cell lines and in vivo xenografts.

Methods: Protein expression of Cox-2 and FoxM1 was determined in a large cohort of 770 clinical CRC samples in a tissue micro-array format by immunohistochemistry. Cell death was measured using live dead assay. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Calcusyn software was utilized to estimate the synergistic doses using chou and Talalay method.

Results: Co-expression of Cox-2 and FoxM1 was detected in 33.3 % (232/697) of CRC's and associated with an aggressive phenotype characterized by younger age (p = 0.0191), high proliferative index marker; Ki-67 (p = 0.004) and MMP-9 (p = 0.0116) as well as activation of AKT (p = 0.0214). In vitro, inhibition of FoxM1 and Cox-2 with pharmacological inhibitors; Thiostrepton and NS398 resulted in efficient down-regulation of FoxM1 and Cox-2 expression along with in-activation of AKT and inhibition of colony formation, invasion and migratory capability of CRC cells. In addition, there was also inhibition of cell viability and induction of apoptosis via the mitochondrial apoptotic pathway in CRC cell lines. Finally, treatment of CRC xenograft tumors in nude mice with combination of Cox-2 and FoxM1 inhibitors inhibited tumor growth significantly via down-regulation of Cox-2 and FoxM1 expression.

Conclusions: These findings demonstrate that co-expression of Cox-2 and FoxM1 might play a critical role in the pathogenesis of CRC. Therefore, targeting of these pathways simultaneously with sub toxic doses of pharmacological inhibitors can be a potential therapeutic approach for the treatment of this subset of CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12943-015-0406-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861127PMC
July 2015

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer.

Mol Med 2015 May 26;21:466-78. Epub 2015 May 26.

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

Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2119/molmed.2014.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607622PMC
May 2015

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

Breast Cancer Res Treat 2015 Jun 16;151(3):541-53. Epub 2015 May 16.

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

PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-015-3430-3DOI Listing
June 2015

Role of X-Linked Inhibitor of Apoptosis as a Prognostic Marker and Therapeutic Target in Papillary Thyroid Carcinoma.

J Clin Endocrinol Metab 2015 Jul 14;100(7):E974-85. Epub 2015 May 14.

Human Cancer Genomic Research Unit (A.R.H., R.B., M.A., Z.J., S.B., A.K.S., S.U., K.S.A.-K.) and Departments of Endocrinology (S.A.-S.) and Pathology (F.A.-D.), King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; and Alfaisal University (K.S.A.-K.), 11533 Riyadh, Saudi Arabia.

Context: Papillary thyroid cancer (PTC) is the second most common cancer in females in Saudi Arabia. However, the pathogenesis of PTC is still not fully elucidated.

Objective: To identify potential genes that play important role in progression of PTC, we studied the role of X-linked inhibitor of apoptosis protein (XIAP) as a potential prognostic marker and therapeutic target in a large cohort of PTC samples and cell lines.

Design: A DNA microarray chip was used to screen for gene copy number. XIAP expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of 1022 clinical samples. In vitro and in vivo studies were performed using Embelin and/or LY294002 on PTC cell lines.

Results: XIAP was found to be amplified in 14 of 29 and overexpressed in 48.8% of PTC cases. XIAP overexpression was significantly associated with old age, extrathyroidal extension, tumor size, nodal involvement, tall-cell variant, advanced stage disease, and significantly poor disease-free survival (P = .0341). XIAP was also significantly associated with phosphorylated AKT (P < .0001), Bcl-Xl (P < .0001), and Ki67 (P = .0006) proteins. Embelin treatment caused growth inhibition and apoptosis in PTC cell lines and induced tumor regression in PTC xenograft in nude mice. Finally, the combination of suboptimal doses of Embelin and LY294002 induced a synergistic apoptotic response in PTC cells.

Conclusion: XIAP dysregulation in PTC confers an aggressive phenotype with poor outcome. In vitro and in vivo studies using an XIAP inhibitor suggest that this subgroup of PTC with overexpression of XIAP can be therapeutically targeted, either alone or in combination, to induce efficient apoptosis in these cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2014-4356DOI Listing
July 2015

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer.

Cancer 2015 Jun 24;121(11):1762-71. Epub 2015 Feb 24.

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

Background: Lynch syndrome (LS; hereditary nonpolyposis colorectal cancer) is a common cause of hereditary colorectal cancer (CRC). CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC. There currently are no clear guidelines for the selection criteria for these patients to screen for LS.

Methods: A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction. BRAF mutation screening, high CpG island methylator phenotype, and analysis for germline mutations were performed in 425 CRC samples. These were all high microsatellite instability (MSI-H) samples (91 cases), all low MSI samples (143 cases), and selected cases from the microsatellite stable group (191 cases) that met revised Bethesda guidelines.

Results: Polymerase chain reaction identified 91 MSI-H cases (11.3%) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only. Of the total of 807 CRC cases, these 8 cases (0.99%) were MSI-H, met the revised Bethesda guidelines, and did not harbor BRAF mutations.

Conclusions: The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations. This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.29288DOI Listing
June 2015

A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.

Mol Cancer 2014 Jul 8;13:168. Epub 2014 Jul 8.

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

Background: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer. Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal carcinomas (CRC) and are predominantly seen in the serrated adenoma-carcinoma pathway characterized by microsatellite instability (MSI-H) and hypermethylation of the MLH1 gene in the setting of the CpG island methylator phenotype (CIMP). Due to the lack of data on the true incidence of BRAF mutations in Saudi Arabia, we sought to analyze the incidence of BRAF mutations in this ethnic group.

Methods: 770 CRC cases were analyzed for BRAF and KRAS mutations by direct DNA sequencing.

Results: BRAF gene mutations were seen in 2.5% (19/757) CRC analyzed and BRAF V600E somatic mutation constituted 90% (17/19) of all BRAF mutations. BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162). Incidence of KRAS mutations was 28.6% (216/755) and a mutual exclusivity was noted with BRAF mutations (p = 0.0518; a trend was seen).

Conclusion: Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia. This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors. These findings indirectly suggest the possibility of a higher incidence of familial hereditary colorectal cancers especially Hereditary non polyposis colorectal cancer (HNPCC) syndrome /Lynch Syndrome (LS) in Saudi Arabia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1476-4598-13-168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109832PMC
July 2014

Bilateral, multicenteric metanephric adenoma associated with Wilms' tumor in a child: a rare presentation with important diagnostic and therapeutic implications.

Int J Urol 2012 Dec 27;19(12):1114-7. Epub 2012 Aug 27.

Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.

Metanephric adenoma is an uncommon benign renal tumor that occurs predominantly in adult females and rarely in children. On histomorphology it shows a resemblance to Wilms' tumor, nephrogenic rests and papillary renal cell carcinoma. Multifocality along with multicentricity has not been documented in English literature till date. From a diagnostic and therapeutic viewpoint, recognition of this entity is of the utmost importance, because it shows a favorable clinical outcome. We describe a rare case of bilateral, multicentric metanephric adenoma associated with triphasic Wilms' tumor (stage II) of the left kidney in a male child.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1442-2042.2012.03134.xDOI Listing
December 2012

A comparison of cytological and histopathological findings and role of immunostains in the diagnosis of soft tissue tumors.

J Cytol 2012 Apr;29(2):125-30

Department of Pathology, J.N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.

Background: Fine needle aspiration cytology (FNAC) has been employed as a useful technique for the initial diagnosis of soft tissue tumors (STT) as well for the identification of recurrent and metastatic cases.

Aim: We conducted this study on soft tissue tumors to find the efficacy of FNAC and to finalize the histological diagnosis with immunostains.

Materials And Methods: The present study was conducted on 126 patients of soft tissue tumors. FNAC and histopathology was performed in all the cases.

Results: Hundred and five cases (83.3%) were diagnosed as benign and 21 cases (16.7%) as malignant. On FNAC, tumors were divided into six cytomorphological categories i.e. lipomatous, spindle cell, round cell, myxoid, pleomorphic and vascular tumors. Seventeen cases were inconclusive on cytology. In five cases, the type of malignancy was changed on histological examination. There were three false positive and two false negative cases giving a positive predictive value of 97.2 % in terms of malignancy, a sensitivity of 98.1% and a specificity of 96.7%.

Conclusions: FNAC has a definite role in forming the initial diagnosis of STT, while histopathology with the aid of immunomarkers provides the final diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0970-9371.97154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391793PMC
April 2012

Endometrial adenocarcinoma with osteoclastic giant cells in stroma: a case report and review of literature.

Arch Gynecol Obstet 2012 Apr 25;285(4):1157-60. Epub 2011 Sep 25.

The Department of Pathology, Jawaharlal Nehru Medical College, AMU, Aligarh, 202002 UP, India.

It is rare to find osteoclastic giant cells (OGCs) as a stromal reaction in uterine adenocarcinoma of endometrium. Here, we report a case of a 60-year-old female diagnosed with adenocarcinoma of endometrium. Total hysterectomy with bilateral salpingo-oopherectomy and removal of pelvic lymphnodes was performed. Histologically, the tumour showed adenocarcinoma of the endometrium with mucin secretion. The stroma showed some plump reactive pleomorphic cells, resembling stromal cells, infiltrated uniformly with OGCs and mononuclear cells (MNCs). The epithelial cells of adenocarcinoma stained positive for cytokeratin (CK 7) (CAM 5.2). The osteoclastic giant cells and mononuclear cells stained positive with CD68 and negative with cytokeratin and vimentin. We conclude that the osteoclastic giant cells originated from reactive histiocytes/monocytes as a stromal reaction to malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00404-011-2089-1DOI Listing
April 2012

Erythema nodosum leprosum: report of two cases.

Diagn Cytopathol 2013 Apr 19;41(4):366-8. Epub 2011 Sep 19.

Department of Pathology, VMMC and Safdarjung Hospital, Safdarjung, New Delhi, India.

Erythema nodosum leprosum (ENL) or type 2 lepra reaction is an inflammatory reaction, which may occur in the course of hanseniasis, may compel the patient to seek medical attention and may result in nerve function impairment and subsequent disability. Thus, recognition and timely management of these patients is critical in order to avoid permanent disability. Fine-needle aspiration cytology is simple and effective tool that aids in the correct diagnosis and management of ENL. Herein, we present two cases of ENL, one with typical and another with atypical presentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dc.21785DOI Listing
April 2013

Mucinous carcinoma in a male breast.

J Cytol 2011 Apr;28(2):84-6

Department of Pathology, VMMC and Safdarjung Hospital, Delhi, India.

Male breast cancer is rare as compared to female counterpart. Pure mucinous carcinoma is an extremely rare histological subtype representing less than 1% of male breast cancers. So far very few cases of pure mucinous carcinoma of male breast have been reported in the literature, most of which were diagnosed after surgical resection. Fine-needle aspiration cytology is a well-established procedure for the evaluation of female breast masses but the diagnosis of malignancy in aspirates from male breast masses is rare. We herein present one case of mucinous carcinoma of breast in a 75-year-old male diagnosed by fine-needle aspiration and confirmed by histopathology. After a follow-up of 12 months the patient is free of any recurrence or metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0970-9371.80751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111715PMC
April 2011

Spindle cell lipoma breast.

Indian J Pathol Microbiol 2008 Apr-Jun;51(2):234-6

Department of Pathology, J.N.M.C.H., A.M.U., Aligarh, India.

Spindle cell lipoma, which usually arises in the soft tissues, is rare in breast and is difficult to differentiate from primary mammary spindle cell tumor. Here, we present the case of a 48-year-old woman with a 3-cm, solitary, well-circumscribed and nontethered mass lying deep within the tissue of left breast, incidentally detected on routine mammography. The spindle cells proved to be immunoreactive to CD 34, but nonreactive to desmin and smooth muscle actin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0377-4929.41666DOI Listing
September 2008