由 EVKVLIN 在 二, 05/12/2015 - 10:10 發表
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| Stage I | T1, N0, M0 |
| Stage II | T2, N0, M0 |
| Stage III | T3, N0, M0 or T1, T2, T3, N1, M0 |
| Stage IV | T4, N0, M0 or Any T, N2 or N3, M0 or Any T, any N, any M |
| Primary, T0 | No primary tumor | |
| Tis | carcinoma in situ | |
| T1 | tumour 2 cm or less | |
| T2 | tumour 4 cm or less | |
| T3 | tumour > 4 cm | |
| T4 | tumour > 4 cm and deep invasion into muscle, bone, deep structures | |
| Lymphatic node involvement, N0 | No nodes | |
| N1 | single homolateral node < 3 cm | |
| N2 | node(s) homolateral < 6 cm | |
| –N2a | metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension | |
| –N2b | metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension | |
| –N2c | metasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension | |
| N3 | nodes > 6 cm and/or bilateral | |
| Tumor metastasis, M0 | No metastasis | |
| M1 | metastasis noted | |
2014/04/23 Seminar
2014/04/23 Seminar Announcement
Topic: A Paracrinal Ineterleukin-6-Mediated Epigenetic Regulation of MiR142-3p Promotes Tumor Initiation in Malignant Glioma
張書銘老師部分
Author information
2Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
3Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
4Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
5Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
6Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
7National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
2014/11 楊順發老師新作!
PLoS One. 2014 Nov 25;9(11):e113129. doi: 10.1371/journal.pone.0113129. eCollection 2014.
High level of plasma matrix metalloproteinase-11 is associated with clinicopathological characteristics in patients with oral squamous cell carcinoma.
Hsin CH1, Chen MK2, Tang CH3, Lin HP1, Chou MY4, Lin CW4, Yang SF5.
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Abstract
BACKGROUND:
Matrix metalloproteinase-11 (MMP-11) is reported to be overexpressed in several cancers and may contribute to tumorigenesis. The current study investigated the association between the clinicopathological characteristics and plasma level of MMP-11 in oral squamous cell carcinoma (OSCC) patients.
METHODOLOGY AND PRINCIPAL FINDINGS:
The plasma MMP-11 concentration was determined by ELISA on 330 male OSCC patients. In addition, the metastatic effects of the MMP-11 knockdown on the oral cancer cells were investigated by cell migration assay. Our results showed that the plasma MMP-11 levels were significantly higher in patients with advanced T status (p = 0.001), lymph node metastasis (p = 0.006) and higher TNM stages (p<0.001). Moreover, treatment with the MMP-11 shRNA exerted an inhibitory effect on migration in SCC9 oral cancer cells.
CONCLUSION:
Our study showed that plasma level of MMP-11 may be useful for assessment of the disease progression, especially lymph node metastasis, in patients with OSCC. PMID: 25423087 [PubMed - in process] PMCID: PMC4244114
2014/10 夏興國老師實驗室Cancer Research新作!
Cancer Res. 2014 Oct 28. pii: canres.0978.2014. [Epub ahead of print]
Downregulated miR-329 and miR-410 promote the proliferation and invasion of oral squamous cell carcinoma by targeting Wnt-7b.
Shiah SG1, Hsiao JR2, Chang WM1, Chen YW1, Jin YT3, Wong TY4, Huang JS5, Tsai ST6, Hsu YM1, Chou ST1, Yen YC1, Jiang SS7, Shieh YS8, Chang IS7, Hsiao M9, Chang JY10.
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Abstract
MicroRNA (miRNA) dysregulation contributes widely to human cancer but has not been fully assessed in oral cancers. In this study, we conducted a global microarray analysis of miRNA expression in 40 pairs of betel quid-associated oral squamous cell carcinoma (OSCC) specimens and their matched non-tumorous epithelial counterparts. Eighty-four miRNAs were differentially expressed in the OSCC specimens compared to the matched tissue. Among these downregulated miRNAs, 19 miRNAs were found and mapped to the chromosome 14q32.2 miRNA cluster region, which resides within a parentally imprinted region designated Dlk-Dio3 and known to be important in development and growth. Bioinformatic analysis predicted two miRNAs from the cluster region, miR-329 and miR-410, which could potentially target Wnt-7b, an activator of the Wnt/β-catenin pathway, thereby attenuating the Wnt/β-catenin signaling pathway in OSCC. Stable ectopic expression of Wnt-7b in OSCC cells overexpressing miR-329 or miR-410 restored proliferation and invasion capabilities abolished by these miRNA. Combining a demethylation agent and a histone deacetylase inhibitor was sufficient to re-express miR-329, miR-410 and Meg3 consistent with epigenetic regulation of these miRNA in human OSCC. Specifically, arecoline, a major betel nut alkaloid, reduced miR-329, miR-410 and Meg3 gene expression. Overall, our results provide novel molecular insights into how betel quid contribute to oral carcinogenesis through epigenetic silencing of tumor suppressor miRNA which target Wnt/β-catenin signaling. PMID: 25351956
Orthotopic non-metastatic and metastatic oral cancer mouse model
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Orthotopic non-metastatic and metastatic oral cancer mouse models.
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Abstract
NEJM Editorial
One of the greatest challenges in the study and treatment of cancer has been that the disease is too heterogeneous: too many tissue types, too many etiologic factors, too much genetic diversity. After the discovery of oncogenes, it was thought that a limited number of genes, the proto-oncogenes, might turn a normal cell into a cancerous one. But soon it was discovered that tumor-suppressor genes antagonize the action of oncogenes, thus increasing genetic diversity in the context of cancer pathogenesis. To date, about 140 genes have been identified that can drive cancer growth when genetically altered.1 The discovery that driver genes can be classified into 1 or more of 12 pathways led to one of the greatest achievements in drug development and the establishment of targeted therapy in cancer.
Recently, whole-genome sequencing revealed a surprising fact: every tumor contains hundreds to thousands of somatic mutations, which are obtained throughout life, and their number is directly correlated with age. Certain types of tumors display many more or many fewer mutations. Melanomas and lung cancers are the outliers and contain approximately 200 nonsynchronous mutations per tumor. It has been hypothesized that this large number of mutations reflects the effect of potent mutagens (e.g., ultraviolet light and cigarette smoking).5 The unique genetic fingerprint of almost every tumor raises the concern that treatments might be destined to fail owing to tumor heterogeneity and the continuous development of mutations.
Despite the long debate about the ability of T cells to destroy tumors,6 the unprecedented recent success of immunotherapy in malignant disorders has provided evidence that the patient's endogenous immune system can be altered to attack established tumors. A major hurdle in tumor immunotherapy is the fact that mechanisms of self-tolerance that prevent autoimmunity also impair T-cell responses against tumors, which do not differ substantially from self. Blockade of the major checkpoint inhibitors cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) has resulted in durable responses in many patients.7,8 However, why other patients have only transient responses or no responses at all remains unclear. It is also unclear how patients should be identified as appropriate candidates for immunotherapy.
In a study now reported in the Journal, Snyder and colleagues9 asked whether the genetic landscape of melanoma might affect clinical benefit from immunotherapy with CTLA-4 blockade. The investigators analyzed tumor DNA using whole-exome sequencing and, as expected, detected a large number of somatic mutations. Mutational burden was higher in patients with a sustained clinical benefit than in those without a sustained benefit. Specific tumor neoepitopes encoded by these mutations were identified, and, after translation of missense mutations into mutant and nonmutant peptides, their ability to initiate major histocompatibility complex (MHC) class I–mediated responses in T cells was assessed by means of a bioinformatics algorithm incorporating prediction for MHC class I binding, T-cell receptor binding, and patient-specific HLA type. Mutant peptides were predicted to bind MHC class I molecules with higher affinity than the corresponding nonmutant peptides.
Moreover, it was determined that a number of tetrapeptide sequences corresponding to mutation-derived neoepitopes were shared by patients with a long-term clinical benefit but were completely absent from patients with a minimal benefit or no benefit. These neoepitopes defined a signature that could predict long-term clinical benefit from CTLA-4 blockade. The quality — not the number — of mutations had the strongest predictive value. Strikingly, many neoepitopes that were common to patients who had a sustained clinical benefit were homologous to viral and bacterial antigens.
These findings are exciting for two main reasons. First, these data provide convincing evidence that in order for a CTLA-4 checkpoint blockade to mediate clinical benefit, T cells must be activated in the context of tumor-associated antigens. In unstimulated T cells, a small amount of CTLA-4 resides in intracellular vesicles of the endosomal and trans-Golgi network and recycles continuously to the cell surface, followed by rapid endocytosis and degradation. T-cell activation leads to an increase in CTLA-4, translocation of CTLA-4–containing vesicles to the immunologic synapse, and the release and expression of CTLA-4 on the cell surface. The stronger the T-cell–receptor signal, the more CTLA-4 accumulates at the immunologic synapse.10 It is conceivable that in patients with melanomas expressing immunogenic neoepitopes, mutant peptides capable of binding MHC class I molecules with high affinity induce T-cell activation, leading to relocalization of CTLA-4–containing intracellular vesicles to the immunologic synapse, release of CTLA-4, and up-regulation of CTLA-4 on the cell surface. Under these conditions, anti–CTLA-4 antibodies reverse the inhibitory effect of CTLA-4, which is mediated by B7-1 and B7-2 ligation, and induce long-term antitumor responses (Figure 1A) In contrast, in patients lacking such mutations, nonmutant peptides corresponding to the nonmutated counterparts of immunogenic neoepitopes have lower affinity for MHC class I molecules and do not induce T-cell activation. Under these conditions, CTLA-4 remains in the intracellular vesicles and is not up-regulated on the cell surface. Consequently, anti–CTLA-4 antibodies yield no clinical benefit (Figure 1B).
Second, these findings indicate that clinical benefit from CTLA-4 blockade depends on responses against epitopes that T cells are likely to recognize, such as those present on viral and bacterial pathogens. It is tempting to speculate that development of these antitumor responses might also be mediated by memory T cells generated during prior exposure to such antigens that were foreign to the host and happened to be homologous to neoepitopes induced by somatic mutations in melanomas. Importantly, a high mutational burden increased the likelihood of the development of specific neoepitopes that would confer clinical benefit from CTLA-4 blockade. In the era of immunotherapy, genetic diversity of cancer may, in fact, be a good thing.
FIGURE 1 Somatic Neoepitopes of Melanomas and Benefit from CTLA-4 Blockade.
Recognition of epitopes by T-cell receptors can be mediated by consensus tetrapeptides in immunogenic peptides. As shown in Panel A, mutant tetrapeptides that bind major histocompatibility complex (MHC) class I molecules with high affinity induce activation of antigen-specific naive or memory T cells that recognize this tumor-specific antigen, leading to translocation of cytotoxic T-lymphocyte antigen 4 (CTLA-4)–containing vesicles to the immunologic synapse and up-regulation of CTLA-4 expression on the cell surface. Ligation of CTLA-4 by B7-1 and B7-2 mediates an inhibitory signal in these tumor-specific T cells. Under these conditions, anti–CTLA-4 antibodies prevent CTLA-4 ligation and CTLA-4–mediated inhibition, resulting in the generation of functional tumor-specific effector T cells, which induce antitumor responses. As shown in Panel B, in the absence of such mutations, nonmutant tetrapeptides corresponding to the nonmutated counterparts of immunogenic somatic neoepitopes have lower affinity for MHC class I molecules and do not induce activation of antigen-specific naive or memory T cells that recognize this tumor-specific antigen. Under these conditions, CTLA-4–containing vesicles do not translocate to the immunologic synapse, CTLA-4 expression is not up-regulated, and anti–CTLA-4 antibodies confer no clinical benefit.
REFERENCES
1Vogelstein B , Papadopoulos N , Velculescu VE , Zhou S , Diaz LA Jr ,Kinzler KW Cancer genome landscapes. Science 2013;339:1546-1558
CrossRef | Web of Science | Medline
2Lynch TJ , Bell DW , Sordella R , et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139
Free Full Text | Web of Science | Medline
3Chapman PB , Hauschild A , Robert C , et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med2011;364:2507-2516
Free Full Text | Web of Science | Medline
4Kwak EL , Bang YJ , Camidge DR , et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-1703[Erratum, N Engl J Med 2011;364:588.]
Free Full Text | Web of Science | Medline
5Alexandrov LB , Nik-Zainal S , Wedge DC , et al. Signatures of mutational processes in human cancer. Nature 2013;500:415-421
CrossRef | Web of Science | Medline
6Rosenberg SA , Spiess P , Lafreniere R A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science1986;233:1318-1321
CrossRef | Web of Science | Medline
7Hodi FS , O'Day SJ , McDermott DF , et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med2010;363:711-723[Erratum, N Engl J Med 2010;363:1290.]
Free Full Text | Web of Science | Medline
8Topalian SL , Hodi FS , Brahmer JR , et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454
Free Full Text | Web of Science | Medline
9Snyder A , Makarov V , Merghoub T , et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med2014;371:2189-2199
Full Text
10Egen JG , Allison JP Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity2002;16:23-35
CrossRef | Web of Science | Medline
Gene expression profiling reveals biological pathways
Oral Oncol. 2015 Jan 2. pii: S1368-8375(14)00376-5. doi: 10.1016/j.oraloncology.2014.12.004. [Epub ahead of print]
Gene expression profiling reveals biological pathways responsible for phenotypic heterogeneity between UK and Sri Lankan oral squamous cell carcinomas.
pdf: 4269
PubMed: http://www.ncbi.nlm.nih.gov/pubmed/25560800
Saeed AA1, Sims AH2, Prime SS3, Paterson I4, Murray PG5, Lopes VR6.
METHODS: We have compared the gene expression profiles of OSCCs and normal oral mucosal tissues from both Sri Lankan and UK individuals using Affymetrix gene expression arrays. The generated data was interrogated using significance analysis of microarrays and Ingenuity Pathway Analysis (IPA).
RESULTS: The gene expression profiles of UK and Sri Lankan OSCC are similar in many respects to other oral cancer expression profiles reported in the literature and were mainly similar to each other.However, genes involved in tumor invasion, metastasis and recurrence were more obviously associated with UK tumors as opposed to those from Sri Lanka.
CONCLUSION: The development of OSCCs in both UK and Sri Lankan populations appears largely mediated by similar biological pathways despite the differences related to race, ethnicity, lifestyle, and/or exposure to environmental carcinogens. However, IPA revealed a highly activated "Cell-mediated Immune Response" in Sri Lankan normal and tumor samples relative to UK cohorts. It seems likely, therefore, that any future attempts to personalize treatment for OSCC patients will need to be different in Western and Asian countries to reflect differences in gene expression and the immune status of the patients.
Common and complex Notch1 mutations in Chinese oral squamous cel
An eleven gene molecular signature for extra-capsular spread in
Efficient replication of EBV in stratified epithelium in vitro
Proc Natl Acad Sci U S A. 2014 Oct 13. pii: 201400818. [Epub ahead of print]
Efficient replication of Epstein-Barr virus in stratified epithelium in vitro.
Temple RM1, Zhu J2, Budgeon L3, Christensen ND4, Meyers C5, Sample CE6.
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Abstract
Epstein-Barr virus is a ubiquitous human herpesvirus associated with epithelial and lymphoid tumors. EBV is transmitted between human hosts in saliva and must cross the oral mucosal epithelium before infecting B lymphocytes, where it establishes a life-long infection. The latter process is well understood because it can be studied in vitro, but our knowledge of infection of epithelial cells has been limited by the inability to infect epithelial cells readily in vitro or to generate cell lines from EBV-infected epithelial tumors. Because epithelium exists as a stratified tissue in vivo, organotypic cultures may serve as a better model of EBV in epithelium than monolayer cultures. Here, we demonstrate that EBV is able to infect organotypic cultures of epithelial cells to establish a predominantly productive infection in the suprabasal layers of stratified epithelium, similar to that seen with Kaposi's-associated herpesvirus. These cells did express latency-associated proteins in addition to productive-cycle proteins, but a population of cells that exclusively expressed latency-associated viral proteins could not be detected; however, an inability to infect the basal layer would be unlike other herpesviruses examined in organotypic cultures. Furthermore, infection did not induce cellular proliferation, as it does in B cells, but instead resulted in cytopathic effects more commonly associated with productive viral replication. These data suggest that infection of epithelial cells is an integral part of viral spread, which typically does not result in the immortalization or enhanced growth of infected epithelial cells but rather in efficient production of virus. PMID: 25313069
Areca nut components affect COX-2, cyclin B1/cdc25C
2Laboratory of Pharmacology, Toxicology and Chemical Carcinogenesis, School of Dentistry and Department of Dentistry, National Taiwan University Hospital; and National Taiwan University Medical College, Taipei, Taiwan.
3Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
NAD(P)H: Quinone Oxidoreductase--NQO1 inhibitor) and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2α production.
Potential Therapeutic Targets for Oral Cancer:
PLoS One. 2014 Jul 16;9(7):e102610.
Potential therapeutic targets for oral cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70.
Bundela S1, Sharma A2, Bisen PS3.
1Defence Research Development Establishment, Defence Research Development Organization, Ministry of Defence, Govt. of India, Gwalior, Madhya Pradesh, India; Department of Postgraduate Studies & Research in Biological Sciences, Rani Durgavati University, Jabalpur, Madhya Pradesh, India.
2Department of Postgraduate Studies & Research in Biological Sciences, Rani Durgavati University, Jabalpur, Madhya Pradesh, India.
3Defence Research Development Establishment, Defence Research Development Organization, Ministry of Defence, Govt. of India, Gwalior, Madhya Pradesh, India; School of Studies in Biotechnology, Jiwaji University, Gwalior, Madhya Pradesh, India.
Abstract
In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL-10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70. PMID: 25029526
extracellular matrix, proteinaceous extracellular matrix, membrane raft, anchored to membrane, cell surface, integral to plasma membrane, extrinsic to membrane
The genomic landscape of nasopharyngeal carcinoma.
The genomic landscape of nasopharyngeal carcinoma.
Fingerprints of Epstein-Barr virus in nasopharyngeal carcinoma
Robert B West Nature Genetics 46, 809–810
The influence of Epstein-Barr virus (EBV) on cancer is not well understood. High-throughput sequencing of nasopharyngeal carcinoma (NPC) illustrates the influences of EBV on oncogenesis and identifies driver pathways that might be therapeutically useful for NPC treatment.
More than 90% of the world population has been infected with EBV. Its presence has been documented in a number of malignancies, including in NPC1. Its true influence on cancer incidence is not well understood, owing in part to ignorance of the inciting events in the vast majority of cancer types. In a new study by De-Chen Lin and colleagues2, the authors present the first genome-wide sequence analysis of NPC, the only common carcinoma that is frequently infected with EBV (although a subset of gastric carcinomas are also EBV infected). NPC represents an unusual carcinoma with respect to its incidence, biology and treatment, and its study can possibly provide insight into the relationship between neoplasia and this ubiquitous virus. NPC incidence is high in endemic areas3 (occurring in Southeast Asians, North Africans and Inuit people), comparable to the incidence of melanoma in the United States, and very low in other areas (<1 case per 100,000 people). Another unusual aspect of NPC is a tremendous lymphocytic infiltrate that often obscures the presence of malignant cells in bright-field microscopy. These infiltrating lymphocytes, often outnumbering the cancer cells by several fold, have posed a challenge to genomic studies of NPC, particularly hybridization microarray approaches.
Fingerprints of EBV
Lin and colleagues present a genome-wide view of the changes in NPC by examining 128 cases by exome sequencing, targeted sequencing and SNP array analysis. Their results provide a framework in which to begin subdividing NPCs according to their biological drivers and clinical implications. In a comparative study using several previously sequenced cancers, they find that NPC results in a relatively low level of genomic alteration, similar to that seen in human papillomavirus (HPV)-associated carcinomas. However, NPCs do not have the characteristic APOBEC mutational signature seen in HPV-associated carcinomas. These comparisons provide insight into the fundamental differences in the ways that EBV and HPV lead to cancer.
The study identifies 144 genes recurrently mutated in the 128 cases. Although some mutations had previously been found in NPC, such as ones in PIK3CA and TP53, seven significantly mutated genes are newly identified in NPC: BAP1, ERBB2, ERBB3, KRAS, NRAS, KMT2D (MLL2) and TSHZ3. Pathway analysis of genomic events identified the chromatin-modification pathway as among the most frequently affected pathways, with ARID1A being the most frequently altered gene in this category. Mutations in this pathway are strongly associated with EBV levels. In this context, it is interesting to note that a study with whole-exome sequencing of gastric cancer4, the only other common carcinoma with frequent EBV involvement, identified a similar association. The sequencing data for gastric cancer showed a significant difference in the mutation rate of ARID1A between EBV-infected gastric cancers (high) and non-EBV-infected gastric cancers (low). Taken together, these findings suggest that altered chromatin remodeling is a general, possibly oncogenic feature of EBV infection in neoplasia. Further work is needed to extend these observations and determine the mechanisms involved.
Other pathways commonly mutated in carcinomas were also found to be altered in NPC (Fig. 1). Mutations in genes controlling the G1/S transition were frequently mutated in NPC. Genes in the ERBB–phosphoinositol 3-kinase (PI3K) signaling pathway were also often altered, and cases bearing these mutations had tumors with more aggressive clinical behavior. As in other head and neck carcinomas, the epithelial cell differentiation pathway was altered, including the NOTCH gene family, albeit with a lower incidence of mutations.
Figure 1: NPC represents a complex tumor microenvironment including EBV and lymphocytes.
NPC represents a complex tumor microenvironment including EBV and lymphocytes.
A number of different drivers can influence NPC development, including EBV, chromatin modification, the ERBB-PI3K pathway, autophagy machinery, epithelial cell differentiation and regulation of the G1/S transition.
Targeting EBV effects
Many cancer genomic studies have focused on outcome prognostication. A far more pressing need for NPC is new treatment targets. NPC is highly sensitive to radiotherapy, and this represents the first line of treatment. However, systemic therapy is important when metastasis is present, which is quite common in these patients. The mutation profiles found in the current study identify new potential therapeutic targets. Although EBV itself is a tantalizing target, such strategies have yet to be realized, and mutations in the chromatin-modification pathway, linked to EBV burden, might prove to be a useful surrogate. The authors find that this pathway, with 67 genes altered in 54 cases, is important for NPC in terms of both anchorage-independent colony formation and cell migration. As such, carcinomas with these mutations might be sensitive to drugs such as histone deacetylase (HDAC) inhibitors. Genomic changes in three autophagic genes (ATG2A, ATG7 and ATG13) were identified and shown by Lin and colleagues to be synergistic with conventional chemotherapy in killing NPC cells in culture. The ERBB-PI3K pathway mutation profile offers another set of potential therapeutic possibilities. The different potential therapeutic responses created by the constellation of mutations in different pathways suggest that the identification of susceptible patients with NPC through clinical sequencing tests might guide oncological planning in the near future.
The data presented by Lin and colleagues provide several new opportunities for future NPC research and treatment and for understanding the influence of EBV in neoplasia. For example, measures of serum EBV levels are already being developed as a biomarker for risk of recurrence5, and the current data might be complementary for screening approaches. It is worth noting that this exome-wide sequencing study does not necessarily capture all the significant genetic events in NPC biology. The whole-exome sequencing approach does not identify the gene fusions that others have reported in over 10% of cases6, 7. Furthermore, there is considerable variation in EBV sequence8, and this variation might influence tumor development, as genetic variation in viruses has been shown elsewhere to be central in oncogenesis9. Nevertheless, this study represents a major step forward in the understanding of NPC.
References
References•
1. zur Hausen, H. et al. Nature 228, 1056–1058 (1970).
2. Lin, D. et al. Nat. Genet. 46, 866–871 (2014).
3. Niedobitek, G. Mol. Pathol. 53, 248–254 (2000).
4. Wang, K. et al. Nat. Genet. 43, 1219–1223 (2011).
5. Lin, J.C. et al. N. Engl. J. Med. 350, 2461–2470 (2004).
6. Chung, G.T. et al. J. Pathol. 231, 158–167 (2013).
7. Valouev, A. et al. Genome Res. 24, 300–309 (2014).
8. Liu, P. et al. J. Virol. 85, 11291–11299 (2011).
9. Shuda, M. et al. Proc. Natl. Acad. Sci. USA 105, 16272–16277 (2008).
Epstein-Barr virus-induced epigenetic alterations following tran
16 Queen, K. J., M. Shi, F. Zhang, U. Cvek, and R. S. Scott. Epstein-Barr virus-induced epigenetic alterations following transient infection. (2013). Int J Cancer. 132: 2076-86. pdf 4245. EBV infection. NP460Tert related. must read. Epstein-Barr virus (EBV) is a known tumor virus associated with an increasing array of malignancies; however, the association of the virus with certain malignancies is often erratic. To determine EBV's contributions to tumorigenesis in a setting of incomplete association, a transient model of infection was established where a clonal CCL185 carcinoma cell line infected with recombinant EBV was allowed to lose viral genomes by withdrawal of selection pressure. Global gene expression comparing EBV-negative, transiently infected clones to uninfected controls identified expression changes in more than 1,000 genes. Among downregulated genes, several genes known to be deoxyribonucleic acid (DNA) methylated in cancer were identified including E-cadherin and PYCARD. A cadherin switch, increased motility and enhanced cellular invasiveness present in EBV-positive cells were retained after viral loss, indicating an epigenetic effect. Repression of PYCARD expression was a result of increased promoter CpG methylation, whereas loss of E-cadherin expression after transient EBV infection did not correlate with increased DNA methylation of the E-cadherin promoter. Rather, repression of E-cadherin was consistent with the formation of a repressive chromatin state. Decreased histone 3 or 4 acetylation at the promoter and 5' end of the E-cadherin gene was observed in an EBV-negative, transiently infected clone relative to the uninfected controls. These results suggest that EBV can stably alter gene expression in a heritable fashion in formerly infected cells, whereas its own contribution to the oncogenic process is masked.
Epstein-Barr virus infection as an epigenetic driver of
Kaneda, A., K. Matsusaka, H. Aburatani, and M. Fukayama. Epstein-Barr virus infection as an epigenetic driver of tumorigenesis. (2012). Cancer research. 72: 3445-50. pdf 3530. Epstein-Barr virus (EBV) establishes latent infection and is associated with tumors, such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancers. We recently reported that EBV(+) gastric cancer shows an EBV(+)/extensively high-methylation epigenotype, and in vitro EBV infection induces extensive DNA methylation with gene repression within 18 weeks. On the basis of the absence of both EBV and high-methylation accumulation in the surrounding mucosa of EBV(+) gastric cancer, it is suggested that an EBV-infected cell acquires extensive methylation to silence multiple tumor suppressor genes in a short time period and transforms into cancer cells, not forming a precancerous field with EBV infection or methylation accumulation. The methylation mechanism induced by EBV infection has not been fully clarified. Differences in EBV genome methylation that are dependent on a different latency status or other epigenomic alterations, such as 3-dimensional conformation and histone modification, may affect host genome methylation. Expressions of viral proteins and small RNAs are also different depending on latency status, and some viral proteins might trigger DNA methylation by inducing DNA methyltransferase overexpression. In this review, we discuss these roles of EBV infection in driving tumorigenesis and their possible association with aberrant DNA methylation.
The dynamic DNA methylomes of double-stranded DNA viruses associ
Combination of bexarotene and the retinoid CD1530 reduces...
Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. (PubMed Link)
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Abstract
We investigated the effects of bexarotene (a retinoid X receptor agonist), CD1530 (a retinoic acid receptor γ selective agonist), and the combination of these two drugs for the prevention of oral carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral-cavity and esophageal squamous-cell carcinoma previously generated in our laboratory. We observed decreased numbers of neoplastic tongue lesions and reduced lesion severity in the 4-NQO plus CD1530 (4N+C) and 4-NQO plus bexarotene plus CD1530 (4N+B+C) groups compared with the 4-NQO group. RNA-Seq analyses showed increases in transcripts in cell proliferation/cell cycle progression pathways in the 4-NQO vs. the untreated group. In addition, β-catenin and matrix metallopeptidase 9 (MMP9) protein levels and reactive oxygen species (ROS), as assessed by 4-hydroxynonenal (4-HNE) staining, were elevated in tongue tissues 17 wk after the termination of the 4-NQO treatment. The 4N+B, 4N+C, and 4N+B+C groups showed dramatically lower levels of β-catenin, MMP9, and 4-HNE staining compared with the 4-NQO group. The major reduction in 4-HNE staining in the retinoid treatment groups suggests a novel mechanism of action, reduction of ROS, by which bexarotene and CD1530 inhibit carcinogenesis.
KEYWORDS: cancer prevention; oral cancer; retinoic acid receptor gamma agonist; retinoid X receptor; tongue squamous cell carcinoma PMID: 24927566
Significance
Oral-cavity squamous-cell carcinoma is one of the most com- mon human cancers in the world. About 60–70% of oral-cavity carcinoma cases are diagnosed only after the tumors have become locally advanced. Therefore, in addition to treatment, prevention of oral cancer is a very important goal. In this study, we found that the combination of the drugs bexarotene and CD1530 was more effective than either drug alone in pre- venting oral carcinogenesis in our mouse model of human oral and esophageal cancers. We envision that the combination of bexarotene and CD1530 could potentially be applied to humans at a high risk for oral cancer, as a very effec- tive strategy for the prevention and treatment of human oral cancer.
A surprising cross-species conservation in the genomic...
A surprising cross-species conservation in the genomic landscape of mouse and human oral cancer identifies a transcriptional signature predicting metastatic disease.
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Abstract
PURPOSE:
Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance.
EXPERIMENTAL DESIGN:
Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature and we assessed its representation in 4 independent human datasets comprising 324 patients using weighted voting and Gene Set Enrichment Analysis (GSEA). Kaplan-Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A qRT-PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy.
RESULTS:
NGS revealed conservation of human driver pathway mutations in mouse OSCC including in Trp53, MAPK, PI3K, NOTCH, JAK/STAT and FAT1-4. Moreover, comparative analysis between The Cancer Genome Atlas (TCGA) and mouse samples defined AKAP9, MED12L and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in 4 independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified OSCC patients with a 93.5% accuracy.
CONCLUSIONS:
These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer
PMID: 24668645 [PubMed - as supplied by publisher]
Figure 5. Independent validation of OCAMP-B and development of a clinical assay for stratification of OSCCs. A, an independent University of Pennsylvania (UPENN) dataset is classified with high accuracy (21/22 tumors) by OCAMP-B–weighted voting (WV output) with respect to lymph node metastatic status (path, known pathologic status), B, schematic illustrating the selection of 42 OCAMP genes and SVM processing on training set samples to identify the best discriminating genes. The final 19-gene list for FFPE is on right with asterisks on 10-gene list for fresh specimens. C, discriminant scores from SVM analysis showing successful stratification in 12 of 13 FFPE and 17 of 18 fresh biopsy test cases of metastatic nodal disease using a qPCR assay.
118 Gene Signature Modified from Table S16. 此list 是 indolence vs aggressiveness 和我們T/N的慣用法相反，請小心使用。
Aurora-A signaling is activated in advanced stage of HNSCC...
Aurora-A signaling is activated in advanced stage of squamous cell carcinoma of head and neck cancer and requires osteopontin to stimulate invasive behavior.
Chien CY1, Tsai HT, Su LJ, Chuang HC, Shiu LY, Huang CC, Fang FM, Yu CC, Su HT, Chen CH.
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1Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Abstract
The clinical significances, cellular effects, and molecular mechanisms by which Aurora-A mediate its invasive effects in HNSCC are still unclear. Here, we found that Aurora-A expression is significantly higher in tumor tissues on 14-microarray of HNSCC in Oncomine-databases. The activity of Aurora-A was not only found in HNSCC specimens, but also significantly correlated with advanced-T-classification, positive-N-classification, TNM-stage and the poor 5-year survival rate. HNSCC-microarray profile showed that osteopontin and Aurora-A exhibited positive correlation. Stimulation of HNC cells with osteopontin results in an increase in Aurora-A expression where localized at the centrosome. Functionally, Aurora-A had the abilities to stimulate cell motility in HNC cells through increase ERK1/2 activity under osteopontin stimulation. Conversely, depletion of Aurora-A expression by siRNAs suppressed ERK1/2 activity as well as inhibition of cell invasiveness. Treatment with anti-CD44 antibodies in HNC cells not only caused a decrease of mRNA/protein of Aurora-A and ERK1/2 activity upon osteopontin stimulation, but also affected the abilities of Aurora-A-elicited cell motility. Finally, immunohistochemical/Western-blotting analysis of human aggressive HNSCC specimens showed a significant positively correlation between osteopontin-Aurora-A and ERK1/2. These findings suggest that Aurora-A is not only an important prognostic factor but also a new therapeutic target in the osteopontin/CD44/ERK pathway for HNSCC treatment. PMID: 24810160
The mutational spectrum of squamouscell carcinoma of the head..
The mutational spectrum of squamous-cell carcinoma of the head and neck: Targetable genetic events and clinical impact.
Abstract
Squamous cell cancer of the Head and Neck (SCCHN) represents a heterogeneous disease entity, with various etiological factors implicated in the genesis of distinct molecular subsets of tumors, which exhibit different biological and clinical behavior. Treatment of SCCHN is expected to change in the next decade as targeted therapies continue to make strides. Recently, next-generation sequencing studies conducted on approximately 190 SCCHN specimens shed light into the molecular pathogenesis of the disease. These studies discovered mutations in genes involved in the differentiation program of squamous epithelium and the Notch/p63 axis (such as NOTCH1, TP63 and FBXW7), and validated genetic alterations derived from previous studies (such as mutations in TP53, CDKN2A, PIK3CA, CCND1 and HRAS) as driver genetic events in SCCHN neoplastic transformation. More recently, comprehensive data from The Cancer Genome Atlas (TCGA) project on 306 SCCHN specimens provided further insight into SCCHN inherent molecular complexity, identifying novel significantly mutated genes, including FAT1, MLL2, TGFRBR2, HLA-A, NFE2l2 and CASP8. Herein, we provide an overview of the mutational spectrum of SCCHN, with emphasis on the clinical implementation of this knowledge. We also discuss the potential integration of new data within the framework of precision cancer medicine.
KEYWORDS: SCCHN, deep sequencing, genetic aberrations, somatic mutation
PMID: 24718888
Table 1. Comparison of the findings of the main large‐scale exome‐sequencing studies
TCGA: The Cancer Genome Atlas
NR: not reported
All values refer to frequency of somatic mutations, unless otherwise indicated.
Table 2. Main targetable oncogenic drivers in SCCHN, available molecular agents targeting these drivers and pertinent ongoing clinical trials
PI3K: Phosphatidylinositol 3‐kinase; CDK: Cyclin‐dependent kinase; MAPK: Mitogen‐activated protein kinase; EGFR: Epidermal growth factor receptor; MTOR: Mammalian target of rapamycin; VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet‐derived growth factor receptor, NFκB: Nuclear Factor kappa‐B; ALK: anaplastic lymphoma kinase, ABL: Abelson kinase; HSP: Heat shock protein, SRC: Rous sarcoma kinase.