An Overview of Molecular Cancer Pathogenesis, Prognosis, and Diagnosis (original) (raw)

2016, Tumors in Domestic Animals

Fundamentals of cancer biology Cancer is a disease of the genome, arising from DNA alterations that dysregulate gene structure or function. 1,2 Damage to the cellular genome or altered expression of genes is a common feature for virtually all neoplasms. 3 Given that there is an inherent error rate in DNA replication, all multicellular organisms face the near certainty of developing a neoplasm if they survive long enough, as essential mutations for neoplastic transformation will eventually develop. Many mutations may be inconsequential, but cancer can develop when nonlethal mutations occur in a small subset of the coding and noncoding regions of the genome, perhaps affecting even just a few of the ~20,000 genes thought to comprise the mammalian genome. 4 There are many agents, in addition to deficiencies in DNA replication fidelity and error repair, that drive tumor formation. These agents include viruses, mutagenic chemicals, and radiation. Unraveling the pathogenesis of cancer has not only helped us understand how a cell transforms into a tumor but has also promoted molecular tests that now help diagnose and provide prognoses for a variety of cancers in humans and animals. Genetic injury Genetic damage is a universal component of the pathogenesis of neoplasia, with somatic mutations in genes identified in 90% of cases, and germ line mutations identified in 20% of human neoplasia and both features found in a small percentage of neoplasms. 1,2,4 In some cases a single base pair mutation is sufficient to alter a critical amino acid, leading to altered protein function and an increased risk for neoplastic transformation. Other types of mutations involve insertions, deletions, or duplications of gene segments. Structural chromosomal changes, such as translocations, which lead to chimeric transcripts or deregulation of gene expression through movement of promoters and enhancer regions adjacent to relevant genes can also drive malignant transformation. In addition, gene copy number increases or decreases (gene dosage) can also occur. Epigenetics DNA sequence mutations are not the only route to neoplasia. 5 Epigenetic mechanisms regulate gene expression without causing structural changes to the genome and also play a role in malignant transformation. 6 Epigenetic changes are reversible, heritable alterations of gene expression without mutation of the genome. Three main forms of epigenetic gene regulation include DNA methylation, histone acetylation, and microRNA expression. Gene expression can be silenced, diminished, or increased by altering methylation patterns in the DNA. Aberrant methylation patterns, such as hypermethylation and hypomethylation, are common in a variety of neoplasms and are linked to abnormal gene expression levels. In particular, methylation of tumor suppressor genes leading to their suppression is recognized in a number of human cancers, including breast, colon, and renal carcinomas. Histone proteins serve as spools that are wound with DNA strands to package cellular DNA into nucleosomes, which when