GFI1(36N) as a therapeutic and prognostic marker for myelodysplastic syndrome (MDS)

Inherited gene variants play an important role in malignant diseases. The transcriptional repressor Growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI1(36N)) and has a prevalence of 3-5% among Caucasians. Since GFI1 regulates myeloid development, we examined the role of GFI1(36N) on MDS disease course. To this end, we determined allele frequencies of GFI1(36N) in four independent MDS cohorts from the Netherlands and Belgium, Germany, the ICGC consortium and the USA. The GFI1(36N) allele frequency in the 723 MDS patients genotyped ranged between 9-12%. GFI1(36N) was an independent adverse prognostic factor for overall survival, AML-free survival and event-free survival in an univariate analysis. After adjusting for age, bone marrow blast percentage, IPSS score, mutational status and cytogenetic findings, GFI1(36N) remained an independent adverse prognostic marker. With regard to therapy, whereas GFI1(36S) homozygous patients showed sustained response to treatment with hypomethylating agents, GFI1(36N) patients show poor sustained response to this therapy. Since allele status of GFI1(36N) is readily determined using basic molecular techniques, we propose to include GFI1(36N) status in future prospective studies for MDS patients to better predict prognosis and guide therapeutic decisions

Expression of the BRCA1 complex member BRE predicts disease free survival in breast cancer.

Item does not contain fulltextBreast cancer is one of the leading causes of cancer mortality in women. Recent advances in gene expression profiling have indicated that breast cancer is a heterogeneous disease and the current prognostication using clinico-pathological features is not sufficient to fully predict therapy response and disease outcome. In this retrospective study, we show that expression levels of BRE, which encodes a member of the BRCA1 DNA damage repair complex, predicted disease-free survival (DFS) in non-familial breast cancer patients. The predictive value of BRE expression depended on whether patients received radiotherapy as a part of their primary treatment. In radiotherapy-treated patients, high BRE expression predicted a favorable DFS (hazard ratio (HR) = 0.47, 95 % confidence interval (CI) = 0.28-0.78, p = 0.004), while in non-treated patients, high BRE expression predicted an adverse prognosis (HR = 2.59, 95 % CI = 1.00-6.75, p = 0.05). Among radiotherapy-treated patients, the prognostic impact of BRE expression was confined to patients with smaller tumors (HR = 0.23, 95 % CI = 0.068-0.75, p = 0.015) and it remained an independent factor after correction for the other prognostic factors age, tumor size, lymph node involvement, and histological grade (HR = 0.50, CI = 0.27-0.90, p = 0.021). In addition, high BRE expression predicted a favorable relapse-free survival in a publicly available dataset of 2,324 breast cancer patients (HR = 0.59, CI = 0.51-0.68, p < 0.001). These data indicate that BRE is an interesting candidate for future functional studies aimed at developing targeted therapies.1 augustus 201