ATRX Alteration Contributes to Tumor Growth and Immune Escape in Pleomorphic Sarcomas

Abstract

Whole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas has been revealed ATRX to be one of the most frequently mutated genes in leiomyosarcomas after TP53 and RB1. While its function is well described in the alternative lengthening of telomeres mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression of genes linked to differentiation in leiomyosarcomas, and to immunity in an additional cohort of 60 poorly differentiated pleomorphic sarcomas. In vitro and in vivo models showed that ATRX down-expression increases tumor growth rate and immune escape by decreasing the immunity load of active mast cells in sarcoma tumors. These data indicate that an alternative to unsuccessful targeting of the adaptive immune system in sarcoma could target the innate system. This might lead to a better outcome for sarcoma patients in terms of ATRX status.

Molecular Determinants of Soft Tissue Sarcoma Immunity: Targets for Immune Intervention

“…An example is represented by epithelioid sarcoma displaying loss of INI1, a chromatin modifier belonging to the SWI/SNF family. Indeed, EZH2 inhibitor has been recently approved by the FDA for this sarcoma [ 41 , 42 ].…”

“…Moreover, it stresses the need to further investigate the relationship between epigenetic change, activation and immune response to identify new potential therapeutic approaches for translocated sarcomas. Of note, this relationship should be also explored in sarcomas with complex karyiotypes, as an association between SWI/SNF chromatin remodeling alteration and immunity has recently been described in pleomorphic sarcomas [ 42 ].…”

Distinct gene mutation profiles among multiple and single primary lung adenocarcinoma

“…As shown in Figure 4A, Nonsense Mutation of ATRX was the most frequent, and ATRX loss has been shown to promote ALT, DNA damage and replicative stress (49)(50)(51). The GSEA analysis indicated that mutation of gene ATRX was related to "humoral immune response" (Supplementary Figure 3), and now it has been reported in many tumors including pleomorphic Sarcomas (52), glioma (53,54), gastric cancer patients (55), while the relationship between mutation of ATRX with cytochrome P450 was not reported.…”

Distinct cellular origins and differentiation process account for distinct oncogenic and clinical behaviors of leiomyosarcomas

“…To classify LMS from the ICGC (59 patients) [64] and TCGA (75 patients) [13] cohorts, we computed the distance to hLMS and oLMS centroids based on the expression of the 1672 DE genes from the Affymetrix cohort. When the cohorts were merged, 102 cases were strongly enough correlated with one centroid ( Figure 1F ), classifying 73 as hLMS and 29 as oLMS.…”