Genetic Risk Profiles for Cancer Susceptibility and Therapy Response

Helmut Bartsch, Heike Dally, Odilia Popanda, Angela Risch, Peter Schmezer

Recent Results in Cancer Research, Vol. 174 © Springer-Verlag Berlin Heidelberg 2007

Abstract

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: Interindividual differences in therapy response are consistently observed with cancer chemothera-peutic 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-hyper-sensitivity (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.

Introduction

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 such DNA damage, e.g., metabolic and DNA repair enzymes, are expected to modify cancer susceptibility (Bartsch and Hietanen 1996; Vineis 2004) as well as therapy response (Eichelbaum et al. 2006). Variations in an individual's metabolic and DNA repair phenotype have now been related to genetic polymorphisms, and many genes encoding carcinogen-metabolizing and DNA-repair enzymes have been identified and sequenced. Consequently, allelic variants (SNPs) that give rise to the observed variation opened new possibilities of studies on individual variability in cancer susceptibility that has been observed by epidemiologists. Scientists became aware that environmental and genetic factors interact in complex diseases.

The incorporation of studies of polymorphisms in metabolic and DNA repair genes into cancer epidemiology is particularly important for at least three reasons: (i) the identification of a subpopulation of subjects who are more susceptible to environmentally induced cancer would increase the power of epidemiological studies; (ii) the role of an etiological agent is strengthened when the enzyme(s) involved in its metabolism and damage removal are known; and (iii) metabolic polymorphisms may be particularly significant in relation to low-level exposures (Vi-neis et al. 1994), influencing the process of risk assessment and of setting acceptable limits of exposure, which should take individual susceptibility into account.

Genes and their products that are involved in cancer susceptibility may also modulate therapeutic outcome of anti-cancer drugs (Spitz et al. 2005). Interindividual differences in therapy response are consistently observed with most chemotherapeutic agents or regimens. Pharma-cogenetic investigations are trying to link inher ited genetic differences to the therapy response by specific drugs. The best recognized examples are genetic polymorphisms of drug-metabolizing enzymes, which affect 30% of all drugs (Eichelbaum et al. 2006), but inherited variations in DNA repair, in drug transporter genes and other drug target genes also likely contribute to the variability in the outcome of cancer treatment (Efferth and Volm 2005; Lee et al. 2005).

Given the number and variability in expression of carcinogen-metabolizing and DNA repair genes and the complexity of human carcinogen exposures, assessment of a single polymorphic enzyme (genotype) for risk prediction or therapy outcome is not sufficient. Therefore, so-called genetic risk profiles are being established taking into account genetic variation of a variety of genes and their products that affect the multistage carcinogenesis process. The utility of such profiles has been shown for instance for enzymes encoded by DNA repair genes that constantly monitor the genome to repair damaged nucleotide residues resulting from environmental and endogenous exposures. Inherited SNPs of DNA repair genes thus can also contribute to variations in DNA repair capacity and hence susceptibility to carcinogens. Recent studies suggested that the combined effect of multiple variant alleles may be more important than the investigation of a single SNP in modulating DNA repair capacity (Matullo et al. 2003; Mohrenweiser et al. 2003). A theoretical model was developed that underlies the rational for individualizing radiotherapy (Burnet et al. 1998). The gaussian distribution of the dose-response curve comprising sensitive and resistant subjects is likely to originate from the combined effects of several low-penetrance genes (Vineis 2004). Genetic profiles should help to identify high-risk individuals for environmentally induced cancer who subsequently can be enrolled in preventive measures. This type of approach may also help clinicians in the future to individualize and optimize anti-cancer drug therapy or radiotherapy and to predict side effects. Some of our current attempts to define such risk profiles are summarized below with special reference to polymorphic genes modulating tobacco smoke-induced lung cancer risk, chemotherapy response in lung cancer patients, and side effects in patients receiving radiotherapy.

Genetic Risk Profiles for Cancer Susceptibility

Genetic Variation in Metabolic Genes and Lung Cancer Risk

We have carried out analyses of a hospital-based case-control study, investigating lung cancer risk, for a number of genetic polymorphisms in metabolic genes, such as those coding for phase I activating and phase II conjugating enzymes. Genotype-specific modulation of lung cancer risk would not normally be expected unless there is environmental exposure to pro-carcinogens; therefore smoking and other environmental exposures must be taken into account. Clinically and etiologically there are important distinctions to be made between different histological tumor types. Given that some studies find an increased lung cancer risk for women compared to men, it is also interesting to stratify by gender where biologically plausible (Risch et al. 1993). Below we detail examples of our analyses where data were stratified by histology and gender.

Stratification by Lung Cancer Histology

Our studies on genetic polymorphisms and lung cancer risk show the importance of stratifying the analyses by lung cancer histology. Etiologically, small cell lung cancer (SCLC) and squamous cell carcinoma (SCC) have the strongest association with smoking because these tumors are found almost exclusively in smokers, whereas adeno-carcinoma also develops in a significant number of non-smokers (Muscat and Wynder 1995). Recently, mutational and epigenetic evidence has even been found for independent pathways for lung adenocarcinomas arising in smokers and never smokers (Toyooka et al. 2006). In addition, the histogenesis of SCLC is completely different from that of NSCLC because it morphologically and immunohistochemically belongs to the neuroendocrine tumors (Kayser 1992; Brambilla et al. 2005).

The MPO-463 polymorphism is a good example, showing that separate analysis of different histological types of lung cancer is important in risk assessment. MPO-463 has functional significance for metabolism and DNA binding of carcinogens present in tobacco smoke. We conducted a case-control study with 625 ever-smoking lung cancer patients that included 228 adenocarcinomas, 224 SCC and 135 SCLC, as well as 340 ever-smoking hospital-based controls. MPO genotyping was performed with capillary PCR followed by fluorescence-based melting curve analysis. Carriers of the MPO-463A variant genotypes showed a protective effect approaching significance (odds ratio [OR], 0.75; 95% CI, 0.55-1.01) when all lung cancer cases were compared with controls. Among histologi-cal types of lung cancer, a weak protective effect was found for both adenocarcinoma (OR, 0.81; CI, 0.55-1.19) and SCC (OR, 0.82; CI, 0.56-1.21) that was stronger and significant for SCLC (OR, 0.58; CI, 0.36-0.95; p=0.029) (Dally et al. 2002) (see Fig. 1).

Since 1997, controversial results have been published regarding the MPO-463A allele and its impact on lung cancer. This seems to be mainly due to differing proportions of histological types of lung cancer as well as differences in the number of never-smokers among cases and controls in several studies. The MPO genotype frequencies may also differ in nonmalignant lung diseases. As lung tumor development is frequently preceded by chronic inflammation of the lung (Mayne et al. 1999), with recruitment of large numbers of neutrophils to the lung and local release of MPO (Grattendick et al. 2002), future case-control studies investigating MPO genotype and lung cancer risk would ideally include information on previous lung diseases for both cases and controls. In conclusion, further (large) case-control studies should preferentially analyze smokers, include a separate analysis of his-tological types of lung cancer, and in such studies clinical assessment of and statistical adjustment for inflammatory nonmalignant lung diseases would be desirable (Dally et al. 2003a).

The highly polymorphic N-acetyltransferases (NAT1 and NAT2) are involved in both activation and inactivation reactions of numerous carcinogens, such as tobacco-derived aromatic amines. The potential effect of the NAT genotypes in individual susceptibility to lung cancer was examined in a hospital based case-control study consisting of 392 Caucasian lung cancer patients (152 adenocarcinomas, 173 SCC, and 67 other primary lung tumors) and 351 controls.

Odds ratio

Fig. 1 Risk, among smokers, for different types of lung cancer for carriers of the MPO-463A allele. The study included 340 ever-smoking hospital controls, 625 ever-smoking lung cancer patients with 228 adenocarcinomas, 224 squamous cell carcinomas, and 135 small cell lung cancer cases (see also Dally et al. 2002)

All lung cancer

Adenocarcinoma

MPO G-463A genotype

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