William B. Coleman

The Role of Genomic Instability in the Development of Human Cancer

Cancer development is a multi-step 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 neoplastic transformation (1–5). Several forms of molecular alteration have been described in human cancers, including gene amplifications, deletions, insertions, rearrangements, and point mutations (5, 6). 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 (4). Statistical analyses of age-specific mortality rates for different forms of human cancer predict that multiple (three to eight) mutations in specific target genes are required for the genesis and outgrowth of most clinically diagnosable tumors (7). In accordance with this prediction, it has been suggested that tumors grow through a process of clonal expansion driven by mutation (1,2,8–10). 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 proliferative potential. The idea that carcinogenesis is a multi-step process is supported by morphologic observations of the transitions between premalignant (benign) cell growths and malignant tumors. In some tumor systems (such as colon), the transition from benign to malignant can be easily documented and occurs in discernible stages, including benign adenoma, carcinoma in situ, invasive carcinoma, and eventually local and distant metastasis (11,12). Moreover, specific genetic alterations have been shown to correlate with each of these well-defined histopathologic stages of tumor development and progression (13,14). 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.

Molecular Pathogenesis of Human Cancer

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.

Molecular Mutations in Human Neoplastic Disease

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 two decades have increased our understanding of carcinogenesis and have identified a genetic basis for the multistep nature of cancer development (1–3). In several human tumor systems, specific genetic alterations have been shown to correlate with well defined histopathologic stages of tumor development and progression (4,5). Although the significance of molecular mutations to the etiological mechanisms of tumor development has been debated, a causal role for such genetic lesions is now commonly accepted for a number of human tumors. Thus, genetic lesions represent an integral part of the processes of neoplastic transformation and tumor progression, and as such represent potentially valuable markers for cancer detection and staging (6–9). Through the application of specific and sensitive nucleic acid 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 out-come, facilitating the application of effective intervention strategies in the treatment of human tumors.

Understanding Molecular Pathogenesis: The Biological Basis of Human Disease and Implications for Improved Treatment of Human Disease

Disease has been a feature of the human existence since the beginning of time. Descriptions of diseases and therapeutic interventions were recorded in the earliest written histories of medicine. Over time, our knowledge of science and medicine has expanded and with it our understanding of the biological basis of disease. In this regard, the biological basis of disease implies that more is understood about the disease than merely its clinical description or presentation. In the last several decades, we have moved from causative factors in disease to studies of molecular pathogenesis. Molecular pathogenesis takes into account the molecular alterations that occur in response to environmental insults and other contributing factors, to produce pathology. By developing a deep understanding of molecular pathogenesis, we will uncover the pathways that contribute to disease, either through loss-of-function or through gain-of-function. By understanding the involvement of specific genes, proteins, and pathways, we will be better equipped to develop targeted therapies for specific diseases. Continued expansion of our knowledge base with respect to underlying mechanisms of disease has resulted in unprecedented patient management strategies. Identification of genetic variants in genes once associated with the diagnosis of a disease process is now being reevaluated as it may impact new therapeutic options. In this chapter we describe three disease entities (Hepatitis C virus [HCV] infection, acute myeloid leukemia [AML], and cystic fibrosis [CF]) as examples of our increased understanding of the pathology represented by these diseases and how novel therapeutics are being introduced into clinical practice.