RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia

Abstract

We explored the relationship of RAS gene mutations with epidemiologic and cytogenetic factors in a case series of children with leukemia. Diagnostic bone marrow samples from 191 incident leukemia cases from the Northern California Childhood Leukemia Study were typed for NRAS and KRAS codon 12 and 13 mutations. A total of 38 cases (20%) harbored RAS mutations. Among the 142 B-cell acute lymphoblastic leukemia (ALL) cases, RAS mutations were more common among Hispanic children (P ¼ 0.11) or children born to mothers o30 years (P ¼ 0.007). Those with hyperdiploidy at diagnosis (450 chromosomes) had the highest rates of RAS mutation (P ¼ 0.02). A multivariable model confirmed the significant associations between RAS mutation and both maternal age and hyperdiploidy. Interestingly, smoking of the father in the 3 months prior to pregnancy was reported less frequently among hyperdiploid leukemia patients than among those without hyperdiploidy (P ¼ 0.02). The data suggest that RAS and high hyperdiploidy may be cooperative genetic events to produce the leukemia subtype; and furthermore, that maternal age and paternal preconception smoking or other factors associated with these parameters are critical in the etiology of subtypes of childhood leukemia.

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

“…Although mutations in the FLT3, NRAS, KRAS, and PTPN11 genes have been suggested to be particularly common in high hyperdiploid childhood ALLs (Armstrong et al, 2004;Taketani et al, 2004;Tartaglia et al, 2005;Wiemels et al, 2005), the previous studies have been small, with Armstrong et al (2004), Taketani et al (2004), and Wiemels et al (2005) investigating only 25, 19, and 56 high hyperdiploid cases, respectively. Tartaglia et al (2004) included 102 pediatric BCP ALLs with a DNA index >1.0, but did not specifically delineate the high hyperdiploid subgroup.…”

“…Recently, Wiemels et al (2005) suggested that RAS mutations are associated with high hyperdiploidy, identifying mutations in codons 12/13 in one of the genes in 30% (17/56) of cases. In addition, Tartaglia et al (2004) found an increased prevalence of RAS mutations in cases with a DNA index >1; however, they did not provide any frequency data.…”

“…For example, the FLT3 gene at 13q12 has been reported to harbor activating point mutations in 20-25% of high hyperdiploid cases when compared with 9-14% in pediatric ALLs in general (Armstrong et al, 2004;Taketani et al, 2004). Furthermore, mutations in the NRAS (at 1p13) or KRAS (at 12p12) genes, which are found in 15% of childhood ALLs, were recently reported in 30% of high hyperdiploid cases, and PTPN11 (at 12q24) mutations have been detected in 14% of BCP ALLs with a DNA index of >1, which is three times higher than the frequency in cases with DNA indices 1 Shu et al, 2004;Tartaglia et al, 2004;Wiemels et al, 2005). However, the possible association between high hyperdiploidy and FLT3, NRAS, KRAS, and PTPN11 mutations has as yet not been confirmed in a larger patient cohort, and it also remains unknown whether mutations of these different genes coexist in hyperdiploid cases or if they are mutually exclusive.…”

“…(Andersson et al, 2004). For analyses of codons 12, 13, and 61 of the NRAS and KRAS genes and of exons 3 and 13 of PTPN11, previously shown to harbor point mutations in pediatric ALLs Shu et al, 2004;Tartaglia et al, 2004;Wiemels et al, 2005), six different PCR reactions were performed. Each of these was done in a total volume of 50 ll, containing 13 PCR buffer (20 mM Tris-HCl, pH 8.4, 50 mM KCl; Invitrogen, Carlsbad, CA), 1.25 mM MgCl 2 , 0.8 mM dNTPs, 0.5 lM of each primer, and 1 U Platinum Taq polymerase (Invitrogen).…”

Secondhand Tobacco Smoke

“…RAS mutations have been consistently correlated with myeloid leukaemias in adults and children, in particular with occupationallyassociated adult myeloid leukemias (Taylor et al, 1992;Barletta et al, 2004). Wiemels et al (2005) studied the relationship of RAS mutations, hyperdiploidy (> 50 chromosomes) and smoking in a case series of 191 acute leukaemia. Smoking was negatively associated with hyperdiploidy (possibly due to the sensitivity of the hyperdiploid clone and consequent differential survival) and hyperdiploid acute leukaemia cases had the highest rates of RAS mutations.…”