7.01.2.3.1 Genetic markers
Molecular biomarkers may be used to identify early responses to DNA damage and to assess cancer risk.45-47 Unscheduled DNA synthesis, chromosome aberrations, sister chromatid exchanges, and the micronucleus tests are some examples of these tumor markers. These markers are also referred to as genetic markers and can be scored in advance of preneoplastic lesions that are usually detected by histological methods.45-47 Genetic markers can also be used to show that the vast majority of cancers originate from a single stem cell. In addition to the clonogenic nature of cancer, there are numerous epigenetic events that create an environment for abnormal cell division, such as chronic inflammation or persistent stimulation of the immune system.
Solid tumors and a majority of hematological malignancies display various degrees of abnormality in the chromosomal karyotype including translocation, deletion, and duplications of chromosomes as well as more subtle aberrations such as rearrangements, deletions, and amplifications.48'49 All of these aberrations may have diagnostic as well as prognostic significance. Chromosome aberrations may be primarily related to the formation of a specific tumor and may be the only genetic abnormality present, as in case of chronic myeloid leukemia, chronic monocytic myeloid leukemia, and other malignancies.48,49 Since these types of translocation are never seen in normal cells, the chromosomal abnormalities may serve as useful tumor markers not only for diagnosis and assessment of disease stage, but also as indicators for a successful treatment or relapse.48-50
A number of chromosomal abnormalities are associated with predisposition to cancer.48,49,51 The molecular pathology of the chromosome rearrangement are well understood and have been shown to inactivate tumor suppressors like the Wilms' tumor gene52 and adenomatous polyposis coli. Other situations include disorders characterized by genomic instability as in xeroderma pigmentosa, in which there is extreme sensitivity to the effects of sunlight and carcinogens due to a reduced ability to repair damaged DNA, or as in Bloom's syndrome, in which there is a defect in a gene encoding a helicase leading to inefficient joining of nucleotides.53,54 The genes involved in these syndromes have been identified and tests have been devised to identify heterozygotes, thus making genetic counseling more precise.53,54
Certain carcinogens increase the risk of developing cancer by increasing the frequency of mutations or by interfering with chromosome organization.55 Genetic markers where the germline mutation or polymorphism is present at birth have been widely used in epidemiological studies, mainly to identify high-risk subjects. Much emphasis has been placed on the so-called major cancer genes that usually show a high penetrance, like BRCA1 and BRAC2. The prevalence of these mutations is very low but the risk of cancer associated with mutations in these genes is very high. As a consequence screening a whole population to detect these relatively rare genes would make no sense. Screening for polymorphism in so-called minor cancer genes such as metabolic and DNA repair genes makes more sense.57,58 Correct identification of the population frequency of a polymorphism including its function in noncoding regions as well as its linkage to other functional polymorphisms is key to each correlation or association study. For most of the known polymorphisms, the presence of an environmental cue may exacerbate the risk associated with such a polymorphism. Although polymorphisms in susceptibility genes are diffuse in the healthy population, their absolute frequency varies with ethnicity.57,58
Localized tumors can be removed effectively by surgery or radiotherapy, while metastatic disease requires relatively ineffective systemic therapy in particular in patients with solid tumors. The identification of patients with early stage disease is imperative to improve the chances of local control and cure. Therefore, candidate markers and genes may have a great potential for cancer screening to facilitate diagnosis, to monitor disease progression, and to assess the risk of recurrence after local therapy.
Thus far, biological markers (biomarkers) have been used to diagnose cancer, and to monitor disease progression and recurrence after therapy.59-62 Biomarkers have substantially improved the understanding of the molecular mechanism of action of carcinogenesis and risk, although they are more useful for monitoring the consequences of the disease and therapy rather than assessing the effects of risk factors on the onset of the disease. For example the serum-based markers calcitonin, prostate-specific antigen, and CA-125 are all elevated in medullary thyroid, prostate cancer, and a small subset of ovarian cancers, respectively.63-65 Urine-based biomarkers like bladder tumor antigen, survivin, and calreticulin have been recently used as diagnostic marker for bladder cancer.66
More recently the marriage between multiple biomarkers and bioinformatics has allowed the discovery and clinical validation of gene and protein profiles resulting in signatures that are characteristic of particular cancers. Cancer signatures are useful for predicting the outcome of cancer (association with cancer stages and prognosis) and/or cancer therapy, and to distinguish invasive versus noninvasive, metastatic versus nonmetastatic, and indolent versus life-threatening cancer types. This is best exemplified for prostate and breast cancers which are diagnosed relatively early. Using biomarker analysis performed on the primary tumor recommendations can be made as to which patients will benefit from no treatment or from localized treatment such as surgery and/or radiation or early systemic therapy, which should likely lead to improved therapeutic success rates and quality of life. Several potential prognostic biomarkers have been proposed and are being used for different tumors.58-66
The diagnosis of cancer is usually based on the recognition by a histopathologist of aberrant cellular patterns in a biopsy sample. More and more frequently, histological examination of fine needle aspirates is being used not only for making the diagnosis but also for evaluating the sites of spread, a process called staging. This examination is supported by DNA or protein-based assays that can be performed on the same biopsy. The use of the polymerase chain reaction (PCR) to detect mutant RAS genes in a fine needle aspirate from a pancreatic biopsy is one example of attempts to use our knowledge of oncogenes for clinical purposes.67
Unfortunately many of the current screening programs to detect early stages of solid tumors are not very efficient, as for example mammographic screening for breast cancer.68 Regular screening is relatively nonspecific and identifying benign lesions requires further investigation and biopsy. Large studies have shown that mammographic screening has only a small effect on overall breast cancer mortality and only in the 50-64 age group.68
Another example of relatively ineffective screening is the use of the biochemical tumor marker prostate-specific antigen to identify men with asymptomatic prostate cancer.65 This is because a large percentage of men over 50 years old actually have prostate cancer which remains confined to the prostate gland and has no significant impact on the individual's health. Removal of these localized tumors may not have any beneficial effect on overall survival as death is mainly caused by the effects of metastatic disease.
Therefore improved modern molecular screening approaches may identify: (1) high-risk patient groups who might benefit from more intensive screening as well as inclusion in trials of preventive agents; and (2) indicators of metastatic potential of a cancer providing a rationale for more aggressive therapy. Understanding the progressive accumulation of genetic damage of breast, pancreatic, thyroid, and colorectal cancer could lead to novel precancer detection systems. An example of this type of novel approach would be the identification by PCR of mutant RAS in fecal material to identify early colorectal cancer.69'70
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