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The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism
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Joana Peixoto Telmo A. Catarino Nathalia Cristina Campanella Weder Menezes Aline Paixão Becker Gisele Caravina de Almeida Marcus M. Matsushita Carlos Clara Luciano Neder Marta Viana‐Pereira Mrinalini Honavar Lígia Castro José Manuel Lopes Bruno Carvalho Rui Manuel Vaz Valdemar Máximo Paula Soares Manuel Sobrinho‐Simões Rui Manuel Reis Jorge Lima 《International journal of cancer. Journal international du cancer》2016,139(2):414-423
Human hotspot TERT promoter (TERTp) mutations have been reported in a wide range of tumours. Several studies have shown that TERTp mutations are associated with clinicopathological features; in some instances, TERTp mutations were considered as biomarkers of poor prognosis. The rs2853669 SNP, located in the TERT promoter region, was reported to modulate the increased TERT expression levels induced by the recurrent somatic mutations. In this study we aimed to determine the frequency and prognostic value of TERTp mutations and TERT rs2853669 SNP in 504 gliomas from Portuguese and Brazilian patients. TERTp mutations were detected in 47.8% of gliomas (216/452). Glioblastomas (GBM) exhibited the highest frequency of TERTp mutations (66.9%); in this glioma subtype, we found a significant association between TERTp mutations and poor prognosis, regardless of the population. Moreover, in a multivariate analysis, TERTp mutations were the only independent prognostic factor. Our data also showed that the poor prognosis conferred by TERTp mutations was restricted to GBM patients carrying the rs2853669 A allele and not in those carrying the G allele. In conclusion, the presence of TERTp mutations was associated with worse prognosis in GBM patients, although such association depended on the status of the rs2853669 SNP. The status of the rs2853669 SNP should be taken in consideration when assessing the prognostic value of TERTp mutations in GBM patients. TERTp mutations and the rs2853669 SNP can be used in the future as biomarkers of glioma prognosis. 相似文献
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Simone L. Scholz Susanne Horn Rajmohan Murali Inga M?ller Antje Sucker Wiebke Sondermann Mathias Stiller Bastian Schilling Elisabeth Livingstone Lisa Zimmer Henning Reis Claudia H. Metz Michael Zeschnigk Annette Paschen Klaus-Peter Steuhl Dirk Schadendorf Henrike Westekemper Klaus G. Griewank 《Oncotarget》2015,6(28):25868-25882
Objectives
Recently, recurrent mutations in regulatory DNA regions, such as promoter mutations in the TERT gene were identified in melanoma. Subsequently, Weinhold et al. reported SDHD promoter mutations occurring in 10% of melanomas and being associated with a lower overall survival rate. Our study analyzes the mutation rate and clinico-pathologic associations of SDHD promoter mutations in a large cohort of different melanoma subtypes.Methods
451 melanoma samples (incl. 223 non-acral cutaneous, 38 acral, 33 mucosal, 43 occult, 43 conjunctival and 51 uveal melanoma) were analyzed for the presence of SDHD promoter mutations by Sanger-sequencing. Statistical analysis was performed to screen for potential correlations of SDHD promoter mutation status with various clinico-pathologic criteria.Results
The SDHD promoter was successfully sequenced in 451 tumor samples. ETS binding site changing SDHD promoter mutations were identified in 16 (4%) samples, of which 5 mutations had not been described previously. Additionally, 5 point mutations not located in ETS binding elements were identified. Mutations in UV-exposed tumors were frequently C>T. One germline C>A SDHD promoter mutation was identified. No statistically significant associations between SDHD promoter mutation status and various clinico-pathologic variables or overall patient survival were observed.Conclusions
Melanomas harbor recurrent SDHD promoter mutations, which occur primarily as C>T alterations in UV-exposed melanomas. In contrast to the initial report and promoter mutations in the TERT gene, our analysis suggests that SDHD promoter mutations are a relatively rare event in melanoma (4% of tumors) of unclear clinical and prognostic relevance. 相似文献4.
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Hong Xie Tiantian Liu Na Wang Viveca Bj?rnhagen Anders H??g Catharina Larsson Weng-Onn Lui Dawei Xu 《Oncotarget》2014,5(20):10048-10057
Telomerase activation through the induction of its catalytic component TERT is essential in carcinogenesis. The regulatory mechanism and clinical significance underlying cancer-specific TERT expression have been extensively investigated in various human malignancies, but little is known about these in Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin tumor. Here we addressed these issues by determining TERT promoter mutations, gene amplification, mRNA expression and association with clinical variables in MCC. TERT mRNA was expressed in 6/6 MCC cell lines and 41 of 43 tumors derived from 35 MCC patients. Telomerase activity was detectable in all 6 cell lines and 11 tumors analyzed. TERT promoter mutations were identified in 1/6 cell lines and 4/35 (11.4%) MCC cases. The mutation exhibited UV signature and occurred in sun-exposed areas. Increased TERT gene copy numbers were observed in 1/6 cell lines and 11/14 (79%) tumors, and highly correlated with its mRNA expression (r = 0.7419, P = 0.0024). Shorter overall survival was significantly associated with higher TERT mRNA levels in MCC patients (P = 0.032). Collectively, TERT expression and telomerase activity is widespread in MCC, and may be attributable to TERT promoter mutations and gene amplification. Higher TERT expression predicts poor patient outcomes. 相似文献
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Ricardo Leão Donghyun Lee Arnaldo Figueiredo Thomas Hermanns Peter Wild Martin Komosa Irene Lau Mathew Mistry Nuno Miguel Nunes Aryeh J. Price Cindy Zhang Tatiana Lipman Cédric Poyet Nadejda Valtcheva Kathrin Oehl Hugo Coelho Rashid Sayyid Ana Melo Gomes Ligia Prado e Castro Joan Sweet João Vinagre Joana Apolónio Derek Stephens Inês Faleiro Kamel Fadaak Patrick O. Richard Girish Kulkarni Alexandre R. Zlotta Robert J. Hamilton Pedro Castelo-Branco Uri Tabori 《International journal of cancer. Journal international du cancer》2019,144(7):1676-1684
In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTpMut) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTpMut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTpMut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher-risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTpMut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THORhigh/TERTpMut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTpwt and TERTpMut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTpMut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer. 相似文献
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Nevus count associations with pigmentary phenotype,histopathological melanoma characteristics and survival from melanoma
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Nicholas J. Taylor Nancy E. Thomas Hoda Anton‐Culver Bruce K. Armstrong Colin B. Begg Klaus J. Busam Anne E. Cust Terence Dwyer Lynn From Richard P. Gallagher Stephen B. Gruber Diane E. Nishri Irene Orlow Stefano Rosso Alison J. Venn Roberto Zanetti Marianne Berwick Peter A. Kanetsky 《International journal of cancer. Journal international du cancer》2016,139(6):1217-1222
Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma‐specific survival is equivocal. Using data from the Genes, Environment and Melanoma (GEM) study, a large population‐based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun‐sensitivity summarized in a phenotypic index, and tumor characteristics. We also assessed the association of nevus count with melanoma‐specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis, and they were inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma‐specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features. 相似文献
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Yan Xing MD MS PhD Brian D. Badgwell MD Merrick I. Ross MD Jeffrey E. Gershenwald MD Jeffrey E. Lee MD Paul F. Mansfield MD Anthony Lucci MD Janice N. Cormier MD MPH 《Cancer》2009,115(11):2505-2513
BACKGROUND:
The objectives of this analysis were to compare various measures associated with lymph node (LN) dissection and to identify threshold values associated with disease‐specific survival (DSS) outcomes in patients with melanoma.METHODS:
Patients with lymph node‐positive melanoma who underwent therapeutic LN dissection of the neck, axilla, and inguinal region were identified from the SEER database (1988‐2005). We performed Cox multivariate analyses to determine the impact of the total number of LNs removed, number of negative LNs removed, and LN ratio on DSS. Multivariate cut‐point analyses were conducted for each anatomic region to identify the threshold values associated with the largest improvement in DSS.RESULTS:
The LN ratio was significantly associated with DSS for all LN regions. The LN ratio thresholds resulting in the greatest difference in 5‐year DSS were .07, .13, and .18 for neck, axillary, and inguinal regions, respectively, corresponding to 15, 8, and 6 LNs removed per positive lymph node. After adjustment for other clinicopathologic factors, the hazard ratios (HRs) were .53 (95% confidence interval [CI], .40 to .71) in the neck, .52 (95% CI, .42 to .65) in the axillary, and .47 (95% CI, .36 to .61) in the inguinal regions for patients who met the LN ratio threshold.CONCLUSIONS:
Among the prognostic factors examined, LN ratio was the best indicator of the extent of LN dissection, regardless of anatomic nodal region. These data provide evidence‐based guidelines for defining adequate LN dissections in melanoma patients. Cancer 2009. © 2009 American Cancer Society. 相似文献10.
Telomerase reverse transcriptase promoter alterations across cancer types as detected by next‐generation sequencing: A clinical and molecular analysis of 423 patients
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Maria Schwaederle PharmD Nithya Krishnamurthy Gregory A. Daniels MD PhD David E. Piccioni MD PhD Santosh Kesari MD PhD Paul T. Fanta MD Richard B. Schwab MD Sandip P. Patel MD Barbara A. Parker MD Razelle Kurzrock MD 《Cancer》2018,124(6):1288-1296
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K G Griewank R Murali B Schilling S Scholz A Sucker M Song D Süsskind F Grabellus L Zimmer U Hillen K-P Steuhl D Schadendorf H Westekemper M Zeschnigk 《British journal of cancer》2013,109(2):497-501
Background:
Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations.Methods:
The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas.Results:
Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma.Conclusion:
Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas. 相似文献12.
Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients
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Hoonsung Choi MD Jae‐Kyung Won MD PhD Jae Hoon Moon MD PhD Sun Wook Cho MD PhD Kyu Eun Lee MD PhD Young Joo Park MD PhD Ka Hee Yi MD PhD Do Joon Park MD PhD Jeong‐Sun Seo MD PhD 《Cancer》2016,122(9):1370-1379
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TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease‐related hepatocellular carcinoma
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Soo Ki Kim Yoshihide Ueda Etsuro Hatano Nobuyuki Kakiuchi Haruhiko Takeda Tomoyuki Goto Takahiro Shimizu Kenichi Yoshida Yoshihiro Ikura Yuichi Shiraishi Kenichi Chiba Hiroko Tanaka Satoru Miyano Shinji Uemoto Tsutomu Chiba Seishi Ogawa Hiroyuki Marusawa 《International journal of cancer. Journal international du cancer》2016,139(11):2512-2518
The number of patients with nonalcoholic fatty liver disease (NAFLD)‐related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD‐related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD‐HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD‐HCC tumor samples from these 10 patients by whole‐exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole‐exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD‐HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole‐exome sequencing and 14 representative HCC‐associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array‐based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD‐HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD‐HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD‐related liver carcinogenesis. 相似文献
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Marco Dell’Aquila MD Vincenzo Fiorentino MD Maurizio Martini MD PhD Sara Capodimonti BD PhD Tonia Cenci BD PhD Celestino Pio Lombardi MD Marco Raffaelli MD Alfredo Pontecorvi MD PhD Guido Fadda MD MIAC Liron Pantanowitz MD MHA Luigi Maria Larocca MD Esther Diana Rossi MD PhD MIAC 《Cancer cytopathology》2021,129(10):819-829
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Kun Wang Tiantian Liu Nan Ge Li Liu Xiaotian Yuan Jikai Liu Feng Kong Chang Wang Hongbo Ren Keqiang Yan Sanyuan Hu Zhonghua Xu Magnus Bj?rkholm Yidong Fan Shengtian Zhao Cheng Liu Dawei Xu 《Oncotarget》2014,5(23):12428-12439
TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies. 相似文献
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Kun Wang Tiantian Liu Li Liu Jikai Liu Cheng Liu Chang Wang Nan Ge Hongbo Ren Keqiang Yan Sanyuan Hu Magnus Bj?rkholm Yidong Fan Dawei Xu 《Oncotarget》2014,5(7):1829-1836
TERT promoter mutations are identified in many malignancies including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC). In contrast, no mutations were found in renal cell carcinoma (RCC) as reported in a recent study. Because the mutant TERT promoter in urine DNA was recently tested as a marker for BC, it is important to ascertain whether these mutations are truly absent in RCCs. Here we determined TERT promoter mutations in 109 patients with RCC and 14 patients with UTUC. The mutations were found in 9/96 (9.3%) clear cell RCC (ccRCC) tumors and 1/8 (13%) chromophobe RCC tumors. Among ccRCC patients, the mutation was correlated with the advanced stages and metastasis, and higher TERT expression. Among UTUCs, the mutation was detected in tumors from 3/5 (60%) patients with renal pelvic cancer and 1/9 (11%) patients with ureter cancer. The mutation was also detected in 1 of 4 urine samples from patients with mutation+ UTUC. Collectively, TERT promoter mutations do occur in RCCs and are associated with aggressive disease. The mutation is more frequent in renal pelvic cancer. Thus, the mutant TERT promoter found in urine may come from not only BC, but also RCC or UTUC. 相似文献
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J Bauer E Kilic J Vaarwater B C Bastian C Garbe A de Klein 《British journal of cancer》2009,101(5):813-815
Background:
Recently, oncogenic G protein alpha subunit q (GNAQ) mutations have been described in about 50% of uveal melanomas and in the blue nevi of the skin.Methods:
GNAQ exon 5 was amplified from 75 ciliary body and choroidal melanoma DNAs and sequenced directly. GNAQ mutation status was correlated with disease-free survival (DFS), as well as other clinical and histopathological factors, and with chromosomal variations detected by FISH and CGH.Results:
Of the 75 tumour DNA samples analysed, 40 (53.3%) harboured oncogenic mutations in GNAQ codon 209. Univariate and multivariate analysis showed that GNAQ mutation status was not significantly correlated with DFS.Conclusion:
The GNAQ mutation status is not suitable to predict DFS. However, the high frequency of GNAQ mutations may render it a promising target for therapeutic intervention. 相似文献20.
Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival
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Hongliang Liu Qiong Shi Yinghui Xu Wenting Wu Dakai Zhu Christopher I. Amos Shenying Fang Jeffrey E. Lee Jiali Han Qingyi Wei 《International journal of cancer. Journal international du cancer》2017,140(6):1270-1279
To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re‐analyzing a published genome‐wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM‐specific survival (CMSS) (p ≤ 0.050 and false‐positive report probability ≤ 0.20), and nine SNPs were validated in the Harvard study (p ≤ 0.050). Among these, three independent SNPs (i.e., DOCK1 rs11018104 T > A, rs35748949 C > T and PAK2 rs1718404 C > T) showed a predictive role in CMSS, with an effect‐allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18‐1.90, p = 7.46E‐04), 1.53 (1.18‐1.97, 1.18E‐03) and 0.58 (0.45‐0.76, 5.60E‐05), respectively]. Haplotype analysis revealed that a haplotype carrying two risk alleles A‐T in DOCK1 was associated with the poorest survival in both MDACC (adjHR = 1.73, 95% CI = 1.19‐2.50, p = 0.004) and Harvard (adjHR = 1.95, 95% CI = 1.14‐3.33, p = 0.010) studies. In addition, patients with an increasing number of unfavorable genotypes (NUGs) for these three SNPs had a poorer survival. Incorporating NUGs with clinical variables showed a significantly improved ability to classify CMSS (AUC increased from 86.8% to 88.6%, p = 0.031). Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients. Further large, prospective studies are needed to validate these findings. 相似文献