Due to progress in medical and biotechnological studies in the recent years scientists have focused on tumors not only within macroscopic or pharmacological perspectives, but also within molecular and cytogenic ones. Molecular epidemiology, a new area of medical knowledge has been singled out. It is currently oriented at the search for biomedical markers which not only signal the early phase of cancer, often undetected in accessible imaging methods, but also indicate higher risk of incidence and they may be used in so-called groups of high-risk. In addition, research is little invasive, as biomarkers are easily accessible in the cellular material or biological liquids.
However, molecular epidemiology cannot replace traditional epidemiology but is a tool enabling its supplementation. Namely, traditional epidemiology studies affiliation between exposure factors (for instance geography, diet, exposure to a given chemical, physical, biological factors) and cancer incidence rate; molecular epidemiology studies, on the other hand, the analysis of factors found in the vast niche between the two (the level of cancer gene, its metabolites or adducts from DNA, mutations, genes’ activations and deactivations and finally the level of cells proliferation stimulation – neoplasis. Nowadays, using tumor markers is not only about early diagnosis, but also about forecasting and monitoring the therapy. Some of them work well in the screening tests. Unfortunately, apart from a quarter million of publications on markers, it is not clear whether substantially changed level of a determined factor in the serum is sufficient to define the cancer recurrences.
Measurement of adducts. the measurement of adducts, which generate cancer genes or their DNA metabolites, seems to be the best biomarker as far as defining the level of exposure to cancer diseases. It creates s the possibility to pick up persons substantially at risk from the population, but it may also already determine the degree of the genome damage by mutations. Research has also been conducted, which pointed to the fact that the measurement of adducts may be important in monitoring therapies using pharmaceuticals (CDDP, alkalizing factors).
Taking into consideration the epidemiological factors, a division of biomarkers has been proposed, which may reflect in its scheme the scope of molecular epidemiology. Biomarkers of exposure to cancer genes substances. Two groups have been distinguished in this category. The first one comprises the biomarkers which may be found in soil, water and air, the second – those found in living organisms. In the latter one, internal doses of biomarkers are classified (determination based on the amount of cancerogenic chemical substance or its metabolite, which penetrated the organism; mutagenic activity detected thanks to laboratory tests taking advantage of cancerogenic substance interaction or its bacteria DNA metabolite – Ames test or DNA of other cells) and doses of biologically effective biomarkers (the level of cancer gene adducts, most often from DNA).
correlation between the number of smoked cigarettes and the type of acetylation and the incidence rate of urinary bladder cancer. It has been proven that among slow acetilators the level of adduct 4-aminobifenyl (a substance found in the nicotine smoke) hemoglobin is higher than among the fast ones and that the number of smoked cigarettes does not have a significant influence. It binds the level of adduct with the features of metabolic predispositions of a given person and it may suggest the fact that in some cases persons with a higher genetic predisposition may have a higher incidence rate as for given types of tumors even if the exposure to cancer genes is lower.
The connection between the consumption of aflatoxine B1 and the liver cancer incidence rate. The level of an adduct which aflatoxine B1 creates with DNA (aflatoxine-N7-guanine) is higher in the urine of persons exposed to this cancerogenic mykotoxine. A correlation has been found between the level of aflatoxine-N7-guanine in the urine and the liver cancer incidence rate. It is the example of DNA cancer genes adducts released during repair processes. In this example what focuses our attention is the simplicity and accessibility of biological material while it is ambiguous whether aflatoxine-N7-guanine solely comes from DNA or also from RNA.
A connection between the length of exposure to cancer genes and the number of DNA-protein crosslinks. One of the results of DNA-protein crosslinks creation may be the inactivation of 53p gene. Shaham showed the correlation between the years of exposure to formaldehyd in conditions of risk and the number of crosslinks. It is suspected that other permeable cancer genes such as chrome, nickel, alkalizing factors, cisplatine or UV radiation give similar results.
Biomarkers of health results induced by cancer genes and their metabolites. They provide information about biological and biochemical changes that took place in the organism’s cells as a result of an interaction of cancerogenic substances or their metabolites on them. Here the attention is focused on mutations, genes’ activations and deactivations, changes in chromosomes, oncoproteins and antioncoproteins presence.
A connection between the appearance of detectable changes in chromosomes and the amount of cancer gene dose, and the time of exposure. Peripheral blood lymphocytes are most often the research material (as in the majority of biomarkers of health results determination) which with a certain probability reflect changes in all the chromosomes of the target tissue cells which is very often inaccessible for examination purposes. The frequency of SCE (sister chromatides exchange) may serve as an example in five days after acute exposure to ethylene oxide. Using cytogenetic examination (e.g. SCE or CA chromosome aberrations) as a biomarker cannot be treated as sufficient to get decisive results.
The accumulation of genetic irregularities in many genes clinically supersedes the appearance of the disease. Mutations in p53 gene and in the race gene appear in the saliva of the examined group already about a year before the clinical appearance of lung cancer. What is more, a specific place of the sequence change seems to correspond to the presence of a given mutagenic factor.
Determining oncoproteins in the biological material (or mutated antioncoprotein) may supersede the appearance of the disease for a few years. The research that highlights it is not, however randomized and many times it is the description of given cases, therefore its results should be carefully analyzed. Among others, the race oncoprotein p21, oncoprotein fes or beta - the transforming growth factor - are brought into discussion while exposed to asbestos, benzopirene (polycyclic aromatic carbohydrates) or polichlorised bifenyls. There is not doubt that the presence of p53 protein in the examined material indicates its mutation (half-life of mutated p53 protein equals to 12 hours whereas the one not modified up to 20 minutes), however, taking into consideration not fully clear and undefined role of the “genome guard” sequence change in the process of tumor transformation one should not draw snap conclusions.
Biomarkers determining individual sensitivity towards cancerogenic substances activity. They examine individual differentiation in response to the activity of cancerogenic factors. This group reflects genetic or acquired factors which influence the character and the extent of cells’ responses to the exposure. They identify those in the population who are genetically, or in an acquired manner, more at risk as for cancer disease when we take into consideration a given exposure to cancer gene.
For years, in order to determine biomarkers of sensitivity, tests have been used that examined the level of medicine in the serum and clearance of its metabolized derivative in the urine, as determining the polymorphism of enzyme which was to be defined. Currently the PCR reaction is used to achieve this, which directly defines changes in the nucleotides’ sequence that codes a given enzyme. Thanks to these methods genotypes of such enzymes that metabolize cancer genes as transferase S-glutatione, cytochrome CYP1A1 and CYP2D6 or N- acethylotransferase were found.
Another group of sensitivity biomarkers are those, which determine the level of genetic differentiation influencing repair processes activity. This group is crucial as it allows detection of the presence of mutated genes inherited after parents in the offspring, such as APC gene or BRCA 1. In such situations the early stages of cancerogenesis are omitted, therefore one should not doubt the arguments for the research in this direction.
Biomarkers specificity depending on the location and the type of the tumor:
Sex cells tumors. Alpha-fetoprotein (AFP), human chorionic gonadotropine (hCG) and LHD are sex cells tumors markers known for 20 years. Because of their diagnostic properties, they are unconditionally recommended already to diagnose diseases, as well as to define the level of progression, forecast, monitor treatment and define the presence of recurrence. No useful values were found for screening. In the case of testis seminoma determining the level of placenta-alkalic phosphatase, which is ectopically released in 80% of cases (the remaining 20% is released by hCG) was found useful. AFP, hCG and LDH are the indicators of tumor progression level recommended by AJCC (the American Joint Committee on Cancer).
Monitoring their concentration in the serum completely entitles to state whether there are metastases or defining the level of response to the chemotherapy. The fall of the level of AFP and hCG after orchidectomy should be correlated with the normal time of half-life of these compounds (for AFP 7 days, hCG – 3 days). Rapidity of changes during first six weeks of the chemotherapy cycle may indicate contingency of recurrences in the first month after it has been finished, that is why the measurement of AFP, hCG and LDH concentration is recommended every week. Undoubtedly, it is one of the greatest achievements of medical studies in a de facto multidisciplinary area of oncology and a lot of research is done in the direction of similar achievements. Norms [12]: AFP in serum: more than 12U/ml (pregnant women 38 – 160 U/ml), waiting for the results: 1 – 2 days; LDH in serum: adults 240 – 480 U/l. Tumors of the lower part of alimentary tract (colon, rectum)
CEA (carcinoembryonic antigen) is present in the prevailing majority of cases in the blood serum. However, it does not justify using it to determine it in screening or for early diagnosis purposes but it is important in forecasting and defining the level of progression. It is a preoperative test recommended by American Cancer Society as an aid to define the histopathological progression of an ulcer and to determine the scope of resection. In the aftersurgery monitoring after resection of isolated metastases to liver CEA should be determined every 2 – 3 months in the two first years since the surgery. Its higher level leads towards metastatic disease. Similarly, when solely a tumor is due to resection, a higher CEA level in at least 2 tests taken in the same frequency may suggest the progression of the disease. In conclusion, determining CEA is helpful while monitoring the therapy but its character and specificity is insufficient to diagnose colon and rectum tumors. Norms: Tumor – foetal antigene (carcinoembryonic) in serum: smoking persons below 5.0 ng/ml, non-smokers below 3.0 ng/ml, results in 2 – 3 days. Breast cancer.
A basic examination recommended by many centers involves determining the level of estrogen and progesterone receptors in all women (in the pre- and post- menopausal age) as an indicator of responses to the hormonal therapy. In the case when the presence of metastases is confirmed determining the level of receptors is used only if its results have influence on the further treatment. There are also no doubts about determining the level of over expression HER-2 / neu (c-erbB-2) while qualifying to a trastuzbam therapy. CA 15-3 and BR 27.29 are definitely the best breast tumors markers to determine in the serum but because of small specificity, low sensitivity in the early phase of the disease and controversial application while bringing therapeutical benefits they are not recommended in the early detection, to screening or staging. Both CA 15-3 and BR 27.29 have the recommendation of Food and Drug Administration to monitor therapy in advanced breast cancer. However, as the benefits after monitoring remain controversial, the appropriateness for determining these markers remains unclear. They may be helpful while defining the failure of the treatment (when clinical changes indicate it) and monitoring the clinical course of breast cancer, which may raise some ethical doubts. Determining CEA level is not either applied in the early disease detection, screening, determining the level of progression or forecasting in the breast cancer cases. Some American centers accept the possibility to use it to monitor the therapy, however due to its small specificity it should closely correlate with the clinical picture.
Norms: Tumor antigene Ca 15-3 in serum : over 30U/ml, results in 2 – 3 days. Ovary cancer CA 125 is definitely the best marker for an early diagnosis of ovary cancer (or even screening) provided women have a positive family history. It helps to differentiate the tumors found in the pelvis on benign and malignant among women in their postmenopausal age. A fall of CA 125 level is discernible after ovaries resection or after cytotoxical chemotherapy. It does not play a significant role in staging, therefore the results cannot be based on TNM classification. It has not been precisely defined whether and how often the concentration of this marker in the serum should be determined, it is suggested to do it once every 2-3 weeks (in the case of its level being doubled a pelvis computer tomography is advised). One should remember that a progression of tumor changes may take place without a substantially changed level of CA 125. Norms: Tumor antigene Ca 125 in serum: above 35U/ml, results in 2 – 3 days. Prostate cancer.
PSA (prostate specific antigen) has been the best known and the most useful tumor marker. Its application begins with screening. Together with per rectum examination or DRE (digital rectal examination) it gives a strong correlation and it is an indication for biopsy with taking a segment of prostate, which is the best diagnostic tool of changes occuring around prostate. Its role in staging has been proven, although due to the lack of official recommendations only auxiliary significance can be ascribed to it. Undoubtedly, the level of PSA is useful in monitoring prostate cancer therapy, however one cannot focus on these measurements solely. There have been cases when the result of determining the PSA level biochemically indicated the presence of metastatic changes, whereas no such changes occurred in fact. Nevertheless, one cannot undermine the importance of PSA concentration test in serum and one has to bear in mind that together with the clinical picture it constitutes a powerful diagnostic tool. Norms: PSA in serum – total: Age 40 - 49: < 2.5 ng/ml, 50 - 59: < 3.5 ng/ml, 60 - 69: < 4.5 ng/ml, 70 - 79: < 6.5 ng/ml; PSA in serum – free fraction: norm up to 0.9 ng/ml. Free PSA/total PSA below 0.1 – high probability of prostate cancer; free PSA/total PSA above 0.25 – high probability of no tumor changes. Results in: 2 - 3 days. Lung cancer.
The measurement of the level of tumor markers is not often found in the cases of lung cancer. Out of a few applied, NSE level measurement is used when differentiating small celled lung cancer. Its serial measurement after the first therapy of this type of a tumor (resection, chemotherapy) may be helpful in determining usually asymptomatic course of the early recurrence or resection completeness. Tumors of neuroendocrinal organs
Tumors of neuroendocrinal organs are rare. Determining the biomarkers may contribute to their differentiation, among all neuroblastomy and pheochromocytomy. In such cases the level of catecholamines, vanillymandelic acid and/or vanillic acid in the urine are determined. Thyroid cancer.
The level of thyreoglobulin is helpful while diagnosing and monitoring the thyroid cancer. A correlation has been proven also when measuring the concentration of calcitonine and the appearance of medullary thyroid cancer.
Markers’ prevalence, data verification, benefits and limits. Determining the level of tumor markers in the serum usually depends strictly on clinical needs. As the treatment algorithms are due to constant modification and the development of biotechnology takes advantage of modern technologies and finds more precise pictures of clinical state, the use of tumor markers also gains in popularity. As it has been mentioned several times, the analysis of the laboratory results has to closely correlate with the features presented in the clinic and it cannot be a sole confirmation of diagnostic presumptions. Obviously, it does not change the fact that they are essential and valuable in the doctor’s activity. Together with doctor’s practical skills they become a powerful tool supporting his or her work. It is worth bearing in mind some essential cues, such as the latency period, which has to take place since implementing the mode of action (e.g. surgerical or pharmacological) for laboratory markers to be a valuable source of information about the patient’s state and not introducing unnecessary confusion.
Being acquainted with the mechanisms of biomarkers concentration changes substantially influences the multidisciplinary image of the patient’s care and, despite the fact that many questions remain unanswered, one should hope that the progress of medical studies will provide the answers in the years to come.
Radoslaw Pilarski is a PhD candidate working on anticancer properties of Uncaria tomentosa - uncariatomentosa.com uncariatomentosa.com - at PAS, Poland. mLingua Worldwide Translations, Ltd. - mlingua.pl mlingua.pl - provides professional language translations.
Tags:
breast cancer,
chemotherapy,
lung cancer,
prostate cancer,
thyroid cancer
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Tags: breast cancer, chemotherapy, lung cancer, prostate cancer, thyroid cancer
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