Cells in the body are permanently attacked by
DNA-reactive species, both from intracellular and environmental sources. Inherited and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and
DNA repair enzymes) can modify
cancer susceptibility as well as
therapy response. Genetic profiles should help to identify high-risk individuals who subsequently can be enrolled in preventive measures or treated by tailored
therapy regimens. Some of our attempts to define such risk profiles are presented.
Cancer susceptibility: Single nucleotide polymorphisms (SNPs) in metabolic and repair genes were investigated in a hospital-based
lung cancer case-control study. When evaluating the risk associated with different genotypes for N-
acetyltransferases (Wikman et al. 2001) and
glutathione-S-
transferases (Risch et al. 2001), it is mandatory to distinguish between the three major histological subtypes of lung
tumors. A promoter polymorphism of the
myeloperoxidase gene MPO was shown to decrease
lung cancer susceptibility mainly in
small cell lung cancer (SCLC) (Dally et al. 2002). The
CYP3A4*1B allele was also linked to an increased SCLC risk and in smoking women increased the risk of
lung cancer eightfold (Dally et al. 2003b). Polymorphisms in DNA repair genes were shown to modulate
lung cancer risk in smokers, and reduced DNA repair capacity elevated the disease risk (Rajaee-Behbahani et al. 2001). Investigations of several DNA repair gene variants revealed that
lung cancer risk was only moderately affected by a single variant but was enhanced up to approximately threefold by specific risk allele combinations (Popanda et al. 2004).
Therapy response: Inter-individual differences in
therapy response are consistently observed with
cancer chemotherapeutic agents. Initial results from ongoing studies showed that certain polymorphisms in drug transporter genes (ABCB1) differentially affect response outcome in histological subgroups of
lung cancer. Stronger beneficial effects were seen in
non-small cell lung cancer (NSCLC) patients following
gemcitabine and in SCLC patients following
etoposide-based treatment. Several DNA repair parameters (polymorphisms,
RNA expression, and DNA repair capacity) were measured in vitro in lymphocytes of patients before
radiotherapy and correlated with the occurrence of acute side effects (radio-
hypersensitivity). Our initial analysis of several repair gene variants in
breast cancer patients (n = 446) who received
radiotherapy revealed no association of single polymorphisms and the development of side effects (moist desquamation of the irradiated normal skin). The risk for this side effect was, however, strongly reduced in normal weight women carrying a combination of XRCC1 399Gln and APE1 148Glu alleles, indicating that these variants afford some protection against radio-
hypersensitivity (Chang-Claude et al. 2005). Based on these data we conclude that specific metabolic and DNA repair gene variants can affect
cancer risk and
therapy outcome. Predisposition to
hereditary cancer syndromes is dominated by the strong effects of some high-penetrance
tumor susceptibility genes, while predisposition to sporadic
cancer is influenced by the combination of multiple low-penetrance genes, of which as a major challenge, many disease-relevant combinations remain to be identified. Before translating these findings into clinical use and application for public health measures, large population-based studies and validation of the results will be required.