Genetic markers to identify lung cancer susceptibility

IT IS common knowledge that not everyone heavily exposed to carcinogens like cigarette smokers get lung cancer. This is explained by the fact that some people have an inbuilt mechanism that helps them flush the carcinogens out of the body. An yet to be published study by Dr. Rajani A. Bhisey at the Cancer Research Institute, Tata Memorial Centre, Mumbai, has identified the genetic markers that can be used to identify such individuals. The study was based on the presence of genetic markers in cigarette smoking individuals already afflicted with cancer in India.

``The primary factor that determines whether a person will get cancer is the level of exposure to carcinogens. Yet, a protective mechanism is seen in some people that helps them to overcome the ill-effects of carcinogens even when they are heavily exposed to it,'' Dr. Rajani said. Her investigations have led to the discovery of a possible susceptibility of individuals to cancer in the absence of glutathione S-transferase (GST), a detoxifying enzyme that helps in flushing out carcinogens from the body.

All carcinogens are lipophilic (fat loving) and have a tendency to get stored in a person's fat. In order to flush them out from the body these carcinogens have to be converted from lipophilic into water-soluble hydrophilic compounds. Hydrophilic compounds pose less danger to the body as these can be easily flushed out.

The conversion of lipophilic to hydrophilic compound or detoxification of carcinogens is achieved by the addition of one atom of oxygen to the carcinogenic compounds. Crytocrome P450- enzyme is one of the important enzymes that bring about this detoxification.

But the very process of detoxification also leads to the formation of reactive intermediates. These are formed during the detoxification process by the addition of oxygen to a carcinogen compound making them electron deficient. The electron deficient compound formed during the flushing out process can actually bring about cancer initiation. This happens when the reactive intermediates are attracted to compounds that have more electrons. For example, the guanine base of DNA that has an extra electron attracts the electron deficient reactive intermediates.

The combination of reactive intermediates with an electron deficient DNA base like guanine forms a DNA adduct. But DNA adducts can damage the DNA structure which in turn can lead to the formation of mutants when the DNA replicates. This is a cause for concern as it can lead to initiation of cancer in a person. This makes the availability of enzymes capable of neutralising cancer-causing compounds vital.

The human body is endowed with such enzymes which can prevent cancer initiation at two stages. GST for example, can neutralise the harmful effects of reactive intermediates thus preventing even the formation of DNA adducts. This is the first stage of prevention of cancer initiation.

The second level involves the repair of DNA damage. A crucial balance between the cancer initiation and neutralising enzymes both at the first and second stages (of cancer prevention) determines the susceptibility of an individual to cancer.

Dr. Rajani's study found the capability of GST alleles in neutralising cancer initiation at the first level. One GST allele is derived from each parent during fertilisation. Some individuals have only one GST allele derived from either parent while others have two alleles derived from both the parents. But in some cases the individual has no GST allele.

These null genotype individuals have poor detoxifiers to neutralise the reactive intermediates thus putting them in the high-risk category. Polymerase chain reaction (PCR) test of blood samples can help in finding out the GST status in an individual.

``We found a statistically significant number of individuals who are smokers and who are presently inflicted with cancer belonging to the null genotype category,'' Dr. Rajani said. ``With this finding it is now possible to say which genes predispose a person to adverse health conditions when they are heavily exposed to carcinogens.''

But is the presence of two GST alleles in a person a sure guarantee to remain cancer free? Quite possible as long as the critical balance between carcinogenic compounds and the carcinogen scavenging enzymes present in the body is not disturbed. Susceptibility to the disease would increase with higher level of exposure making it difficult to keep the disease at bay.

R. Prasad

Chennai

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