Cancer Biology and Genetics

Introduction

Cancer is a collection of many different diseases and is often not uniformly categorized by even the tissue of origin. For example, hormone receptor–positive breast cancers are distinct in biology, prognosis, and treatment compared with hormone receptor–negative breast malignancies. A unifying feature shared by all human cancers is that they have a genetic basis, even though familial cancer syndromes are relatively uncommon compared with sporadic cancers. However, both heritable and sporadic cancers require the accumulation of DNA mistakes or alterations that lead to a step-wise progression of events, ultimately resulting in cancer. These DNA alterations are typically classified as mutations, copy number changes, gene rearrangements, and chromosome copy number changes. Cancer also results when DNA undergoes epigenetic changes that do not involve alterations to the DNA sequence but produce modifications that result in either the silencing or activation of genes in an aberrant fashion

Cancer Is a Disease of Cumulative DNA Alterations

When the balance of cell proliferation as compared with cell death or quiescence is perturbed, either due to abnormally increased proliferation or to decreased cell death or stasis, the initial steps of carcinogenesis have begun. Genes that mediate cell proliferation and cell death are often the early drivers of cancer, and many of these genes are mutated or altered in diverse types of cancer.

Two broad categories of cancer genes are termed oncogenes and tumor suppressor genes . Oncogenes, which are the accelerators of cancer growth, drive abnormal cell proliferation through various mechanisms. Common oncogenes that are often mutated or altered in human cancers include KRAS , BRAF , PIK3CA , and ERBB2 (HER2). The functions of oncogenes are diverse, but many mutations and alterations that occur in oncogenes constitutively activate critical growth-promoting pathways that then drive cellular proliferation. Conversely, tumor suppressor genes act as the brakes of cell growth. Their normal function is to control cell cycling by monitoring and stopping proliferation when appropriate. Any disruption in the function of tumor suppressor genes would predictably lead to a net gain in cell numbers, possibly even without additional contributions of increased cell proliferation. Examples of tumor suppressor genes commonly mutated in human cancers include TP53 , CDKN2A , CDKN2B , and others. Most cancers have genetic alterations involving both tumor suppressor genes and oncogenes, but the types of genetic alterations and consequences for therapies can vary dramatically between different malignancies.

DNA Alterations in Oncogenes and Tumor Suppressor Genes

Given the distinct yet complementary roles of oncogenes and tumor suppressor genes, it is perhaps not surprising that certain types of genetic alterations are associated more frequently with one or the other class of genes. Activating mutations within oncogenes, for example, tend to be heterozygous (i.e., only one allele is mutated) because a gain-of-function mutation would exert an effect even in the presence of the normal protein still being produced by the other wild-type allele ( Fig. 166-1A ). These mutations in oncogenes typically occur in regions that are known to regulate the corresponding protein’s activity, such as kinase domain mutations that render the protein constitutively activated. An increased copy number of an oncogene can have a similar effect. Other examples are translocations and rearrangements, such as when the BCR-ABL translocation juxtaposes two genes so that the oncogene’s normal function is in an “always on” state. In contrast, tumor suppressor genes generally require a loss-of-function genetic alteration, which by necessity usually requires alterations in both alleles of the cell ( Fig. 166-1B ). Accordingly, loss-of-function mutations observed in many tumor suppressor genes generally lead to premature truncation of the protein, such as nonsense mutations and insertion/deletion frameshift mutations. In addition, larger genomic alterations, such as deletions or loss of an entire gene or chromosome, are another mechanism for inactivating tumor suppression. Beyond these generalizations in the types of genetic alterations seen in oncogenes and tumor suppressor genes, exceptions also exist. For example, TP53 is a tumor suppressor gene, yet the most frequent mutations found in human cancers are missense mutations, rather than frame shifts or deletions. These common missense mutations confer a dominant negative effect and prevent the p53 protein from forming tetramers, thereby usually resulting in a loss-of-function, although gain-of-function mutations in TP53 have also been described. In contrast, certain deletions in the epidermal growth factor receptor (EGFR) gene ( ERBB1 ) eliminate autoregulatory domains, thereby resulting in constitutive activation of this oncogene. Ultimately the nature and type of mutations in oncogenes and tumor suppressor genes are predicated on the domains of the protein that would readily lend themselves to activate or inactivate the gene, respectively.