DTwo studies developed in a research line at the Cancer Genetics Laboratory of the Department of Clinical Medicine at the Faculty of Medical Sciences (FCM) at Unicamp identified polymorphic genes associated with acute myeloid leukemia and breast cancer. The work was supervised by the doctor and coordinator of the Clinical Oncology discipline at FCM, Carmem Silvia Passos Lima.

Genes act differently in metabolism

Polymorphic genes define eye color, skin color, hair type and other physical characteristics transmitted from parents to children. They also act in a variety of ways in the metabolism of substances that are toxic to the body or hormones, in the formation of blood vessels to irrigate cells and in the repair of damage to cellular DNA. In the same way that an individual can inherit blue or brown eyes from their parents, they can also inherit a greater or lesser capacity to inactivate toxic substances or hormones, for example.

According to Carmen, the normal cell that makes up the organs and tissues of the human body goes through a vital cycle: it divides, matures and dies. When damaged, generally due to abnormalities in one or more of its genes, it divides uncontrollably and produces numerous abnormal cells. Cancer invades neighboring structures and reaches other parts of the body through metastases. In this way, the destruction of various organs and tissues occurs and, if the sufferer does not receive adequate treatment, death.

Still according to Carmem, cancer results from the interaction between genetic susceptibility and factors or conditions related to the way of life and the environment in which individuals live, which, apparently, have different weights in the origin of the different types of the disease.

“It is already known in medicine that mutations in the BRCA1 and BRCA2 genes are associated with hereditary breast and ovarian cancer, which represent between 5% and 10% of the total cases of these diseases”, says the doctor.

According to the research director, another type of cancer, sporadic, is strongly associated with environmental factors, such as infections, the use of addictive substances, inadequate diet and occupational exposure to carcinogens. This type of cancer represents 70% to 85% of cases.

A third type of cancer, familial, can be identified in 10% to 20% of patients and appears to result from a genetic predisposition, such as that determined by polymorphic genes, associated with the action of environmental factors. “It is not the fact that someone was born into a certain family that causes them to get cancer. The individual may inherit a genetic predisposition, but to develop the disease they must be exposed to toxic substances or their own hormones. Therefore, the occurrence of this type of cancer will depend on what he does with his life, his habits and addictions”, explained Carmen.

Her interest in the subject arose when she was still a student at the Faculty of Medicine of Ribeirão Preto, at a time when she was not even thinking about pursuing a university career. Carmen noted that her ancestors on her mother's side, Italian immigrants, had an inadequate diet, drank wine daily and were often smokers.

Despite this “lifestyle”, they died at an advanced age from cardiovascular diseases. On the other hand, his ancestors on his father's side, four hundred Portuguese, were followers of a proper diet, did not have the vices of smoking or drinking, but died of cancers of different types.

“At the time, there was no clear explanation for this. Today, it is known that polymorphic genes involved in the metabolism of carcinogens and hormones can explain the greater occurrence of different cancers in members of the same family”, explained Carmen.

Contact with toxic substances can cause certain types of cancer, such as acute myeloid leukemia. Contact with the hormone estrogen is associated with breast cancer. Genes involved in the metabolism of these substances can alter the risk for diseases. The identification of their genotypes makes it possible to stratify individuals into groups at greater or lesser risk for cancer.

Thus, certain genotypes function as “markers” of individuals prone to acute myeloid leukemia or breast cancer. These individuals deserve to receive additional guidance for disease prevention.

Acute myeloid leukemia – In one of the studies, medical student Gabriela Góes Yamaguti evaluated three polymorphisms present in two genes that act in the metabolism of environmental carcinogens, such as polycyclic aromatic hydrocarbons (PAH) present in tobacco, gasoline, thinner, varsol, aguaráz and kerosene. To support her study, Gabriela evaluated patients with acute myeloid leukemia at the Unicamp Blood Center and normal individuals.

The study author found that individuals with the combination of variant genotypes of the three gene polymorphisms had a 12 times greater risk of developing acute myeloid leukemia.

“The ability of an individual to inactivate or activate PAHs is determined, at least in part, by polymorphic genes. Individuals with the most common, so-called wild genotype, of certain gene polymorphisms quickly inactivate these chemical agents. Those with the variant genotype are less effective in this action and, consequently, suffer more from its effects, which can induce mutations in the cell's DNA”, explained Gabriela.

Breast cancer – In the case of breast cancer, for the disease to develop, it is necessary to form blood vessels to irrigate, oxygenate and nourish the tumor. This is what the research of biologist and doctoral candidate Gustavo Jacob Lourenço showed. The gene that codes for the production of endostatin, a potent inhibitor of angiogenesis, is polymorphic in humans. The variant genotype of this gene polymorphism appears to produce endostatin with lower activity. Carriers of this genotype apparently produce a greater number of blood vessels than others and, therefore, are more susceptible to the occurrence of breast cancer.

“The study had already been conducted on men with prostate cancer, but not on women with breast cancer. The risk of breast cancer occurring in women with the variant genotype was extremely higher than that observed in women with the wild genotype,” said Gustavo.

The variant genotype was present in 5% of women with breast cancer at the Center for Comprehensive Attention to Women's Health (Caism), but was not identified in healthy women. The research also demonstrated that the number of blood vessels was greater in breast tumors from patients with the variant genotype than in breast tumors from patients with the wild genotype.

“Gustavo identified a group of women at high risk for breast cancer. As the number of vessels in tumors from women with different genotypes were different, it can be inferred that the polymorphism acts in the formation of the tumor's blood vessels. Gabriela's discovery was also very important. She identified a group of individuals at high risk for acute myeloid leukemia, a disease that, although uncommon, causes death in 60% to 70% of cases”, commented Carmen.

Ovary cancer – In the same line of research, doctor Regina Sagarra has been studying, for three years, inherited susceptibility to ovarian cancer associated with gene polymorphisms in the production of blood vessels. Ovarian cancer represents 4% of gynecological neoplasms and is an invasive and complex tumor with moderate sensitivity to chemotherapy. Treatment for patients with the disease therefore depends on a good surgical approach to completely remove the tumor and its extensions. The work is still in the sample collection phase from patients treated at Caism.

“We tried to find out whether isolated or associated genotypes of genes that stimulate or inhibit the formation of blood vessels alter the risk for ovarian cancer,” said Regina.

“Although therapeutic advances in oncology are undeniable, cancer is still considered a lethal disease. Some polymorphic genes can function as 'markers' of individuals at high risk for certain types of cancer, who deserve to receive special attention for disease prevention”, explained Carmen.

Patients at risk will be called

The calculation of the risk of occurrence of acute myeloid leukemia was carried out with patients treated at the Blood Center and healthy individuals from the Campinas region, called study controls. In total, more than 300 blood samples were collected. Controls and family members of patients from high-risk groups for acute myeloid leukemia will be called for a consultation by the oncogenetics group at the oncology outpatient clinic at HC at Unicamp.

“From an ethical point of view, it is our duty to educate these individuals about the risks of acute myeloid leukemia associated with exposure to environmental carcinogens. In general, they will be advised to avoid certain professions, such as working in petrochemical industries, steel industries and gas stations or contact with carcinogens, including tobacco”, explained Carmen.

Those who require special guidance on how to avoid occupational exposure to chemical agents will be evaluated by doctors in the field of occupational medicine.

Relatives of patients with breast cancer with the variant genotype will also be invited for consultation at the oncogenetics clinic so that other women at high risk for the disease in the same family can be identified.

“These patients will deserve special attention to prevent the disease with conventional exams such as self-palpation, mammography, ultrasound and magnetic resonance imaging of the breasts”, said Gustavo.

According to the author of the study, the research evaluated only an isolated sample of the population of women in the region. Additional studies with a larger sample size and involving women from other regions of the country will be essential to obtain consistent conclusions about the role of the gene in the risk of breast cancer.

“If the results obtained are confirmed, it seems justified to carry out genotyping as a routine test in adult women”, said Carmen. The cost of a genotyping is R$8,00 while a mammogram costs R$40,00 to R$260,00, according to a survey carried out by the team. However, according to Carmen, one exam will not replace the other. Genotyping will serve to identify women at high risk for breast cancer, who may undergo mammography earlier or more frequently than others.

HC service expands database

Scientists are awarded in Brazil and abroad