Basis for Molecular Genetics in Cancer

Abstract

Oncogenesis is the process whereby normal cells are transformed into cancer cells. The multistep evolution is characterized by a progression of changes at the cellular, genetic, and epigenetic levels that ultimately reprogram a cell to undergo uncontrolled cell division, thereby forming a malignant mass (Hanahan and Weinberg, Cell 100:57–70, 2000 and Hanahan and Weinberg, Cell 144:646–674, 2011).

Carcinogenesis is caused by mutation of the genetic material of normal cells, which upsets the normal balance between proliferation and cell death. This disequilibrium results in uncontrolled cell division, and rapid proliferation of cells can lead to benign tumors and some of which may turn into malignant tumors. Malignant tumors can invade other organs and spread to distant locations as metastasis.

More than one single mutation is usually necessary to oncogenesis. In fact, a series of several mutations to certain classes of genes is usually required before a normal cell transforms into a cancer cell. For example, on average 15 “driver mutations” and 60 “passenger” mutations are found in colon cancers (Wood et al., Science 318:1108–1113, 2007).

Mutations in key genes that play vital roles in cell division and apoptosis as well as mutations in DNA repair genes will cause a cell to proliferate in an uncontrolled manner. Genetic changes can occur at many levels, from aneuploidy, gain or loss of entire chromosomes, to a mutation affecting a single DNA nucleotide resulting in silencing or activating the function of key genes.

There are two main categories of genes that are affected by these changes: (1) Oncogenes may be normal genes that are expressed at inappropriately high levels or altered genes that have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells, and (2) tumor suppressor genes are genes that inhibit cell division, survival, or other properties of normal cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes.

Large-scale alterations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. Small-scale mutations include point mutations, microdeletions, and microinsertions, which may occur in the promoter of a gene and affect its expression (as in TERT promoter Huang et al., Science 339:957–959, 2013) or, more frequently, may occur in the gene’s coding sequence and alter the function or stability of its protein product.

Oncogenesis requires the acquisition by the cell of essential physiological skills that reflects its genetic abnormalities. The study of these multiple genetic aberrations, which arise either at the chromosome level or at the nucleotidic level, is a crucial step for the integrative understanding of tumorigenic process.