Secondary malignancies

An underlying genetic disorder is suggested for those cases myelodysplastic syndrome or acute leukemia that seem to have been caused by environmental toxins or exposure to cytotoxic drugs. The term “molecular epidemiology” was coined by Perera and Weinstein in 1982. It is defined as “the science that deals with the contribution of potential genetic and environmental risk factors identified at the molecular and biochemical level, to the etiology, distribution and control of disease in groups of relatives and in populations”. Polymorphisms of genes coding for proteins involved in DNA repair, DNA synthesis and drug and toxin metabolism have all been implicated in the causation of primary MDS and treatment-related MDS/AML.

Although decline in nucleotide excision repair, telomere maintenance and non-homologous end-joining leading to diminished stem cell functional capacity is a natural consequence of ageing It has been recently demonstrated that some patients with MDS have an inactivating Ser327Cys polymorphism in the gene coding for 8-oxoG DNA glycosylase (hOGG1), a key component of the base excision repair pathway. Other genetic polymorphisms that increase susceptibility to these diseases include the G/C variant at position 135 in the 5’ untranslated region of the RAD51 gene and the Thr241Met variant of the XRCC3 gene. Both genes are involved in DNA repair. These are but the latest examples of a huge area of research. Over 520 different amino acid substitution variants have been identified in the systematic screening of 91 human DNA repair genes for sequence variation. At least a third of these are classed as possibly or probably damaging.

The methylene tetrahydrofolate reductase (MTHFR) enzyme directs tetrahydrofolate towards methionine synthesis and away from dUMP synthesis, which is required for DNA synthesis and repair. Two MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. In a recent publication, both have been associated with the development of treatment-related MDS/AML.

Metabolism of cytotoxic drugs and potentially carcinogenic compounds is two-stage process. In phase I the substance is converted to its maximally mutagenic metabolite by cytochrome P450 enzymes. These enzymes are encoded by polymorphic genes. For example, the most abundant component of the cytochrome P450 system in human liver is CYP3A, which metabolizes etoposide, teniposide, cyclophosphamide, ifosphamide and the vinca alkyloids. A variant in the 5’ promoter region of the gene (CYP3A-V) diminishes production of the epipodophylotoxin catechol metabolite, which is a precursor of the DNA-damaging quinine. This variant is much less likely to be present in patients with treatment-related MDS/AML.

The phase I hepatic enzyme CYP2E1 metabolizes benzene to benzene oxide which spontaneously forms phenol and the same enzyme further metabolizes this to hydroquinone, a potent genotoxin. Detoxification of hydroquinone requires a phase II enzyme, nicotinamide adenine dinucleotide (P)H:quinine oxidoreductase (NQO1). Defects in the NQO1 pathway lead to accelerated telomere shortening and clonal hematopoiesis. The NQO1 polymorphism at codon 187 was studied by Naoe and his colleagues. The homozygous Ser/Ser genotype was significantly more common in treatment-related MDS/AML than in de novo AML or healthy individuals.

Anemic episodes preceding the development of acute leukemia after exposure to ionizing radiation were reported anecdotally in the early literature. Survivors of the atom bomb attacks in Japan exhibited features in their blood that would be today termed as MDS. It is now well established that secondary MDS occurs following bone marrow injury by alkylating agents and ionizing radiation. It is important to recognize that treatment with other cytotoxic and immunosuppressive agents may also lead to the development of MDS. The effect of the topoisomerase II inhibitors such as the epipodophyllotoxins and the anthracyclines and mitoxantrone in generating chromosomal translocations, particularly affecting the MLL gene at chromosomal band 11q23, are well known. Less familiar is the effect of antimetabolites such as 5-fluorouracil, azathioprine and fludarabine. Furthermore, the use of G-CSF for neutropenic support or to generate autologous stem cells for peripheral blood harvest has been implicated in the causation of secondary MDS.

The molecular epidemiology of MDS is extremely complex and we little understand how silent polymorphisms interact with unknown genotoxins to produce the disease. In the next decade we must expect that greater unraveling of this conundrum will lead us to both prevention and therapy.