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Tert promoter mutations in gliomas and subset of tumors

A glioma and promoter technology, applied in the fields of botanical equipment and methods, biochemical equipment and methods, microbial measurement/testing, etc., can solve the problem of lack of homologous recombination

Pending Publication Date: 2016-06-15
DUKE UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be postulated that the absence of a functional ATRX / DAXX complex allows homologous recombination to cause ALT

Method used

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  • Tert promoter mutations in gliomas and subset of tumors
  • Tert promoter mutations in gliomas and subset of tumors
  • Tert promoter mutations in gliomas and subset of tumors

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Experimental program
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Embodiment 2

[0035] Relying on the availability of samples in the laboratory, the inventors attempted to evaluate at least 20 individual samples of common tumor types and a small number of samples of rare tumor types. Among those tumor types in which the inventors' experimental studies showed a large number of mutations, additional tumors were evaluated. Melanoma and tumors of the lung, stomach, and esophagus were excluded because they had been adequately evaluated in the cited seminal papers (14, 15). When using primary tumors without utilizing cell lines, the inventors ensured that the proportion of tumor cells was greater than 50% by histopathological examination of frozen sections of tissue blocks used for DNA purification. In those cases where the tumor content was less than 50%, the inventors microdissected the lesion to enrich the tumor content to greater than 50%. Primers were designed to amplify a region containing two TERT mutations, C228T and C250T, corresponding to positions 1...

Embodiment 3

[0046] sarcoma

[0047] One of the most frequent TERT promoter mutations was found in myxoid liposarcoma (19 of 24 tumors, 79% of tumors had mutations). Myxoid liposarcoma accounts for more than one third of all liposarcomas and -10% of all adult soft tissue sarcomas (16). Patients are relatively young, and their peak age range is between 30 and 50 years old. At the gene level, the most characteristic change is the t(12;16)(q13;p11) chromosomal translocation, which results in the fusion of the FUS and DDIT3 genes (16, 17). The cellular origin of these tumors is unknown, but preadipocyte progenitors and mesenchymal stem cells have been implicated (18); after embryogenesis, the division activity of these cells is thought to be low. Other sarcomas are also thought to arise from mesenchymal cells that do not self-renew in the absence of injury, and are not TERT-H (Table 1). These sarcomas included synovial sarcomas (0% of 16 tumors) and osteosarcomas (4.3% of 23 tumors). Of no...

Embodiment 4

[0068] Embodiment 4--ALT to TERT

[0069] ALT has been observed more frequently in tumors of the central nervous system, especially glial tumors, than in tumors of any other tissue type. Considering that TERT promoter mutations are also commonly found in glial tumors, the relationship between these two features could be determined with high confidence. The tumors depicted in Figure 2 have previously been assessed for ATRX alterations, which are almost perfect surrogates for the ALT phenotype (11, 37). The inventors' data showed that 50 glial tumors had ATRX mutations and 83 glial tumors had TERT mutations; 0 of 83 tumors with TERT mutations had ATRX mutations (P<0.0001, Fisher's exact probability test , two-tailed).

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Abstract

We surveyed 1230 tumors of 60 different types and found that tumors could be divided into types with low (<15%) and high (>=15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

Description

[0001] technical field of invention [0002] The invention relates to the field of mutation detection. In particular, mutations in non-coding regions of the human genome are involved. Background of the invention [0003] Telomeres are nucleoprotein complexes located at the ends of eukaryotic chromosomes and are required to maintain the integrity of the chromosomes. Hundreds of nucleotides of the telomeric repeat cap each chromosome end, and in the absence of telomerase activity, telomeres shorten with each cell division (1). Ultimately, uncapped telomeres trigger cell death, or senescence. Cancer cells divide seemingly permanently, so it needs some telomere maintenance mechanism to avoid this fate. Because telomerase activity is generally higher in cancer cells than in normal cells, it was initially thought that telomerase in cancer cells was somehow activated (2–6). However, it was subsequently realized that telomerase activity is maintained only in normal cells of self-r...

Claims

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Application Information

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IPC IPC(8): C12Q1/68C12N15/12
CPCC12Q2600/112C12Q2600/156C12Q1/6886
Inventor H·严B·沃格尔斯坦N·帕帕佐普洛斯K·W·肯斯勒Y·焦C·贝蒂加高达D·D·比格纳
Owner DUKE UNIV
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