Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

Abstract

HMGA2, CDK4, and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor, well-differentiated liposarcoma, and dedifferentiated liposarcoma. We studied the frequency of amplification of these genes in a series of 48 dedifferentiated liposarcomas and 68 atypical lipomatous tumors/well-differentiated liposarcomas. We correlated their amplification status with clinicopathological features and outcomes. Histologically, both CDK4 (P = 0.007) and JUN (P = 0.005) amplifications were associated with dedifferentiated liposarcoma, whereas amplification of the proximal parts of HMGA2 (5′-untranslated region (UTR) and exons 1-3) was associated with atypical lipomatous tumor/well-differentiated liposarcoma (P = 0.01). CDK4 amplification was associated with axial tumors. Amplification of 5′-UTR and exons 1-3 of HMGA2 was associated with primary status and grade 1. Shorter overall survival was correlated with: age 464 years (P = 0.03), chemotherapy used in first intent (Po0.001), no surgery (P = 0.003), grade 3 (Po0.001), distant metastasis (Po0.001), node involvement (P = 0.006), and CDK4 amplification (P = 0.07). In multivariate analysis, distant metastasis (HR = 8.8) and grade 3 (HR = 18.2) were associated with shorter overall survival. A shorter recurrence-free survival was associated with dedifferentiated liposarcoma (Po0.001), grade 3 (Po0.001), node involvement (Po0.001), distant metastasis (P = 0.02), recurrent status (P = 0.009), axial location (P = 0.001), and with molecular features such as CDK4 (P = 0.05) and JUN amplification (P = 0.07). Amplification of 5′-UTR and exons 1-3 (P = 0.08) and 3′-UTR (P = 0.01) of HMGA2 were associated with longer recurrence-free survival. Distant metastasis was associated with shorter recurrence-free survival (HR = 5.8) in multivariate analysis. Dedifferentiated liposarcoma type was associated with axial location, grade 3 and recurrent status. In conclusion, we showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis, whereas CDK4 and JUN amplifications were associated with dedifferentiated liposarcoma histology and a bad prognosis. In addition, we also provided the first description of the molecular evolution of a well-differentiated liposarcoma into four successive dedifferentiated liposarcoma relapses, which was consistent with our general observations.

Current classification, treatment options, and new perspectives in the management of adipocytic sarcomas

“… 16 In particular, molecular cytogenetic analysis and immunohistochemistry staining have assessed the prognostic value of CDK4 amplification, which seems to be significantly associated with a worse prognosis in DDLPS (88.2% in DDLPS vs 58.9% in ALT/WDLPS). 17 From a histologic point of view, the new World Health Organization classification divides ALT/WDLPS into three subclasses according to their morphologic aspect: adipocytic, sclerosing, and inflammatory. Even though three histologic variants are identified, these subclasses have no clinical significance.…”

Comprehensive Bioinformatic Analysis Genes Associated to the Prognosis of Liposarcoma

“…Gobble et al [ 9 ] calculated a risk score for each patient using 588 genes and found that patients with low risk scores had a 3-year DRFS of 83% versus 45% for high risk score patients; they also showed that TOP2A , PTK7 , and CHEK1 were overexpressed in liposarcoma samples of all 5 subtypes and in liposarcoma cell lines. Saâda-Bouzid et al [ 22 ] showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis, whereas CDK4 and JUN amplifications were associated with de-differentiated liposarcoma histology and a bad prognosis. In the present study, to identify the genes crucial to liposarcoma tumorigenesis and define genes significantly related to the prognosis of patients, we conducted comprehensive analysis of 2 microarray datasets.…”

Recent translational research into targeted therapy for liposarcoma

“…The MDM2 (also known as HDM2) gene is located at chromosome 12q15 and is amplified in most WD/DDLPS ( Table 1) (32)(33)(34). Amplification of MDM2 inhibits the activity of p53, which leads to its loss of function as a tumor suppressor (35)(36)(37).…”

“…Amplification of MDM2 inhibits the activity of p53, which leads to its loss of function as a tumor suppressor (35)(36)(37). Similarly, the cyclin dependent kinase-4 gene (CDK4) is also amplified in most WDLPS and DDLPS cases ( Table 1) (29,32,38). At the molecular level, CDK4 inactivates retinoblastoma (Rb) protein and promotes cell-cycle transition from G1 phase to S phase (39).…”

“…Similar to MDM2 and CDK4, the YEATS domain containing 4 gene (YEATS4) is also located on 12q13-q15 ( Table 1). As a transcription factor participating in p53 regulation, YEATS4 has also shown promising potential in target therapy (17,29,32).…”