Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma

Slatter, Tania L.; Hsia, Howard; Samaranayaka, Ari; Sykes, Peter; Clow, William Bill; Devenish, Celia; Sutton, T.; Royds, Janice A.; Ip, Philip; Cheung, Annie Nga‐Yin; Hung, Noelyn

doi:10.1002/cjp2.11

Cited by 34 publications

(31 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All mutations were either nonsense or frameshift alterations most likely leading to a truncated protein product. Loss of ATRX expression has been reported in leiomyosarcomas of various sites [ 20 – 22 ] and a recent meeting abstract on ULMSs reported genomic alterations of this gene in 32% (8/25) of the studied tumors, supporting our findings [ 23 ]. We successfully analyzed ATRX protein levels in 44 ULMSs and showed that 52% of the tumors, including all reliably analyzed mutation-positive lesions, had clearly reduced expression.…”

Section: Discussionsupporting

confidence: 91%

“…In general, TP53 alterations are the most common genetic changes in human cancers and they are particularly associated with an aggressive phenotype. Recently, loss of ATRX expression was associated with poor clinical outcome in ULMS [ 21 , 22 ]. Larger sample series with information on both TP53 and ATRX are required to confirm these findings.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12

et al. 2016

View full text Add to dashboard Cite

Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Specifically, a significant correlation between ALT activity and mutations or abnormal expression of ATRX chromatin remodeler and/or its binding partner H3.3-specific histone chaperone DAXX gene has been observed [9]. In particular, the loss of ATRX has been found to be highly associated with ALT-positivity in different subtypes of sarcomas with complex karyotypes [29], including dedifferentiated liposarcoma [24], angiosarcoma [30], and uterine smooth muscle tumors [31]. Moreover, the loss of ATRX or DAXX genes has been found to be associated with poor prognosis (i.e., death or recurrence) in smooth muscle tumors of uncertain malignant potential and early-stage uterine leiomyosarcoma [31].…”

Section: Ta Dfsmentioning

confidence: 99%

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

Recagni

Bidzinska

Zaffaroni

et al. 2020

Cancers

View full text Add to dashboard Cite

Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients’ outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.

show abstract

“…Most studies recently focused on molecular markers able to predict progression risk and prognosis of a LMS. Slatter et al correlated the presence of ALT and PML bodies (APBs) to a poor prognosis of LMS [52]. Next-generation sequencing confirmed the presence of ATRX mutations in LMS and their association with a poor survival [53].…”

Section: Molecular Featuresmentioning

confidence: 99%

Uterine Sarcomas: An Updated Overview. Part 1: Smooth Muscle Tumors

Zappacosta¹,

Fanfani²,

Zappacosta³

et al. 2018

Neoplasm

View full text Add to dashboard Cite

Uterine sarcomas (USs) account for 3-9% of uterine malignant neoplasia and about 5% of all gynaecologic malignancies. Despite their low prevalence, these tumors stimulate a great interest because of their aggressiveness, poor prognosis and high mortality rate. According to the last World Health Organization (WHO) classification and the International Federation of Gynecology and Obstetrics Committee (FIGO) staging, USs are categorized as pure mesenchymal tumors (endometrial stromal sarcoma, leiomyosarcoma and undifferentiated uterine), and mixed tumors (carcinosarcoma and adenosarcoma). Due to their non-specific signs and symptoms, USs are commonly diagnosed in advanced stage, more often after surgery for a suspected leiomyoma. Although surgery followed by adjuvant therapies represent the common choices for USs, they show poor efficacy due to the early occurrence of metastasis, and the high resistance of tumors to radio-and chemotherapy. Presently, specific expression profiles and new cytotoxic agents are under investigation. In these reviews, we summarized clinical and pathological features, imaging characteristics, therapeutic approaches, genomic and molecular aberration associated with smooth muscle neoplasia (Part 1) and endometrial stromal neoplasia (Part 2); the goal is to understand the biology and the molecular signature of these tumors, in order to focus on their best management.

show abstract

Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma

Cited by 34 publications

References 33 publications

Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12

Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

Uterine Sarcomas: An Updated Overview. Part 1: Smooth Muscle Tumors

Contact Info

Product

Resources

About