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Epidemiology

Defined traces

Genes and cultural habits affect the risk of the growth of head and neck tumors

It is now a little easier to understand how malignant tumors in the mouth, pharynx, larynx and thyroid, the four most common forms of cancer in underdeveloped countries such as Brazil and India appear. An extensive genetic analysis carried out by sixty five (65) São Paulo researchers has unveiled that around 950 genes that, are either more active that normal, or less active, upset the regular functions of the cells and favor the appearance of these problems, almost always curable if identified in their initial phase. The next step for this study, published this month in Cancer Research, is to verify the degree of activity of each of the genes in relation to these tumors, which each year victimize around 22,000 people in the country and in the most serious cases deform faces and make speaking and eating difficult (brain tumors are treated separately). From the in-depth analysis of the genes, which will consume some years of research, new forms of treatment and tests that could precociously detect tumors in the mouth, pharynx, larynx and thyroid, today recognized only through clinical examinations, could spring forward.

In parallel, research groups essentially made up of medical doctors, in three Brazilian and one Canadian institutions, have related the location of tumors with habits and the history of the patient’s life, showing the main reasons that increase the possibility of the development of cancer of the head and neck in the Brazilian population, which has one of the highest rates of these types of cancer in the world, with around ten cases for every 1000,000 men, and three cases for every 100,000 women.

Besides the now uncontrollable genetic inheritance that increases from 1.2 to 8.5 times the chances of developing a cancer, depending on the parental background and the location of the tumors, factors relatively controllable have proved to be important as causes of these problems. Drinking too much beer, wine or harder drinks, increase between 2 and 12 times the risk of the development of a cancer, especially in the mouth or the pharynx, which show themselves in the form of painless wounds that do not heal.

Recent studies give dimension to the risks of cancer, evidently of higher risk for those who smoke a lot, followed by a diet poor in fruit and vegetables or even for those who do not brush their teeth at least once per day. The numbers are worrying, but should not be taken as alarming as they indicate probabilities and not certainties. Those who drink alcohol or smoke run a greater risk of developing cancer in the same way as a person who goes out into the streets today is more subject to being run over that another person who passes his time at home.

Prospecting
The genetic analysis is a consequence of the Human Genome Cancer Project, funded by FAPESP and the Ludwig Institute for Cancer Research. In March of 2001, the Cancer Genome had entered into its final stage, with the publication on the internet of a data bank with 1.2 million fragments of the genetic material of tumors from seven regions of the body. One sixth of these fragments – or 213,000 unconnected strips of DNA – had been related to cancers of the mouth, pharynx, larynx and thyroid. This was a volume of information thirty five times greater than that produced throughout the world at that moment in time.

“In the face of such information, we decided to analyze this rich material before another group from abroad became interested in the data”, explains the biologist Eloiza Tajara, from the São Paulo State University (Unesp) in Sao José do Rio Preto, who coordinated the study in partnership with the geneticist Emmanuel Dias Neto, from the University of Sao Paulo (USP). “During 2001, when I had worked at the Cancer Hospital, I had the desire to produce results with a greater possibility of practical application”, says Dias Neto, one of the inventors of a DNA sequencing method known as Orestes, which allows the finding active genes and has shown itself very helpful for the selection of genes in this study. Dr. Dias Neto transferred to USP’s Psychiatry Institute the following year, got himself involved in other research, but did not leave to the side the work that he had initiated.

During almost three years, the team under his direction fitted together the 213,000 DNA fragments from the tissues of the head, throat and thyroid. Of these around 190,000 were from the tumors of the mouth, pharynx, larynx and thyroid, collected by the surgical team headed by Dr. Luiz Paulo Kowalski, from the A. C. Camargo Cancer Hospital.  To these samples of abnormal tissue were added some 23,000 fragments of genes of healthy cells, which would serve as a standard for comparison. After having eliminated the repeated or duplicated strips of genes, the researchers attained the mark of 4,100 active genes only in these four tumors. Among them there are almost 950 genes with some new form of alteration capable of modifying the behavior of the cells and making them multiply in an uncontrolled fashion, bringing about a tumor. A further 500 genes, whose functions are unknown, were also found, half of them located on a strip of genetic material on which it had been believed that there were no genes.

A more detailed analysis of these 950 genes should point out their characteristics for the determined forms of cancer: these are the oncogenes, which could function as the disease’s biological markers, an example being the gene responsible for the production of a factor related to zuotin 1 (ZRF1), a protein involved in the control of cellular multiplication. The São Paulo team verified that in general this gene is around two times more abundant in mouth tumors and up to thirteen times in cancer of the larynx, the cartilaginous tube that allows the passage of air to the lungs. The identification of the oncogenes is important because the proteins produced by them, when found in the blood, could indicate the spread of the cancer through the body. According to Dias Neto, in this survey genes active only in the healthy cells of these organs will be found, which could  be used in genetic therapies to combat the tumors.

Habits and risks
To these discoveries can be added those made by Dr. Kowalski’s teams from the A. C. Camargo Cancer Hospital, and from the Brazilian epidemiologist Eduardo Franco, currently at McGill University in Canada. After having interviewed 1,568 people without cancer and a further 784 with tumors of the head and neck, taken care of at three state capitals, namely – Sao Paulo, Curitiba and Goiania -, they clarified the risk factors, genetic and environmental, associated with the development of tumors of the mouth, pharynx, larynx and thyroid, in particular a very aggressive type, the squamous cell carcinoma (SCC), responsible for 90% of the cases of cancer of the head and neck. The findings – made in collaboration with Benedito Oliveira, from the Erasto Gaertner Hospital in Curitiba, and Maria Curado from the Araújo Jorge Hospital in Goiania – have resulted in ten scientific papers published over the last fifteen years in specialized international magazines.

Of all of the risk factors evaluated, one of them cannot be avoided: hereditary. Anyone who has a close relative – fathers, brothers or sons – with a malignant tumor in any part of their body runs the risk, from 1.2 to 2.4 times greater, of developing cancer of the head or neck. This possibility varies considerably depending upon the location of the tumor and the parental relationship: if a family member had a cancer of the head or neck the risk is 3.7 times greater and can reach 8.5 times in the case of the affected person being a brother or sister, according to the analysis of these researchers published in the International Journal of Cancer.

But one really needs to dedicate special attention to other factors, very often controllable.  Drinking huge quantities of alcohol, a habit of 13% of men and 3% of women in Brazil, increases the risk of developing cancer, specially in the mouth and pharynx, possibly because of action of the alcohol itself or of its byproducts upon the layer of cells that covers these organs. According to another article from this group of doctors, published during 2001 in Cancer Causes and Control, the probability of developing some of these cancers grows at least four times more for anyone who drinks a glass of beer per week over a fifteen-year period. And the risk is six times greater for the person who drinks up to ten doses of cachaça per week or ten times more elevated for those who, instead of cachaça, prefer a good whisky.

The probability of developing a larynx tumor, which shows itself in the form of throat pain and long lasting hoarseness, goes up at least five times for the people who smoke any type of tobacco – a habit maintained by one third of the adult population – and remains between eight and eleven times greater for those who smoke an industrialized cigarette, loose tobacco or a pipe. The results published in 1999 in Epidemiology also showed that this risk diminishes considerably between five and ten years after having quit smoking (industrialized cigarettes or loose tobacco). Besides the physical and functional damages, an additional complication came forward: the loss of self esteem, which leads almost half the people with head or neck cancer to suffer depression – and one in every one hundred to take their own life, the second highest level of suicide among those with cancer.

Some Brazilian cultural habits also show themselves to be dangerous. The use of wood burning fires, as yet common in the interior of the country, raises by 2.7 times the probability of a person having one of these four forms of cancer, the researchers related in the International Journal of Epidemiology. It is the burning of wood or charcoal that releases gases and particles which are suspects of causing cancer in those who inhale them. Similar indices were observed among people who do not maintain good mouth hygiene. By not brushing their teeth at least once per day, they double the risk of having tongue cancer and increase by 2.4 times the chances of cancer of the pharynx, the muscular tube that connects the mouth to the digestive system and the larynx. The inappropriate use of dentures, which are ill-fitting and hurt the gums, multiplies by nine the occurrence of tongue cancer, in accordance with an article in Oral Oncology.

Misinformation worsens this picture, which it is already worrying. In general, people do not recognize the initial symptoms of cancer – lesions in the mouth or a persistent sore throat – and take a long time to find a doctor or dentist. Many health professionals, for their part, take up to three months to complete a diagnosis. This is a lot of time. The main reason for the non-success of therapy for head and neck cancer in the country, this slowness produces serious consequences: when a patient is sent to a cancer specialist, his/her illness is at such an advance stage that there is very little to be done.

In a recent analysis, published in January 2004 in Head and Neck,  Kowalski’s team verified that the therapies used at the Cancer Hospital of Sao Paulo are as efficient as those applied at one of the most important cancer centers in the world, the Sloan Kettering Memorial Hospital in the United States. “The difference is that here two thirds of the patients reach the hospital with a tumor in an advanced stage, whilst there, with the diagnosis occurring earlier, only one third of the patients have an advanced stage cancer”, explains Kowalski. Solutions? “We must carry out public campaigns to alert people to the risk factors associated with these forms of cancer and the initial signs of the illness, as well as, clearly, improving the training of our body of doctors and dentists.”