Maximus Peto’s Commentary
Here we are with yet another report of loss of ATRX/DAXX implicated in ALT activity, this time in uterine leiomyomas. I scanned the full-text to see if I could find anything particularly interesting to report or clarify, and here is something that seemed interesting: “The great majority of conventional ULs harbor mutations in MED12 or overexpress HMGA2.3 Tumors with either one of these driver mutations display relatively few other mutations. Here, 53 of 64 conventional tumors (83%) displayed either a MED12 mutation or HMGA2 overexpression…All tumors with ATRX/DAXX loss or ALT were wild‐type for MED12 and HMGA2 (Table 1).” It seems interesting that **all** tumors with loss of ATRX/DAXX loss or ALT-positivity did not have mutations in, or overexpression of, a protein that 83% of tumors had. I wonder why these are so mutually exclusive.
Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas.
Cancer. 2018 Dec 15;124(24):4650-4656.
Ahvenainen TV, Mäkinen NM, von Nandelstadh P, Vahteristo MEA, Pasanen AM, Bützow RC, Vahteristo PM
PubMed publication date (edat): 11/14/2018
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.
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.
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.
These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential.
Free Full-Text: https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.31754