Article

Inherited susceptibility to pediatric acute lymphoblastic leukemia.

Nature Genetics (Impact Factor: 29.65). 10/2009; 41(9):957-8. DOI: 10.1038/ng0909-957
Source: PubMed

ABSTRACT Although genome-wide analyses have identified somatic alterations contributing to the pathogenesis of pediatric acute lymphoblastic leukemia (ALL), few studies have identified germline variants conferring risk of this disease. Two reports now provide the first genome-wide glimpse into the role of inherited alleles in ALL pathogenesis.

1 Follower
 · 
40 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.Oncogene advance online publication, 27 January 2014; doi:10.1038/onc.2013.587.
    Oncogene 01/2014; DOI:10.1038/onc.2013.587 · 8.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr Virus (EBV) and Plasmodium falciparum co-infections. Malaria appears to dysregulate immunity that would otherwise control EBV thereby contributing to eBL etiology. Juxtaposed to human genetic variants associated with protection from malaria, it has been hypothesized that such variants could decrease eBL susceptibility, historically referred to as 'the protective hypothesis'. Past studies attempting to link sickle cell trait (HbAS), which is known to be protective against malaria, with protection from eBL were contradictory and underpowered. Therefore, using a case-control study design we examined HbAS frequency in 306 Kenyan children diagnosed with eBL compared to 537 geographically-defined and ethnically-matched controls. We found 23.8% HbAS for eBL patients which was not significantly different compared to 27.0% HbAS for controls (OR = 0.85 [95% CI, 0.61-1.17]; p-value = 0.33). Even though cellular EBV titers, indicative of the number of latently infected B cells, were significantly higher (p-value < 0.0003) in children residing in malaria holoendemic compared to hypoendemic areas, levels were not associated with HbAS genotype. Combined, this suggests that while HbAS protects against severe malaria and hyper-parasitemia, it is not associated with viral control or eBL protection. However, based on receiver operating characteristic (ROC) curves factors that enable the establishment of EBV persistence, in contrast to those involved in EBV lytic reactivation, may have utility as an eBL precursor biomarker. This has implications for future human genetic association studies to consider variants influencing control over EBV in addition to malaria as risk factors for eBL. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2014; 134(3). DOI:10.1002/ijc.28378 · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Childhood acute lymphoblastic leukemia (ALL), a heterogeneous disease that includes multiple subtypes is defined by cell lineage and chromosome anomalies. Previous genome-wide association studies have reported several ARID5B and IKZF1 single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. High-resolution melting (HRM) analysis is a rapid and convenient technique to detect SNPs; we thereby detected SNPs in ARID5B and IKZF1 genes. We enrolled 79 pediatric ALL patients and 80 healthy controls. Polymorphic variants of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) were detected by HRM, and SNPs were analyzed for association with childhood ALL. The distribution of genotype rs7073837 in ARID5B significantly differed between ALL and controls (P=0.046), while those of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs10740055 and rs7089424) did not. We analyzed the association for SNPs with B lineage ALL to find rs7073837 in ARID5B, conferring a higher risk for B lineage ALL (odds ratio, OR=1.70, 95% confidence interval, CI=1.01-2.87, P=0.049). HRM is a practical method to detect SNPs in ARID5B and IKZF1 genes. We found that rs7073837 in ARID5B correlated with a risk for childhood B lineage ALL.
    Blood Cells Molecules and Diseases 11/2013; DOI:10.1016/j.bcmd.2013.10.003 · 2.33 Impact Factor