Salk JJ, Horwitz MSPassenger mutations as a marker of clonal cell lineages in emerging neoplasia. Sem Cancer Biol 20(5): 294-303

Department of Pathology, University of Washington School of Medicine MB 357705, 1959 NE Pacific St., Seattle, WA 98195, United States.
Seminars in Cancer Biology (Impact Factor: 9.33). 10/2010; 20(5):294-303. DOI: 10.1016/j.semcancer.2010.10.008
Source: PubMed


Cancer arises as the result of a natural selection process among cells of the body, favoring lineages bearing somatic mutations that bestow them with a proliferative advantage. Of the thousands of mutations within a tumor, only a small fraction functionally drive its growth; the vast majority are mere passengers of minimal biological consequence. Yet the presence of any mutation, independent of its role in facilitating proliferation, tags a cell's clonal descendants in a manner that allows them to be distinguished from unrelated cells. Such markers of cell lineage can be used to identify the abnormal proliferative signature of neoplastic clonal evolution, even at a stage which predates morphologically recognizable dysplasia. This article focuses on molecular techniques for assessing cellular clonality in humans with an emphasis on how they may be used for early detection of tumorigenic processes. We discuss historical as well as contemporary approaches and consider ways in which powerful new genomic technologies might be harnessed to develop a future generation of early cancer diagnostics.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The evolution of cancer and RNA viruses share many similarities. Both exploit high levels of genotypic diversity to enable extensive phenotypic plasticity and thereby facilitate rapid adaptation. In order to accumulate large numbers of mutations, we have proposed that cancers express a mutator phenotype. Similar to cancer cells, many viral populations, by replicating their genomes with low fidelity, carry a substantial mutational load. As high levels of mutation are potentially deleterious, the viral mutation frequency is thresholded at a level below which viral populations equilibrate in a traditional mutation-selection balance, and above which the population is no longer viable, i.e., the population undergoes an error catastrophe. Because their mutation frequencies are fine-tuned just below this error threshold, viral populations are susceptible to further increases in mutational load and, recently this phenomenon has been exploited therapeutically by a concept that has been termed lethal mutagenesis. Here we review the application of lethal mutagenesis to the treatment of HIV and discuss how lethal mutagenesis may represent a novel therapeutic approach for the treatment of solid cancers.
    Preview · Article · Oct 2010 · Seminars in Cancer Biology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is a disease caused by the accumulation of genetic alterations in specific genes. Elucidation of the human genome sequence, in conjunction with technical advances in the ability to perform whole exome sequencing, have provided new insight into the mutational spectra characteristic of this lethal tumour type. Most recently, exomic sequencing has been used to clarify the clonal evolution of pancreatic cancer as well as provide time estimates of pancreatic carcinogenesis, indicating that a long window of opportunity may exist for early detection of this disease while in the curative stage. Moving forward, these mutational analyses indicate potential targets for personalised diagnostic and therapeutic intervention as well as the optimal timing for intervention based on the natural history of pancreatic carcinogenesis and progression.
    Preview · Article · Jul 2011 · Gut
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that regulate gene expression at the posttranscriptional level by blocking translation or inducing degradation of messenger RNA targets. It has been shown that miRNAs participate in a wide spectrum of essential biologic processes including cell cycle, differentiation, development, apoptosis and hematopoiesis, revealing one of the major regulators of human gene expression. Recent studies have shown evidences of abnormal expression of miRNAs in solid and hematological tumors, as well as the association of altered miRNAs with oncogenic or tumor suppressor functions, suggesting a key role of miRNAs in carcinogenesis. Moreover, unique profiles of altered miRNAs expression seem to allow distinction from normal tissue, prediction of disease outcomes, and evaluation of tumor aggressiveness in several types of cancer, including lung cancer. These unique and highly stable miRNAs patterns seems not to depend of age and race, and these characteristics highlight their potential diagnostic and prognosis utility. These findings are particularly promising for lung cancer, a worldwide leading cause of cancer-related deaths with a poor survival rate, despite the discovery of novel therapies. This review describes the potential of miRNAs as biomarkers for diagnosis, cancer classification and estimation of prognosis in lung cancer; and the approaches used to detect and quantify these miRNAs; including the current information about circulating miRNAs as potential biomarkers in lung cancer. This review also provides a description of miRNAs biogenesis, nomenclature and available database for miRNA sequences.
    Full-text · Article · Sep 2011 · Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion
Show more