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Acute lymphoblastic leukaemia in children – is there a role for MTHFR?

Over the last 10 years genetic variation in folate metabolism has received considerable scientific attention, but findings have been inconsistent, with many studies based on small numbers. Koppen et al (2010) recently reported on a meta-analysis of 14 studies that had investigated genetic polymorphisms in enzymes involved in folate metabolism in relation to both childhood and adult acute lymphoblastic leukaemia (ALL), concluding that both MTHFR 677 C>T and MTHFR 1298A>C were likely to be associated with decreased susceptibility to ALL in childhood. 
 
We were however, somewhat surprised to see the authors combined data from children and adults in the same plot, despite the fact that two previous meta-analyses, neither of which were referenced by Koppen et al (2010), stratified their data by diagnostic age (Pereira et al, 2006; Zintzaras et al, 2006). Indeed, the meta-analysis plots of childhood ALL (Figures 1 and ​and22 reproduced from Koppen et al, 2010) included two studies that contained no data on children at all (Skibola et al, 1999; Gemmati et al, 2004) as well as one study that comprised both children and adults (Chiusolo et al, 2004). Whilst this was acknowledged in the text in the case of the study by Gemmati et al (2004), no such recognition was afforded our ownUKstudy (Skibola et al, 1999). Moreover several published studies where no association with MTHFR 677 was observed are missing from the review, including data from Canada (Krajinovic et al, 2004)(n = 270), Turkey (Balta et al, 2003) (n = 144) and Slovenia (Petra et al, 2007) (n = 68). 
 
 
 
Fig. 1 
 
MTHFR 677CT and susceptibility to childhood ALL reproduced from Koppen et al, 2010. 
 
 
 
 
 
Fig. 2 
 
MTHFR 1298AC and susceptibility to childhood ALL, reproduced from Koppen et al, 2010. 
 
 
 
From their comprehensive meta analysis of 4894 individuals Pereira et al (2006) concluded that whilst the MTHFR 677 polymorphism is important for risk of ALL, it is confined to adults. This is supported by recent data from the largest study to date, which included 939 children with ALL recruited into the United Kingdom Childhood Cancer Study (http://www.UKCCS.org) (Lightfoot et al, 2010). 
 
Given the missing childhood data and the inclusion of adult data, we believe that the conclusion for a protective role for MTHFR among children drawn by the authors of the recent meta-analysis (Koppen et al, 2010), is misleading.