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Fulltext DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the Efficacy of Checkpoint Inhibitor

Wang C, Zainal NS, Chai SJ, Dickie J, Gan CP, Zulaziz N, et al.

Front Immunol, 2021;12:763086.
PMID: 34733290 DOI: 10.3389/fimmu.2021.763086

HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.
Valproic acid: growth inhibition of head and neck cancer by induction of terminal differentiation and senescence

Gan CP, Hamid S, Hor SY, Zain RB, Ismail SM, Wan Mustafa WM, et al.

Head Neck, 2012 Mar;34(3):344-53.
PMID: 21438066 DOI: 10.1002/hed.21734

There are limited studies on the effects of drugs that modulate epigenetic regulation for head and neck squamous cell carcinoma (HNSCC). This study determined the effect of valproic acid (VPA) on HNSCC.
Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma

Zanaruddin SN, Saleh A, Yang YH, Hamid S, Mustafa WM, Khairul Bariah AA, et al.

Hum Pathol, 2013 Mar;44(3):417-26.
PMID: 23026198 DOI: 10.1016/j.humpath.2012.06.007

The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC.
Fulltext Identification of immunogenic MAGED4B peptides for vaccine development in oral cancer immunotherapy

Lim KP, Chun NA, Gan CP, Teo SH, Rahman ZA, Abraham MT, et al.

Hum Vaccin Immunother, 2014;10(11):3214-23.
PMID: 25483651 DOI: 10.4161/hv.29226

The ever-increasing number of tumor-associated antigens has provided a major stimulus for the development of therapeutic peptides vaccines. Tumor-associated peptides can induce high immune response rates and have been developed as vaccines for several types of solid tumors, and many are at various stages of clinical testing. MAGED4B, a melanoma antigen, is overexpressed in oral squamous cell carcinoma (OSCC) and this expression promotes proliferation and cell migration. In this study, we have identified 9 short peptides derived from MAGED4B protein that are restricted in binding to the HLA subtypes common in the Asian population (HLA-A2, A11, and A24). The peptides had good binding affinity with the MHC-Class I molecules and stimulated ex-vivo IFN-gamma and Granzyme-B production in blood samples from OSCC patients, suggesting that they are immunogenic. Further, T cells stimulated with peptide-pulsed dendritic cells showed enhanced T-cell cytotoxic activity against MAGED4B-overexpressing OSCC cell lines. In summary, we have identified MAGED4B peptides that induce anti-tumor immune responses advocating that they could be further developed as vaccine candidates for the treatment of OSCC.
Fulltext In vitro evaluation of dual-antigenic PV1 peptide vaccine in head and neck cancer patients

Chai SJ, Fong SCY, Gan CP, Pua KC, Lim PVH, Lau SH, et al.

Hum Vaccin Immunother, 2019;15(1):167-178.
PMID: 30193086 DOI: 10.1080/21645515.2018.1520584

Peptide vaccines derived from tumour-associated antigens have been used as an immunotherapeutic approach to induce specific cytotoxic immune response against tumour. We previously identified that MAGED4B and FJX1 proteins are overexpressed in HNSCC patients; and further demonstrated that two HLA-A2-restricted 9-11 amino acid peptides derived from these proteins were able to induce anti-tumour immune responses in vitro independently using PBMCs isolated from these patients. In this study, we evaluated the immunogenicity and efficacy of a dual-antigenic peptide vaccine (PV1), comprised of MAGED4B and FJX1 peptides in HNSCC patients. We first demonstrated that 94.8% of HNSCC patients expressed MAGED4B and/or FJX1 by immunohistochemistry, suggesting that PV1 could benefit the majority of HNSCC patients. The presence of pre-existing MAGED4B and FJX1-specific T-cells was detected using a HLA-A2 dimer assay and efficacy of PV1 to induce T-cell to secrete cytotoxic cytokine was evaluated using ELISPOT assay. Pre-existing PV1-specific T-cells were detected in all patients. Notably, we demonstrated that patients' T-cells were able to secrete cytotoxic cytokines upon exposure to target cells expressing the respective antigen post PV1 stimulation. Furthermore, patients with high expression of MAGED4B and FJX1 in their tumours were more responsive to PV1 stimulation, demonstrating the specificity of the PV1 peptide vaccine. Additionally, we also demonstrated the expression of MAGED4B and FJX1 in breast, lung, colon, prostate and rectal cancer suggesting the potential use of PV1 in these cancers. In summary, PV1 could be a good vaccine candidate for the treatment of HNSCC patients and other cancers expressing these antigens.
Fulltext Potentially malignant disorders of the oral cavity: current practice and future directions in the clinic and laboratory

Dionne KR, Warnakulasuriya S, Zain RB, Cheong SC

Int J Cancer, 2015 Feb 1;136(3):503-15.
PMID: 24482244 DOI: 10.1002/ijc.28754

Despite commendable progress in the prevention, detection, and treatment of a wide variety of solid tumor types, oral squamous cell carcinoma (OSCC) remains a significant health burden across the globe. OSCC carcinogenesis involves accumulation of genetic alterations that coincide with the multistep malignant transformation of normal oral epithelium. OSCC is often first diagnosed at late stages of the disease (advanced regional disease and/or metastasis). Delayed diagnosis precludes successful treatment and favorable outcomes. In clinical practice, opportunities exist to identify patients with oral potentially malignant disorders (OPMDs), which precede the development of cancer. This review addresses the current status of laboratory and clinical research on OPMDs, with emphasis on leukoplakia and erythroplakia. OSF is also presented, though there is a paucity of published studies on this disorder. We focus on findings that could translate into earlier diagnosis and more efficacious treatment of those lesions with significant malignant potential. We explore how markers of OPMD malignant transformation might be implemented into current diagnostic practice to help clinicians objectively stratify patients into treatment/follow-up groups according to relative risk. We provide an overview of recently concluded and ongoing OPMD chemoprevention trials. We describe laboratory OPMD models that can be used to not only to reveal the genetic and molecular intricacies of oral cancer but also to develop novel screening methods and therapeutic approaches. Finally, we call for targeted screening programs of at-risk populations in order to facilitate diagnosis and treatment of OPMD and early OSCC.
Fulltext Collagen Triple Helix Repeat Containing-1 (CTHRC1) Expression in Oral Squamous Cell Carcinoma (OSCC): Prognostic Value and Clinico-Pathological Implications

Lee CE, Vincent-Chong VK, Ramanathan A, Kallarakkal TG, Karen-Ng LP, Ghani WM, et al.

Int J Med Sci, 2015;12(12):937-45.
PMID: 26664254 DOI: 10.7150/ijms.11605

Collagen Triple Helix Repeat Containing 1 (CTHRC1) is a protein often found to be over-expressed in various types of human cancers. However, correlation between CTHRC1 expression level with clinico-pathological characteristics and prognosis in oral cancer remains unclear. Therefore, this study aimed to determine mRNA and protein expression of CTHRC1 in oral squamous cell carcinoma (OSCC) and to evaluate the clinical and prognostic impact of CTHRC1 in OSCC.
Establishment and characterization of Asian oral cancer cell lines as in vitro models to study a disease prevalent in Asia

Hamid S, Lim KP, Zain RB, Ismail SM, Lau SH, Mustafa WM, et al.

Int J Mol Med, 2007 Mar;19(3):453-60.
PMID: 17273794

We have established 3 cell lines ORL-48, -115 and -136 from surgically resected specimens obtained from untreated primary human oral squamous cell carcinomas of the oral cavity. The in vitro growth characteristics, epithelial origin, in vitro anchorage independency, human papilloma-virus (HPV) infection, microsatellite instability status, karyotype and the status of various cell cycle regulators and gatekeepers of these cell lines were investigated. All 3 cell lines grew as monolayers with doubling times ranging between 26.4 and 40.8 h and were immortal. Karyotyping confirmed that these cell lines were of human origin with multiple random losses and gains of entire chromosomes and regions of chromosomes. Immunohistochemistry staining of cytokeratins confirmed the epithelial origin of these cell lines, and the low degree of anchorage independency expressed by these cell lines suggests non-transformed phenotypes. Genetic analysis identified mutations in the p53 gene in all cell lines and hypermethylation of p16INK4a in ORL-48 and -136. Analysis of MDM2 and EGFR expression indicated MDM2 overexpression in ORL-48 and EGFR overexpression in ORL-136 in comparison to the protein levels in normal oral keratinocytes. Analysis of the BAT-26 polyadenine repeat sequence and MLH-1 and MSH-2 repair enzymes demonstrated that all 3 cell lines were microsatellite stable. The role of HPV in driving carcinogenesis in these tumours was negated by the absence of HPV. Finally, analysis of the tissues from which these cell lines were derived indicated that the cell lines were genetically representative of the tumours, and, therefore, are useful tools in the understanding of the molecular changes associated with oral cancers.
Erratum to: Zebrafish phenotypic screen identifies novel Notch antagonists

Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.

Invest New Drugs, 2017 04;35(2):250.
PMID: 28185040 DOI: 10.1007/s10637-017-0437-0
Zebrafish phenotypic screen identifies novel Notch antagonists

Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.

Invest New Drugs, 2017 04;35(2):166-179.
PMID: 28058624 DOI: 10.1007/s10637-016-0423-y

Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.
Significant association of high-risk human papillomavirus (HPV) but not of p53 polymorphisms with oral squamous cell carcinomas in Malaysia

Saini R, Tang TH, Zain RB, Cheong SC, Musa KI, Saini D, et al.

J Cancer Res Clin Oncol, 2011 Feb;137(2):311-20.
PMID: 20419384 DOI: 10.1007/s00432-010-0886-8

PURPOSE: The purpose of this study was to evaluate the role of HPV and p53 polymorphisms in oral squamous cell carcinomas (OSCC) affecting Malaysian population.
METHODS: We analysed frozen samples from 105 OSCC as well as 105 oral specimens derived from healthy individuals. PCR assays targeting two regions of the virus were used. PCR amplification for the analysis of p53 codon 72 arginine/proline alleles was carried out in a separate reaction.
RESULTS: HPV DNA was detected in 51.4% OSCC samples, while 24.8% controls were found to be HPV positive. HPV was found to be significantly associated with OSCC (P
GENIPAC: A Genomic Information Portal for Head and Neck Cancer Cell Systems

Lee BKB, Gan CP, Chang JK, Tan JL, Fadlullah MZ, Abdul Rahman ZA, et al.

J Dent Res, 2018 07;97(8):909-916.
PMID: 29512401 DOI: 10.1177/0022034518759038

Head and neck cancer (HNC)-derived cell lines represent fundamental models for studying the biological mechanisms underlying cancer development and precision therapies. However, mining the genomic information of HNC cells from available databases requires knowledge on bioinformatics and computational skill sets. Here, we developed a user-friendly web resource for exploring, visualizing, and analyzing genomics information of commonly used HNC cell lines. We populated the current version of GENIPAC with 44 HNC cell lines from 3 studies: ORL Series, OPC-22, and H Series. Specifically, the mRNA expressions for all the 3 studies were derived with RNA-seq. The copy number alterations analysis of ORL Series was performed on the Genome Wide Human Cytoscan HD array, while copy number alterations for OPC-22 were derived from whole exome sequencing. Mutations from ORL Series and H Series were derived from RNA-seq information, while OPC-22 was based on whole exome sequencing. All genomic information was preprocessed with customized scripts and underwent data validation and correction through data set validator tools provided by cBioPortal. The clinical and genomic information of 44 HNC cell lines are easily assessable in GENIPAC. The functional utility of GENIPAC was demonstrated with some of the genomic alterations that are commonly reported in HNC, such as TP53, EGFR, CCND1, and PIK3CA. We showed that these genomic alterations as reported in The Cancer Genome Atlas database were recapitulated in the HNC cell lines in GENIPAC. Importantly, genomic alterations within pathways could be simultaneously visualized. We developed GENIPAC to create access to genomic information on HNC cell lines. This cancer omics initiative will help the research community to accelerate better understanding of HNC and the development of new precision therapeutic options for HNC treatment. GENIPAC is freely available at http://genipac.cancerresearch.my/ .
Mouse Models for Head and Neck Squamous Cell Carcinoma

Zhou J, Liu C, Amornphimoltham P, Cheong SC, Gutkind JS, Chen Q, et al.

J Dent Res, 2024 May 09.
PMID: 38722077 DOI: 10.1177/00220345241240997

The prognosis and survival rate of head and neck squamous cell carcinoma (HNSCC) have remained unchanged for years, and the pathogenesis of HNSCC is still not fully understood, necessitating further research. An ideal animal model that accurately replicates the complex microenvironment of HNSCC is urgently needed. Among all the animal models for preclinical cancer research, tumor-bearing mouse models are the best known and widely used due to their high similarity to humans. Currently, mouse models for HNSCC can be broadly categorized into chemical-induced models, genetically engineered mouse models (GEMMs), and transplanted mouse models, each with its distinct advantages and limitations. In chemical-induced models, the carcinogen spontaneously initiates tumor formation through a multistep process. The resemblance of this model to human carcinogenesis renders it an ideal preclinical platform for studying HNSCC initiation and progression from precancerous lesions. The major drawback is that these models are time-consuming and, like human cancer, unpredictable in terms of timing, location, and number of lesions. GEMMs involve transgenic and knockout mice with gene modifications, leading to malignant transformation within a tumor microenvironment that recapitulates tumorigenesis in vivo, including their interaction with the immune system. However, most HNSCC GEMMs exhibit low tumor incidence and limited prognostic significance when translated to clinical studies. Transplanted mouse models are the most widely used in cancer research due to their consistency, availability, and efficiency. Based on the donor and recipient species matching, transplanted mouse models can be divided into xenografts and syngeneic models. In the latter, transplanted cells and host are from the same strain, making syngeneic models relevant to study functional immune system. In this review, we provide a comprehensive summary of the characteristics, establishment methods, and potential applications of these different HNSCC mouse models, aiming to assist researchers in choosing suitable animal models for their research.
Human telomerase reverse transcriptase expression in oral carcinogenesis--a preliminary report

Kumar SK, Zain RB, Ismail SM, Cheong SC

J Exp Clin Cancer Res, 2005 Dec;24(4):639-46.
PMID: 16471328

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, is strongly associated with telomerase activity implicated in cellular immortalization and tumorigenesis. In situ detection of hTERT will aid in determining the localization of telomerase positive cells. The aim of this study was to detect hTERT protein expression in multistep oral carcinogenesis using paraffin embedded tissue samples, and to study the relationship of hTERT expression with different histological stages in oral carcinogenesis. Normal (n = 4), hyperplastic (n = 4), dysplastic (n = 4) and neoplastic (n = 10) oral epithelia representing different histological stages in oral carcinogenesis were included in the study. hTERT protein detection was done by immunohistochemistry (IHC) technique. Nuclear staining intensities were noted and the hTERT-labelling index was determined. Dysplastic and neoplastic oral epithelia showed an increased percentage of hTERT positive cells (Grade 4: > 50% positive staining nuclei) with intense staining in the basal, parabasal and superficial layers of the epithelia, unlike normal oral mucosa which showed intense staining only in the basal and parabasal cell layers, which are the normal proliferative progenitor compartments. hTERT protein expression was elevated with the corresponding advancement of the histological stages of oral carcinogenesis, from normal to hyperplasia to dysplasia to carcinoma. There seems to be an upregulation of hTERT protein expression during the progression of oral cancer, therefore, this may indicate the feasibility of IHC detection of hTERT protein in oral carcinogenesis as a potential diagnostic or prognostic marker.
Barriers to early detection and management of oral cancer in the Asia Pacific region

Ng SW, Syamim Syed Mohd Sobri SN, Zain RB, Kallarakkal TG, Amtha R, Wiranata Wong FA, et al.

J Health Serv Res Policy, 2022 Jan 22.
PMID: 35068209 DOI: 10.1177/13558196211053110

OBJECTIVE: Oral cancer is amenable to early detection but remains a prominent cause of mortality in the Asia Pacific region. This study aimed to identify barriers to early detection and management of oral cancer in the Asia Pacific region.
METHODS: A mixed-methods approach was employed triangulating findings from a survey and focus groups. The survey was conducted among seven representative members of the Asia Pacific Oral Cancer Network (APOCNET) across six countries. Focus groups were conducted to gain deeper insights into the findings of the survey.
RESULTS: The identified barriers were a lack of national cancer control strategies and cancer registries and the limited availability of trained health care professionals. Overcoming these challenges in the Asia Pacific region where resources are scarce will require collaborative partnerships in data collection and novel approaches for continuous professional training including eLearning. Further, to overcome the lack of trained health care professionals, innovative approaches to the management of oral potentially malignant lesions and oral cancer including telemedicine were suggested.
CONCLUSION: The findings of this study should be taken into account when charting national cancer control plans for oral cancer and will form the basis for future collaborative studies in evaluating effective measures to improve oral cancer detection and management in low- and middle-income countries.
Calibration improves the agreement in grading oral epithelial dysplasia-Findings from a National Workshop in Malaysia

Kallarakkal TG, Zaini ZM, Ghani WMN, Karen-Ng LP, Siriwardena BSMS, Cheong SC, et al.

J Oral Pathol Med, 2024 Jan;53(1):53-60.
PMID: 38081145 DOI: 10.1111/jop.13501

INTRODUCTION: A major pitfall of many of the established oral epithelial dysplasia (OED) grading criteria is their lack of reproducibility and accuracy to predict malignant transformation. The main objective of this study was to determine whether calibration of practicing oral pathologists on OED grading could improve the reproducibility of the WHO 2017 and the binary OED grading systems.
METHODS: A nationwide online exercise was carried out to determine the influence of calibration on the reproducibility of the WHO 2017 and the binary OED grading systems.
RESULTS: A significant improvement was observed in the inter-observer agreement for the WHO 2017 OED grading system (K 0.196 vs. 0.448; Kw 0.357 vs. 0.562) after the calibration exercise. The significant difference (p = 0.027) in the level of agreement between those with five or more years and less than 5 years of experience was no more observed (p = 0.426) after the calibration exercise. The percent agreement for binary grading was significantly higher (91.8%) for buccal mucosal lesions as compared to lesions on the tongue after the calibration exercise.
CONCLUSION: This study validates the significance of calibration in improving the reproducibility of OED grading. The nationwide exercise resulted in a statistically significant improvement in the inter-observer agreement for the WHO 2017 OED grading system among a large number of oral pathologists. It is highly recommended that similar exercises should be organized periodically by professional bodies responsible for continuing education among oral pathologists to improve the reliability of OED grading for optimal treatment of oral potentially malignant disorders.
Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies

Vaithilingam RD, Safii SH, Baharuddin NA, Ng CC, Cheong SC, Bartold PM, et al.

J Periodontal Res, 2014 Dec;49(6):683-95.
PMID: 24528298 DOI: 10.1111/jre.12167

Studies to elucidate the role of genetics as a risk factor for periodontal disease have gone through various phases. In the majority of cases, the initial 'hypothesis-dependent' candidate-gene polymorphism studies did not report valid genetic risk loci. Following a large-scale replication study, these initially positive results are believed to be caused by type 1 errors. However, susceptibility genes, such as CDKN2BAS (Cyclin Dependend KiNase 2B AntiSense RNA; alias ANRIL [ANtisense Rna In the Ink locus]), glycosyltransferase 6 domain containing 1 (GLT6D1) and cyclooxygenase 2 (COX2), have been reported as conclusive risk loci of periodontitis. The search for genetic risk factors accelerated with the advent of 'hypothesis-free' genome-wide association studies (GWAS). However, despite many different GWAS being performed for almost all human diseases, only three GWAS on periodontitis have been published - one reported genome-wide association of GLT6D1 with aggressive periodontitis (a severe phenotype of periodontitis), whereas the remaining two, which were performed on patients with chronic periodontitis, were not able to find significant associations. This review discusses the problems faced and the lessons learned from the search for genetic risk variants of periodontitis. Current and future strategies for identifying genetic variance in periodontitis, and the importance of planning a well-designed genetic study with large and sufficiently powered case-control samples of severe phenotypes, are also discussed.
ERG oncoprotein expression in prostate carcinoma patients of different ethnicities

Kelly GM, Kong YH, Dobi A, Srivastava S, Sesterhenn IA, Pathmanathan R, et al.

Molecular and clinical oncology, 2015 Jan;3(1):23-30.
PMID: 25469265

Overexpression of the erythroblast transformation-specific-related gene (ERG) oncoprotein due to transmembrane protease, serine 2 (TMPRSS2)-ERG fusion, the most prevalent genomic alteration in prostate cancer (CaP), is more frequently observed among Caucasian patients compared to patients of African or Asian descent. To the best of our knowledge, this is the first study to investigate the prevalence of ERG alterations in a multiethnic cohort of CaP patients. A total of 191 formalin-fixed paraffin-embedded sections of transrectal ultrasound-guided prostate biopsy specimens, collected from 120 patients treated at the Sime Darby Medical Centre, Subang Jaya, Malaysia, were analyzed for ERG protein expression by immunohistochemistry using the anti-ERG monoclonal antibody 9FY as a surrogate for the detection of ERG fusion events. The overall frequency of ERG protein expression in the population evaluated in this study was 39.2%. Although seemingly similar to rates reported in other Asian communities, the expression of ERG was distinct amongst different ethnic groups (P=0.004). Malaysian Indian (MI) patients exhibited exceedingly high expression of ERG in their tumors, almost doubling that of Malaysian Chinese (MC) patients, whereas ERG expression was very low amongst Malay patients (12.5%). When collectively analyzing data, we observed a significant correlation between younger patients and higher ERG expression (P=0.04). The prevalence of ERG expression was significantly different amongst CaP patients of different ethnicities. The higher number of ERG-expressing tumors among MI patients suggested that the TMPRSS2-ERG fusion may be particularly important in the pathogenesis of CaP amongst this group of patients. Furthermore, the more frequent expression of ERG among the younger patients analyzed suggested an involvement of ERG in the early onset of CaP. The results of this study underline the value of using ERG status to better understand the differences in the etiology of CaP initiation and progression between ethnic groups.
Fulltext Assembly and activation of the Hippo signalome by FAT1 tumor suppressor

Martin D, Degese MS, Vitale-Cross L, Iglesias-Bartolome R, Valera JLC, Wang Z, et al.

Nat Commun, 2018 07 09;9(1):2372.
PMID: 29985391 DOI: 10.1038/s41467-018-04590-1

Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
HPV infection and the alterations of the pRB pathway in oral carcinogenesis

Lim KP, Hamid S, Lau SH, Teo SH, Cheong SC

Oncol Rep, 2007 Jun;17(6):1321-6.
PMID: 17487385 DOI: 10.3892/or.17.6.1321

Inactivation of the retinoblastoma (pRB) pathway is a common event in oral squamous cell carcinoma particularly through the aberrant expression of the components within this pathway. This study examines the alterations of molecules within the pRB pathway by looking at the presence of homozygous deletions in p16(INK4A) and the expression patterns of pRB, cyclin D1 and CDK4, as well as the presence of human papillomavirus (HPV) in our samples. In our study, 5/20 samples demonstrated deletions of p16(INK4A) exon 1alpha. pRB overexpression was found in 20/20 samples, the expression was mainly observed in all layers of the epithelia, particularly in the basal layer where cells are actively dividing and aberrant pRB expression was found in 12/20 samples. Cyclin D1 and CDK4 overexpression was detected in 6/20 and 2/20 samples respectively in comparison to hyperplasias where both proteins were either not expressed or expressed at minimal levels (<10%). Strikingly, HPV was found to be present in all of our samples, suggesting that HPV plays a significant role in driving oral carcinogenesis. Notably, 17/20 of our samples showed more than one alteration in the pRB pathway, however, we did not find any significant relationship between the presence of HPV, homozygous deletion of p16(INK4A) and overexpression of pRB, cyclin D1 and CDK4. Collectively, this data demonstrates that alterations in the pRB pathway are a common event and involve the aberration of more than one molecule within the pathway. Furthermore, the involvement of HPV in all our samples suggests that HPV infection may play an important role in oral carcinogenesis.

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