The inactivation of tumor suppressor genes located within 9p21 locus (CDKN2A, CDKN2B) occurs in up to 30% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but its independent prognostic significance remains controversial. In order to investigate the prognostic impact of deletions and promoter methylation within 9p21, 641 children with newly diagnosed BCP-ALL using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) were investigated. A total of 169 (26.4%) microdeletions in 9p21 were detected, of which 71 were homozygous. Patients with CDKN2A homozygous deletions were older at diagnosis (p < .001), more frequently steroid resistant (p = .049), had higher WBC count (p < .001), higher MRD at Day 15 (p = .013) and lower relapse-free survival [p = .028, hazard ratio: 2.28 (95% confidence interval: 1.09-4.76)] than patients without these alterations. CDKN2A homozygous deletions coexisted with IKZF1 and PAX5 deletions (p < .001). In conclusion, CDKN2A homozygous deletions, but not promoter methylation, are associated with poor response to treatment and increased relapse risk of pediatric BCP-ALL.
We prospectively examined whether surface expression of Cytokine Receptor-Like Factor 2 (CRLF2) on leukemic blasts is associated with survival and induction treatment response in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Flow cytometric analysis of bone marrow-derived leukemia cells revealed that 7.51% (29/286) of 386 pediatric BCP-ALL patients were CRLF2-positive (CRLF2pos) at diagnosis. The median minimal residual disease (MRD) was lower in CRLF2pos than CRLF2-negative (CRLF2neg) patients on day 15 (MRD15) after induction therapy [0.01% (0.001-0.42%) vs. 0.45% (0.05-3.50%); p=0.001]. By contrast, the MRD15 was higher in Ikaros family Zinc Finger Protein 1 (IKZF1)-deleted BCP-ALL patients than in BCP-ALL patients without IKZF1 deletions [1.18% (0.06-12.0%) vs 0.33% (0.03-2.6%); p=0.003]. Subgroup analysis showed that MRD15 levels were lower in IKZF1Δ/CRLF2pos patients than in IKZF1Δ/CRLF2neg patients [0.1% (0.02-5.06%) vs. 2.9% (0.25-12%); p=0.005]. Furthermore, MRD15 levels were higher in IKZF1WT/CRLF2neg patients than in IKZF1WT/CRLF2pos patients [0.40% (0.04-2.7%) vs. 0.001% (0.001-0.01%)]. Despite the low MRD15 levels, IKZF1Δ/CRLF2pos patients showed poorer relapse-free survival (RFS) than other patient groups (p=0.003). These findings demonstrate that surface CRLF2 expression is associated with increased risk of relapse in pediatric BCP-ALL patients harboring IKZF1 deletions.
The role of HLA-G is extensively studied in cancer due to its inhibition of the immune response. Several polymorphisms in the HLA-G gene have been reported to significantly affect its expression. We, therefore, investigated whether functionally relevant HLA-G polymorphisms, HLA-G-725C/G/T, and HLA-G 14-base pair, have any influence on the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its clinical course. The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA-G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA-G-725GG or the HLA-G-725GC genotype were lower, and those of the HLA-G ins/ins genotype were higher in the patients compared with the controls. Patients carrying the HLA-G-725CC genotype presented a higher probability of overall survival (OS) than subjects with other genotype combinations of HLA-G-725C/G/T (P = 0.003). The homozygous HLA-G del/del had a lower probability of OS than subjects carrying the HLA-G deletion/insertion (del/ins) or the HLA-G ins/ins genotype (P = 0.009). Two HLA-G genotype-based risk groups were defined according to the genotype distribution. The high-risk (HR) group presented a shorter OS than low-risk (LR) patients (P = 0.001). In a multivariate analysis adjusted for International Prognostic Index (IPI) factors, both the intermediate high/high IPI-risk group (P < 0.0001) and the HR genotype group (P = 0.004) independently increased the risk of death. This is the first study indicating an important role of HLA-G polymorphisms for the clinical course of DLBCL. The potential influence of HLA-G polymorphisms on the susceptibilityto DLBCL thus deserves further study.
There is growing evidence that genetic variations in the human leukocyte antigen (HLA) genes play a role in the etiology and clinical course of NHL. HLA-G belongs to the non-classical class I major histocompatibility complex-1 (MHC-I) polymorphic molecules and due to its suppression of immune response it is able to facilitate tumor escape from immunosurveillance. Several polymorphisms in the HLA-G gene have been reported to significantly affect its expression. Therefore, we investigated whether functionally relevant HLA-G polymorphisms, HLA-G-725C/G/T and HLA-G 14-bp, have any influence on the susceptibility to, and clinical course of, diffuse large B-cell lymphoma (DLBCL). The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA-G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA-G-725GG or the HLA-G-725GC genotype were lower (OR [odds ratio]= 0.47, P= 0.004), and those of the HLA-G ins/ins genotype were higher (OR= 2.08, P= 0.004) in the patients compared to controls. In univariate logistic regression analysis, neither HLA-G -725C/G/T nor HLA-G 14-bp influenced the probability of achieving a remission. There was no influence of HLA-G polymorphisms on the probability of progression-free survival (PFS). However, the patients carrying the HLA-G-725CC genotype presented a higher probability of 5-year overall survival (OS) than subjects with other genotype combinations of HLA-G-725C/G/T (38.2% vs 21.7%, P=0.003, log-rank test). The estimated 5-year OS among the homozygotes HLA-G del/del was 18.9% compared to the 35.3% in the subjects carrying the HLA-G del/ins or the 46.1% in those with the HLA-G ins/ins genotype (P=0.009, log-rank test). In a multivariate Cox analysis adjusted for IPI factors, we found that both the HLA-G -725C/G/T polymorphism (P= 0.01) and the IPI (P< 0.0001) retained their independent prognostic impact on OS The influence of the particular genotypes of the HLA-G -725C/G/T and the HLA-G 14-bp polymorphism on OS allow us to single out two HLA-G genotype-based risk groups. The low risk (LR) group included the patients carrying the HLA-G -725CC genotype and the HLA-G del/ins or the HLA-G ins/ins genotype. In contrast, the high risk (HR) group comprised those patients with other HLA-G genotype combinations. It is worth noting that the estimated 5-year OS rate of patients with LR genotypes was 42.7% in comparison to the 19.3% (P= 0.001, log-rank test) in patients with HR genotypes. An additional multivariate analysis, including HLA-G genotype-based risk groups and the IPI, revealed that both the intermediate high/high IPI risk group (P< 0.0001) and the HR genotype group (P= 0.004) independently increased the risk of death. This is the first study indicating an important role for HLA-G polymorphisms in the clinical course of DLBCL. The potential influence of HLA-G polymorphisms on the susceptibility to DLBCL deserves further study. It would seem that the inherited ability of the host to suppress anti-tumor immune response and then facilitate tumor escape from immunosurveillance might contribute to the pathogenesis and prognosis of B-cell malignancies. Disclosures Robak: MorphoSys AG: Research Funding.
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