Basis for reclassification of nasopharyngeal carcinoma
Author: Shao, Jian-Yong
Date: 2012-04-12
Location: MTC lecture hall, Theorells väg 1, Karolinska Institutet, Solna.
Time: 09.00
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
Abstract
Nasopharyngeal carcinoma (NPC) shows broad differences in racial and geographical distribution, radiosensitivity, and a multifactorial etiology. This thesis aims to identify molecular biomarkers with potentially valuable for prognostic implications in NPC.
This thesis involved a series of studies which were performed on cohorts of patients with NPC to investigate the genetic alterations, Epstein-Barr virus (EBV) infection, and gene expression profiles, and to assess their correlations with clinicopathological parameters and survival of NPC patients. The results indicated that overexpression of caveolin-1 (Cav-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in NPC were significantly associated with TNM stage, metastasis, and poor prognosis (Paper I). Loss of heterozygosity (LOH) on 9p21, 16q and 19q13 may be responsible for tumor aggression behavior and progression of NPC, with a possible interaction between allelic loss and EBV infection in the etiology of NPC (Paper II). EBV latent membrane protein (LMP) 1 overexpression was significantly correlated with p53 accumulation in NPC, CD8+ T cell infiltration, and matrix metalloproteinase (MMP) 9 overexpression in NPC cells. Moreover, plasma EBV DNA was detectable at a high frequency in primary NPC (96%). Higher plasma EBV-DNA levels were positively correlated with advanced TNM stages, lymph node metastasis, and NPC relapses (Papers III-V). Overexpression of LMP1 regulated the mTOR signaling pathway in NPC, possibly through phosphorylation of AKT/mammalian target of rapamycin (mTOR)/phospho-P70S6 kinase (P70S6K)/4EBP1. LMP1 expression was closely correlated with expression of p-mTOR, p-P70S6K and p-4EBP1 in NPC tumors, while expression levels of p-P70S6K, p-4EBP1 and LMP1 were significantly correlated with overall survival in NPC patients (Paper V).
Paper VI presents a new molecular NPC-space vector modulation (SVM) classifier, which integrates sex and seven genes, including LMP1, CD147, Cav-1, p-P70S6K, MMP11, survivin, and secreted protein acidic and rich in cysteine (SPARC). This NPC-SVM classifier could refine the classification of NPC patients into high- and low-risk groups, which demonstrated significant differences in 5-year disease-specific survival (DSS) rates in a group of 411 validation patients (86.2% vs. 37.6%, p<0.001). Paper VII presents a new histological classification study, which was developed mainly on the basis of morphological characteristics and tumor cell differentiation. Of 3,839 tumors, 2,057 (53.6%) were histologically classified as undifferentiated epithelial cell carcinoma (UECC), 942 (24.5%) as undifferentiated mixed epithelial-sarcomatoid cell carcinoma (UESCC), 640 (16.7%) as undifferentiated sarcomatoid cell carcinoma (USCC), and 200 (5.2%) as squamous cell carcinoma (SCC). Based on the new histological classification system, the 5-year DSS rates were 76.4% for UECC, 66.0% for UESCC, 56.0% for USCC, and 32.7% for SCC. Stratified according to the new classification, patients with UECC and UESCC who received radiochemotherapy (RCT) showed better 5-year DSS rates than those who received radiotherapy (RT) alone.
In summary, the results of these studies indicate that LOH, differentially-expressed genes, and EBV markers can act as prognostic biomarkers in NPC patients. The NPC-SVM classifier and the new proposed histopathological classification provide better discriminative prediction of NPC prognosis than the current WHO classification, as well as a means of monitoring the therapeutic efficacy of RCT and RT in advanced-stage NPC patients.
This thesis involved a series of studies which were performed on cohorts of patients with NPC to investigate the genetic alterations, Epstein-Barr virus (EBV) infection, and gene expression profiles, and to assess their correlations with clinicopathological parameters and survival of NPC patients. The results indicated that overexpression of caveolin-1 (Cav-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in NPC were significantly associated with TNM stage, metastasis, and poor prognosis (Paper I). Loss of heterozygosity (LOH) on 9p21, 16q and 19q13 may be responsible for tumor aggression behavior and progression of NPC, with a possible interaction between allelic loss and EBV infection in the etiology of NPC (Paper II). EBV latent membrane protein (LMP) 1 overexpression was significantly correlated with p53 accumulation in NPC, CD8+ T cell infiltration, and matrix metalloproteinase (MMP) 9 overexpression in NPC cells. Moreover, plasma EBV DNA was detectable at a high frequency in primary NPC (96%). Higher plasma EBV-DNA levels were positively correlated with advanced TNM stages, lymph node metastasis, and NPC relapses (Papers III-V). Overexpression of LMP1 regulated the mTOR signaling pathway in NPC, possibly through phosphorylation of AKT/mammalian target of rapamycin (mTOR)/phospho-P70S6 kinase (P70S6K)/4EBP1. LMP1 expression was closely correlated with expression of p-mTOR, p-P70S6K and p-4EBP1 in NPC tumors, while expression levels of p-P70S6K, p-4EBP1 and LMP1 were significantly correlated with overall survival in NPC patients (Paper V).
Paper VI presents a new molecular NPC-space vector modulation (SVM) classifier, which integrates sex and seven genes, including LMP1, CD147, Cav-1, p-P70S6K, MMP11, survivin, and secreted protein acidic and rich in cysteine (SPARC). This NPC-SVM classifier could refine the classification of NPC patients into high- and low-risk groups, which demonstrated significant differences in 5-year disease-specific survival (DSS) rates in a group of 411 validation patients (86.2% vs. 37.6%, p<0.001). Paper VII presents a new histological classification study, which was developed mainly on the basis of morphological characteristics and tumor cell differentiation. Of 3,839 tumors, 2,057 (53.6%) were histologically classified as undifferentiated epithelial cell carcinoma (UECC), 942 (24.5%) as undifferentiated mixed epithelial-sarcomatoid cell carcinoma (UESCC), 640 (16.7%) as undifferentiated sarcomatoid cell carcinoma (USCC), and 200 (5.2%) as squamous cell carcinoma (SCC). Based on the new histological classification system, the 5-year DSS rates were 76.4% for UECC, 66.0% for UESCC, 56.0% for USCC, and 32.7% for SCC. Stratified according to the new classification, patients with UECC and UESCC who received radiochemotherapy (RCT) showed better 5-year DSS rates than those who received radiotherapy (RT) alone.
In summary, the results of these studies indicate that LOH, differentially-expressed genes, and EBV markers can act as prognostic biomarkers in NPC patients. The NPC-SVM classifier and the new proposed histopathological classification provide better discriminative prediction of NPC prognosis than the current WHO classification, as well as a means of monitoring the therapeutic efficacy of RCT and RT in advanced-stage NPC patients.
List of papers:
I. Zi-Ming Du, Chang-Wei Kou, Chun-Fang Hu, Jing Chen, Hai-Yun Wang, Li-Xu Yan, Li-Fu Hu, Ingemar Ernberg, Yi-Xin Zeng and Jian-Yong Shao. Clinical Significance of Elevated Spleen Tyrosine Kinase Expression in Nasopharyngeal Carcinoma. Head Neck. 2012 Jan 27.
Fulltext (DOI)
Pubmed
II. Xin An, Feng-Hua Wang, Ding PR, Ling Deng, Wen-Qi Jiang, Li Zhang, Jian-Yong Shao, Yu-Hong Li. Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy. Cancer. 2011 Feb 11.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Yan Zhang, Li-Xu Yan, Qi-Nian Wu, Zi-Ming Du, Jing Chen, Ding-Zhun Liao, Ma-Yan Huang, Jing-Hui Hou, Qiu-Liang Wu, Mu-Sheng Zeng, Wen-Lin Huang, Yi-Xin Zeng and Jian-Yong Shao. miR-125b is Methylated and Functions as A Tumor Suppressor by Regulating the ETS1 proto-oncogene in Human Invasive Breast Cancer. Cancer Res. 2011 May 15;71(10):3552-62.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Zi-Ming Du, Li-Fu Hu, Hai-Yun Wang, Li-Xu, Yan, Yi-Xin Zeng, Jian-Yong Shao, Ingemar Ernberg. Upregulation of MiR-155 in Nasopharyngeal Carcinoma is partly driven by LMP1 and LMP2A and downregulates a Negative Prognostic Marker JMJD1A. PLoS ONE. 2011 Apr 26;6(4):e19137.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Yu-Hong Li, Chun-Fang Hu, Qiong Shao, Ma-Yan Huang, Jing-Hui Hou, Dan Xie, Yi-Xin Zeng, Jian-Yong Shao. Elevated Expressions of Survivin and VEGF Protein Are Strong Independent Predictors of Survival in Advanced Nasopharyngeal Carcinoma. J Transl Med. 2008, 3;6(1):1.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Zi-Ming Du, Chang-Wei Kou, Chun-Fang Hu, Jing Chen, Hai-Yun Wang, Li-Xu Yan, Li-Fu Hu, Ingemar Ernberg, Yi-Xin Zeng and Jian-Yong Shao. Clinical Significance of Elevated Spleen Tyrosine Kinase Expression in Nasopharyngeal Carcinoma. Head Neck. 2012 Jan 27.
Fulltext (DOI)
Pubmed
II. Xin An, Feng-Hua Wang, Ding PR, Ling Deng, Wen-Qi Jiang, Li Zhang, Jian-Yong Shao, Yu-Hong Li. Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy. Cancer. 2011 Feb 11.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Yan Zhang, Li-Xu Yan, Qi-Nian Wu, Zi-Ming Du, Jing Chen, Ding-Zhun Liao, Ma-Yan Huang, Jing-Hui Hou, Qiu-Liang Wu, Mu-Sheng Zeng, Wen-Lin Huang, Yi-Xin Zeng and Jian-Yong Shao. miR-125b is Methylated and Functions as A Tumor Suppressor by Regulating the ETS1 proto-oncogene in Human Invasive Breast Cancer. Cancer Res. 2011 May 15;71(10):3552-62.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Zi-Ming Du, Li-Fu Hu, Hai-Yun Wang, Li-Xu, Yan, Yi-Xin Zeng, Jian-Yong Shao, Ingemar Ernberg. Upregulation of MiR-155 in Nasopharyngeal Carcinoma is partly driven by LMP1 and LMP2A and downregulates a Negative Prognostic Marker JMJD1A. PLoS ONE. 2011 Apr 26;6(4):e19137.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Yu-Hong Li, Chun-Fang Hu, Qiong Shao, Ma-Yan Huang, Jing-Hui Hou, Dan Xie, Yi-Xin Zeng, Jian-Yong Shao. Elevated Expressions of Survivin and VEGF Protein Are Strong Independent Predictors of Survival in Advanced Nasopharyngeal Carcinoma. J Transl Med. 2008, 3;6(1):1.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Ernberg, Ingemar
Issue date: 2012-03-22
Rights:
Publication year: 2012
ISBN: 978-91-7457-699-3
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