Cancer represents a significant health problem worldwide. The successful curative treatment of almost every form of this disease depends on early diagnosis and, in the case of solid tumors, surgical resection with or without adjuvant therapy. Intensive research efforts during the last several decades have increased our understanding of carcinogenesis and have identified a genetic basis for the multistep process of cancer development (1-3). In several human tumor systems, specific genetic alterations have been shown to correlate with well-defined histopatho-logic stages of tumor development and progression (4,5). Although the significance of mutations to the etiological mechanisms of tumor development has been debated, a causal role for such genetic lesions is now commonly accepted for many human tumors. Thus, genetic lesions represent an integral part of the processes of neoplastic transformation, tumorigenesis, and tumor progression, and as such, they represent potentially valuable markers for cancer detection and staging (6,7). Through the application of specific and sensitive molecular methodologies, the clinical laboratory of the future will be able to effectively screen populations at high risk for the development of cancer, potentially impacting the early detection and diagnosis of human cancers. In addition, development of new molecular diagnostic assays will expand the ability of clinicians to accurately stage tumor development, monitor progression of metastatic disease, and evaluate therapeutic outcome, facilitating the application of effective intervention strategies in the treatment of human tumors.
2. CANCER: A MULTISTEP GENETIC DISEASE
Cancer development is a multistep process through which cells acquire increasingly abnormal proliferative and invasive behaviors. Furthermore, cancer represents a unique form of genetic disease, characterized by the accumulation of multiple somatic mutations in a population of cells undergoing neoplas-tic transformation (1-3,8,9). Several forms of molecular alteration have been described in human cancers, including gene amplifications, deletions, insertions, rearrangements, and point mutations (9). In many cases, specific genetic lesions have been identified that are associated with the process of neoplastic transformation and/or tumor progression in a particular tissue or cell type (3). Statistical analyses of age-specific mortality rates for different forms of human cancer predict that multiple mutations in specific target genes are required for the genesis and outgrowth of most clinically diagnosable tumors (10). In accordance with this prediction, it has been suggested that tumors grow through a process of clonal expansion driven by mutation (1,8,11,12). In this model, the first mutation leads to limited expansion of progeny of a single cell, and each subsequent mutation gives rise to a new clonal outgrowth with greater pro-liferative potential. The idea that carcinogenesis is a multistep process is supported by morphologic observations of the transitions between premalignant (benign) cell growth and malignant tumors. In colorectal cancer (and some other tumor systems), the transition from benign lesion to malignant neoplasm can be easily documented and occurs in discernible stages, including benign adenoma, carcinoma in situ, invasive carcinoma, and, eventually, local and distant metastasis (13). Moreover, specific genetic alterations have been shown to correlate with each of these well- defined histopathologic stages of tumor development and progression (5,14). However, it is important to recognize that it is the accumulation of multiple genetic alterations in affected cells, and not necessarily the order in which these changes accumulate, that determines tumor formation and progression. These observations suggest strongly that the molecular alterations observed in human cancers represent integral (necessary) components of the process of neoplastic transformation and tumor progression. From the clinical perspective, the process of accumulation of genetic alterations and mutations, over time, during neoplastic transformation, tumorigenesis, and tumor progression provides a window of opportunity for early detection, diagnosis, and intervention (6,7,15). However, the selection of appropriate molecular markers will depend on the nature and temporal occurrence of the various genetic alterations that govern the establishment of a particular tumor type and the relationship between these genetic alterations and the histopathological features of the developing tumor.
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