From biology to clinic: Biomarkers of genetic instability.

Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006 CS07-03 Cancer is a result of accumulation of multiple genetic and epigenetic alterations which allow a cell to overcome physiological regulations and to possess malignant phenotypes including immortalization, unchecked proliferation, resistant to apoptosis, stimulation of angiogenesis, and gaining capability to invade and metastasize. A number of molecular events occur in early carcinogenesis and allow the accumulation of the multiple genetic and epigenetic alterations or acceleration of the accumulation process. Therefore, these molecular events may serve as risk biomarkers to predict cancer risk. Furthermore, the accumulated genetic and epigenetic alterations are the consequences of the instability and therefore can also be used as biomarkers to assess the malignant potentials of the premalignant tissues. In the effort to develop cancer preventive strategies, it is important to identify individuals with different levels of cancer risk in order to apply distinct preventive measures. However, it is difficult to classify high risk population based on their risk levels. The improved understanding of molecular process in early carcinogenesis in the past decade has led development of biomarkers with great potential in assessing genetic instability and cancer risk. These markers may also be useful in evaluating chemopreventive agents. In patients with upper aerodigestive tract cancers, tobacco is the major source of carcinogens which damage DNA and lead to genetic instability. However, individuals' cancer risk is influenced by inherited genetic makeup, particular DNA repair capability. A poor DNA repair capability may be a result of polymorphism in the genes critical in the DNA repair pathways and will make those individuals more susceptible to DNA damage and genetic instability. Individuals' DNA repair capability can be measured at three levels: genetic level by SNP analysis; expression level by mRNA or protein analysis; and functional level by phenotypic assays. These assays are typically conducted in lymphocytes whereas they are relevant in the target tissues where cancers arise is not clear. In our ongoing study, we attempt to address this important issue by comparing DNA repair capability in lymphocytes and genomic deletion frequencies in tumor tissues of the same individuals with oral cancer. Our results showed that the cancer tissues with a higher deletion frequency correlate with a poorer DNA repair capability in the lymphocytes, which supports a role of inherited DNA repair capacity in development of genetic instability. More important markers for cancer risk assessment are probably in the target tissues, particularly in premalignant lesions of the corresponding organs, because the alterations measured directly contribute to malignant transformation of the cells. One of the early requirements for cells to remain alive during accumulation of genetic and epigenetic alterations is the immortalization, although immortalization alone is not sufficient for malignant transformation. The major mechanism to immortalize epithelial cells in carcinogenesis is activation of telomerase. Therefore, telomerase activation may be used as an essential marker for malignant transformation and risk assessment together with other biomarkers measuring results of genetic instability. The most common genetic alteration in tobacco-related cancers is genetic deletions and amplifications which can be measured by using microsatellites as allelic imbalance or loss of heterozygosity (LOH). Several independent studies have shown that LOH at critical chromosomal loci can be used to predict oral cancer development in individuals with oral premalignant lesions (OPL). In our ongoing oral cancer prevention clinical trial, LOH at the critical chromosomal loci has been implemented as the eligibility criteria for patients with OPL to enter into the clinical trial. When we embrace the new concept of individualized cancer prevention strategy, biomarkers will play an increasingly important role in selection of high risk populations and subgroup populations likely to response to a particular preventive regimen.