Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas

Abstract

BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype. METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs. RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres. CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential. Cancer 2018;124:4650-4656.

ALT Positivity in Human Cancers: Prevalence and Clinical Insights

“…LMS can arise in many soft tissue sites, such as the retroperitoneum and large blood vessels, but more commonly, it arises from mesodermal tissue (smooth muscle) of the uterine wall [ 164 ]. Diagnosing uterine leiomyosarcoma (ULMS) can be difficult; they may sometimes be mistakenly diagnosed as uterine leiomyoma (benign uterine fibroids) [ 166 ]. Finding genetic contributions that are characteristic of LMS will aid the earlier and proper diagnosis and treatment of LMS.…”

“…Interestingly, the ALT phenotype is rarely found in leiomyomas (benign uterine tumors) ( Table 2 ), suggesting that ALT may be specific to ULMS and STUMP, and therefore could be used as a diagnostic biomarker for the more aggressive uterine tumors. These findings are important and merit follow-up as ULMS and STUMP are often misdiagnosed for uterine leiomyoma due to overlapping symptoms and/or histology [ 166 , 172 ].…”

Genome wide methylation profiling of selected matched soft tissue sarcomas identifies methylation changes in metastatic and recurrent disease

“…DAXX (Death Domain-Associated) forms a dimer with ATRX (Alpha-Thalassemia/Mental Retardation Syndrome X-linked) and dysfunction of this ATRX/ DAXX complex is associated with alternative lengthening of telomeres (ALT), which occurs in a proportion of LMSs [35][36][37] . Moreover, loss of ATRX and/or DAXX has shown to predict aggressive clinical behaviour in LMSs and other smooth muscle tumours [36][37][38] . Accordingly, we identified hypomethylation of DAXX in Mets2 versus Mets1, which would correlate with gene loss / silencing in aggressive LMSs.…”

ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas

“…Loss of ATRX in uterine tumors is a key difference between benign and malignant tumors. In this location, it has been proposed to use ATRX loss as a marker of the highly probable evolution of benign tumors toward malignancy (Ahvenainen et al, 2018). In other LMS locations, ATRX loss is linked to the "other" LMS group.…”