Telomerase activity in gastrointestinal stromal tumors

Sakurai, Shunsuke; Fukayama, Masashi; Kaizaki, Yasuharu; Saito, Ken; Kanazawa, Kyotaro; Kitamura, Masatsugu; Iwasaki, Yoshiaki; Hishima, Tsunekazu; Hayashi, Masatoshi; Koike, Masato

doi:10.1002/(sici)1097-0142(19981115)83:10<2060::aid-cncr3>3.0.co;2-#

Cited by 60 publications

(36 citation statements)

References 29 publications

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“…29 Although the tumor cells in gastrointestinal stromal tumors are typically relatively uniform, exceptional cases of 'dedifferentiated' tumors with anaplastic features, and heterologous rhabdomyosarcomatous differentiation following tyrosine kinase inhibitor treatment have been reported. 30,31 Recently, a KRAS-mutated KIT/PDGFRA-wild type gastrointestinal stromal tumor was found to have ATRX mutations.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomerespositive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Po 0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

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Section: Discussionmentioning

confidence: 99%

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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“…10 Previous reports associate telomerase activity in GIST with higher tumor malignancy risk, metastasis and worse prognosis. [29][30][31] We found a low frequency of TERT mutations in GIST, but any statistical association was found with tumor aggressiveness; however, most TERT-mutated GISTs displayed high recurrence risk features. Although our series is undersized to allow definitive conclusions, it would be of interest to further evaluate whether TERT promoter mutations associate with a higher expression of telomerase in GISTs, and to assess whether TERT promoter mutations associate with poor prognosis as reported in other cancers such as cancers of the thyroid, 32 melanoma 9 and brain.…”

Section: Discussionmentioning

confidence: 99%

Low frequency of TERT promoter mutations in gastrointestinal stromal tumors (GISTs)

et al. 2014

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Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene, mainly at positions c. − 124 and c. − 146 bp, are frequent in several human cancers; yet its presence in gastrointestinal stromal tumor (GIST) has not been reported to date. Herein, we searched for the presence and clinicopathological association of TERT promoter mutations in genomic DNA from 130 bona fide GISTs. We found TERT promoter mutations in 3.8% (5/130) of GISTs. The c. − 124C4T mutation was the most common event, present in 2.3% (3/130), and the c. − 146C4T mutation in 1.5% (2/130) of GISTs. No significant association was observed between TERT promoter mutation and patient's clinicopathological features. The present study establishes the low frequency (4%) of TERT promoter mutations in GISTs. Further studies are required to confirm our findings and to elucidate the hypothetical biological and clinical impact of TERT promoter mutation in GIST pathogenesis.

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“…The smaller contingent of p53 positive cells could mean that p53 alterations are not adamant to GIST early steps in carcinogenesis and may occur later in this process 37,38 . Also p53 deletion is not frequent and missense mutation seems confined to less than 50% of neoplastic cells 39 .…”

Section: Discussionmentioning

confidence: 99%

Ki-67 expression score correlates to survival rate in gastrointestinal stromal tumors (GIST)

et al. 2012

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PURPOSE: To evaluate the immunohistochemical expression of p16, Ki-67, p53 and Bcl-2 proteins in gastrointestinal stromal tumors (GIST); to assess the possible association between these variables and clinical and histopathological factors of cancer; and to check for prognostic value of these variables (survival and recurrence). METHODS: A sample of 55 patients treated surgically for GIST in three hospitals was studied. The surgically excised tumors were confirmed as GIST by KIT, vimentin, desmin S100 protein, CD117, 1A4 and CD34 assessment in paraffin blocks. RESULTS: Only 9 (16%) cases of GIST were positive for p53, p16 was positive among 43.6%; 80% of GISTs showed staining for Bcl-2. The proliferative index (expressed as the proportion of positive cells) assessed by immunohistochemical expression of Ki-67 was high in 49% of cases. Elevated Ki-67 scores were associated to high histological grade (p=0.0026) and mitosis index, MI (p=0.0001). High Ki-67 index was associated to death. Expression of p53, p16 and Bcl-2 did not correlate to morphological or clinical variables. CONCLUSIONS: Ki-67 immunohistochemical evaluation should be included in preoperative evaluation of GIST biopsies or surgical specimens as a prognostic tool for clinical staging; and all other proteins studied (Bcl-2, p53 and p16) did not play a role in GIST metabolic or carcinogenic process, remaining without prognostic value.

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Telomerase activity in gastrointestinal stromal tumors

Cited by 60 publications

References 29 publications

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

Low frequency of TERT promoter mutations in gastrointestinal stromal tumors (GISTs)

Ki-67 expression score correlates to survival rate in gastrointestinal stromal tumors (GIST)

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