Loss-of-Function Mutations of BCOR Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.

From Descriptive to Functional Genomics of Leukemias Focusing on Genome Engineering Techniques

“…Briefly, we mention the impact of frequently identified somatic mutations, such as FLT3 , NPM1 , TP53 , RUNX1 , ASXL1 , IDH1 , IDH2 , DNMT3A , CEBPA , TET2 , NRAS , KRAS , BCORL1 mutations [ 87 , 88 , 89 , 90 , 91 , 92 ]. In addition, several previously published papers detailed the descriptive genomics of AML patients and the well-known impact of the mentioned genetic abnormalities [ 93 , 94 , 95 , 96 ]. Due to the frequent co-occurrence of genetic abnormalities on the AML genome, it is essential to note the importance of the comprehensive genetic evaluation for an accurate diagnostic, prognostic, risk stratification, and therapy.…”

Standard Risk-Assessment of AML Doesn't Predict the Outcome in Older AML Patients Undergoing Non-Intensive Chemotherapy

“…En effet, l'acquisition d'une LAM nécessite généralement l'acquisition de trois à cinq mutations « driver » co-occurentes. La complexité d'association des mutations entre elles dans ce processus est représentée par la (13,14). Cependant, ces impacts pronostiques ont été établis chez des sujets jeunes, ne tenant pas compte des spécificités des sujets plus âgés.…”

Disparities in acute myeloid leukemia treatments and outcomes

“…In addition, there were differences in the frequencies of several AML-associated gene mutations between social deprivation index (SDI) groups such as lower percentage of mutations in the BCO R, IDH1 , and STAG2 genes in patients belonging to the high SDI group [26 ▪ ]. Since both BCO R [27–29] and IDH1 [30] mutations adversely affect prognosis of younger adults with AML, their lower frequencies in the high SDI group patients (whose outcomes are worse), indicate an important contribution of the SDI to survival disparities. This view was supported by the results of the multivariable analysis, in which a high SDI score remained associated with shorter overall survival (OS) after adjustment for 2017 ELN genetic-risk groups, highlighting that patients’ socioeconomic status predicts outcome independently from genetics-based clinical risk stratification.…”