Mammography and Beyond Developing Technologies for the Early Detection of Breast Cancer (2001) / Chapter Skim
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3 Technologies in Development: Genetics and Tumor Markers
3 Technologies in Development: Genetics and Tumor Markers
Pages 105-132
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From page 105... ...
, and thus, the search for genetic markers continues. In addition, scientists are also looking for biomarkers in serum, as well as breast tissues and fluids, that may predict the risk for cancer or reveal the presence of cancer.
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From page 106... ...
Much of the research on the biology of human breast cancer to date has been done with biopsy tissues obtained in the process of diagnosing a breast abnormality and then preserved in specimen banks. The goal of establishing such banks is to make samples available to scientists studying genetic alterations and changes in gene expression in cancer cells by the methods described in this chapter.
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From page 107... ...
Another major goal of this research is to identify the appropriate biological markers to be used for functional imaging methods, as described in Chapter 2. In other cases, such as the analysis of blood samples or breast fluids, the goal is to predict a woman's risk of developing breast cancer or to identify markers of malignancy before the cancer can be detected by traditional imaging methods or physical examinations.
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From page 109... ...
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From page 110... ...
Most of the currently available tests are labor intensive, but a recent technological advance known as "DNA microarrays" could potentially allow faster high-throughput analysis of samples. Microarrays, which first emerged in the mid-199Os, consist of thousands of different oligonucleotides spotted onto specific locations on glass microscope slides or silicon chips, which are then hybridized with labeled sample DNA (Figure 3-1~.
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From page 111... ...
Furthermore, there is significant heterogeneity among the mutations in these large genes that can predispose individuals to breast cancer, and each of the available tests has limitations in the types of mutations that it can reliably detect. Thus, selection of a particular test and interpretation of the results of that test can be difficult unless an affected relative has already been shown to carry a specific mutation.
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From page 112... ...
Because of the uncertainties in interpreting negative results, as well as the implications of positive results, genetic testing for breast cancer susceptibility should be accompanied by genetic counseling before and after the test. However, no standard of care for such counseling exists.
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From page 113... ...
has recently launched testing services in Canada, lapan, Ireland, and the United Kingdom through exclusive licenses with laboratory service companies in those countries (Cancer Letter, March 2000~. In the United States, Myriad recently signed a multiyear agreement with several large medical insurers to include the tests for BRCA in its list of covered services for its members (Cancer Letter, February 2000~.
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From page 114... ...
The majority can be accounted for by mutations in the BRCA1 and BRCA2 genes, but other genes have also been linked to a significantly increased risk for breast cancer. For example, families with Li-Fraumeni cancer syndrome, which is most often due to mutations in the p53 tumor suppressor gene, show increased susceptibility to a variety of cancers, including breast cancer (Malkin et al., 1990~.
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From page 115... ...
A major goal in studying polymorphisms in women with breast cancer is to more accurately predict which individuals are likely to develop breast cancer or to die from the disease. Polymorphic sites in many genes have been studied to determine whether they are associated with an increased risk for breast cancer, and a number have been reported to confer elevated risk.
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From page 116... ...
The two organizations plan to specifically investigate associations between genetic polymorphisms and breast cancer (Cancer Letter, March 2000)
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From page 117... ...
Most of the techniques described in this section are being used as research tools in studies with biopsy tissues, with the hope that the knowledge gained from this research will eventually be used to more accurately diagnose breast cancer and predict outcomes. SOMATIC GENETIC ALTERATIONS Somatic alterations in cancer cells include genetic changes such as amplification and deletion of DNA sequences, chromosomal rearrangements, and base change mutations.
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From page 118... ...
, as well as later-stage cancers, but to date it is not yet clear whether specific LOH events are associated with progression to invasive or metastatic cancer (Alfred and Moshin, 2000~. Epigenetic Changes Scientists have traditionally focused on changes in DNA sequences like mutations and deletions as the cause for altered cell functions in human cancer.
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From page 119... ...
Yan et al., 2000~. Although the method has thus far been used to examine only cultured cell lines, results from preliminary studies indicate that analysis of hypermethylation patterns could potentially be used to classify tumors.
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From page 120... ...
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From page 121... ...
Using microarrays to examine differences in mRNA expression patterns, breast tumors could be classified into subtypes that related to physiological variation, but it is not yet known whether different subtypes are associated with different clinical outcomes or response to therapy (Perou et al., 2000~. The relative levels of mRNA species can be regulated at the stage of gene transcription or RNA degradation.
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From page 122... ...
Protein Expression and Function Knowledge of the RNA expression patterns of cells is not sufficient for determination of cellular behavior. The RNA expression level is not necessarily indicative of protein levels, because protein expression can be modulated at various stages, from the regulation of mRNA translation into protein to the targeting of the protein for degradation pathways.
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From page 123... ...
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From page 124... ...
However, this method requires large amounts of protein and thus has been limited to cultured cells or homogenized tissues that contain a variety of cell types. Recent technological advances, including laser capture microdissection, new methods for cell sorting and mass spectroscopy4 and improved bioinformatics may soon allow highthroughput analysis of the specific cell populations within tissues and tumors (Liotta and Petricoin, 2000~.
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From page 125... ...
It would therefore be advantageous to study normal breast development and function, as well as breast cancer etiology, progression, and treatment, with human mammary cells. A major goal in this area of research is the isolation of specific cell lines derived from a variety of relevant human tissue types, including normal breast epithelium, atypical hyperplasia DCIS, early and late stages of breast cancer, and histologically normal tissue adjacent to the tumor.
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From page 126... ...
COLLECTION AND ANALYSIS OF BREAST FLUIDS Adult breast tissues secrete fluid into the breast ductal system even in the absence of pregnancy and lactation, and this fluid can be aspirated using breast massage and a modified breast pump. A number of studies have been undertaken to determine whether such nipple aspiration fluid (NAF)
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From page 127... ...
Molecular biology-based assessment of cells obtained by NAF or breast ravage could potentially identify genetic or epigenetic changes, in addition to cellular morphology, that could perhaps be predictive of breast cancer. Such assessment could include examination for chromosomal abnormalities or the use of DNA arrays to identify changes in the DNA of the cells.
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From page 128... ...
The small prospective study found that RCP levels were significantly elevated in women with breast cancer and that the RCP assay could predict the presence of breast cancer with a sensitivity of 92 percent, a specificity of 88 percent, a positive predictive value of 89 percent, and a negative predictive value of 92 percent. However, the results of this very preliminary study have not yet been validated, and the test has not been examined in the setting of breast cancer screening.
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From page 129... ...
Methods that rely on the collection and characterization of tumor cells in circulation are still largely in the experimental stages. The cancer cells must first be separated from the normal blood cells in circulation, which outnumber the cancer cells by many orders of magnitude.
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From page 130... ...
A recent report by NCI's Breast Cancer Progress Review Group (BCPRG) concluded that NCI study sections have historically given tissue banking efforts and the associated correlative clinical studies such low priority that they have been unfundable (Breast Cancer Progress Review Group, 1998~.
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From page 131... ...
The field of bioinformatics is relatively new, and thus, the recently developed training programs have not kept pace with the demand for individuals with the necessary experience to tackle these issues. Given the enormous number of genetic and epigenetic changes already identified and the vast heterogeneity within and among breast tumors, this may indeed be the greatest challenge of all.
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From page 132... ...
Making sense of the many molecular changes in breast tumors will be extremely challenging, but the end result could potentially have an enormous impact on reducing the burden of breast cancer.
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