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Each year, there are an estimated 18 million new cancers diagnosed worldwide with more than 9 million people succumbing to the disease.1 In the most basic terms, cancer is simply uncontrolled cell growth. However, the reality is that cancer represents a highly complex, dynamic process that manipulates normal cellular processes in order to maintain growth and survival advantages that are not subject to traditional regulation. Although cancer arises through multiple different mechanisms and manifests in a variety of forms, fundamentally it represents a disease of genetic alterations that result in characteristic histologic, radiologic, and clinical findings. In this chapter, we will discuss the role and impact of genomic alterations in cancer. However, before we can understand how genomes go awry in cancer, we must first review basic features of “normal” human genomes. The next section provides an introduction to genes and their expression. Those with an advanced background in genetics and molecular biology may be comfortable skipping ahead to “Mutations and Cancer.”


DNA Structure

The human genome comprises all the information necessary to build and maintain a functional organism. The basic units of the genome are deoxyribonucleic acids (DNA), a polymeric molecule composed of repeating nucleotide subunits. Each nucleotide is composed of three parts: (1) a phosphate group, (2) a five-carbon sugar, and (3) one of four cyclic nitrogen-containing bases. There are four distinct nitrogen bases in our genomes: adenine, guanine, thymine, and cytosine (Figure 1-1A). These bases are classified according to their chemical structure into two groups. Adenine and guanine have two-ring structures and are called purines; thymine and cytosine have one-ring structures and are called pyrimidines.


DNA structure. (A) Chemical structure of nitrogen bases of DNA. (B) Two-dimensional schematic demonstrating antiparallel orientation of two DNA strands.

As demonstrated by the revolutionary work of James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin, the structure of DNA is a double helix, composed of two DNA strands that are coiled about one another in a spiral.2 Each strand has an alternating phosphate-sugar backbone, with the nucleotide bases projecting inward toward the bases of the opposite strand, called the complementary strand. By convention (but also reflecting the chemical nature of DNA synthesis), the backbone of each strand is oriented from the first phosphate, called 5′, to the last sugar, called 3′. Importantly, the two strands have an “antiparallel” orientation, meaning that each strand is oriented opposite to the other, which can be illustrated by a short DNA molecule shown in two dimensions (Figure 1-1B). For the top strand in this illustration, the backbone (oriented from 5′ phosphate to 3′ sugar) runs from left to right, but for the opposite strand, the backbone runs from right to left.


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