RESPONSE: Re: Prognostic Significance of a Short Sequence Insertion in the MCL-1 Promoter in Chronic Lymphocytic Leukemia

Extract

The Correspondences by Freeman et al., Vargas et al., Iglesias-Serret et al., Nenning et al., and Dicker et al. address four key points regarding MCL-1 promoter nucleotide insertions.

Mutations or polymorphisms?

Because our control group was too small (n = 18) to determine population prevalence, we simply referred to these promoter changes as nucleotide insertions. Based on an analysis of 55 additional control samples, we have now found that the allele frequencies in the Saskatchewan population are 0.98 for the wild-type allele and 0.01 each for 6- and 18-nucleotide insertion alleles ( Fig. 1A and B ). The presence of these nucleotide insertions in other healthy populations is also reported in four of the five letters. Vargas et al. refer to their presence in the healthy controls; the frequencies of the +18 allele were 11.8% in Freeman et al., 17.5% in Iglesias-Serret et al., and 27.5% in Dicker et al., and the frequencies of the +6 allele were 20.3%, 12.5%, and 23.7%, respectively. The frequency of these nucleotide insertions in 134 patients with acute lymphoblastic leukemia reported by Nenning et al. is similar to what we observed in patients with chronic lymphocytic leukemia (CLL). Interestingly, Dicker et al. also report a novel 12-nucleotide insertion with a frequency of 1.4% in CLL case patients. Although there can be exceptions, the commonly accepted definition of a mutation is that the least common allele has a frequency of less than 1%. The presence of these nucleotide insertions in more than 1% of healthy population suggests that the MCL-1 promoter nucleotide insertions are polymorphisms, not mutations.