The War on Cancer - An Anatomy of Failure, A Blueprint for the Future

Chapter 4
OUR CURRENT UNDERSTANDING (p. 37-38)

1. THE GENETIC BASIS OF CANCER

1.1 First the basics

Cancer is not one disease but an assortment of over 200 diverse diseases that can arise from all tissues and organs. For example, cancers arising from blood cells are called leukemias; those arising from organ tissues such as the liver or the lungs are called solid tumors. More than one type of cancer can originate from an organ or tissue, as is the case of Lymphomas, a group of malignancies of the lymphatic system, encompassing more than 20 related cancers, depending on the classification used ^69,70.

Cancers can exhibit slow growth patterns compatible with long and symptom-free survival, such as indolent lymphomas or chronic lymphocytic leukemia ^71,72, or can quickly progress causing symptoms and death in only a few months, as is the case of acute myelocytic leukemia and pancreatic cancer ⁷³. Likewise, some cancers quickly spread distally from the site of origin, such as colon, prostate, and lung cancer that often reach liver, bone, and brain, respectively. Others tend to invade locally as is the case of head and neck cancers.

Yet, despite their heterogeneous origin, distinct clinical features, and vastly different course and outcome, the underlying genetic processes leading to their development, growth, and dissemination are similar. The master blueprint that determines the structure and function of all organisms, including man, is called the "genome". Each of the approximately 30 trillion cells that make a human being contains a copy of the entire genome and its approximately 30,000 "genes", neatly packaged in 46 microscopic units called "chromosomes" found bundled in the cell "nucleus".

Genes are deoxyribonucleic acid (DNA) sequences that contain the code for cells to produce proteins, which are the signals that control the structure and function of each cell, of each organ, and ultimately of the entire organism. These cell-produced, cell-targeted protein signals are at the center of the interdependent relationship that characterizes both the harmonious function of normal cells, and the aberrant behavior of cancer cells. Thus, the genome can be thought of as the book of life where chromosomes are chapters and genes are the carefully crafted sentences made of precise words spelled with "nucleotide bases", all sequentially arranged on the DNA molecule.

During the process of cell division and of human reproduction the entire genome must be duplicated and passed from cell to cell and from parent to offspring. While this process is prodigiously accurate, "spelling" errors do occur. Minor alterations are corrected by "DNA repair" genes. Major errors activate "gate-keeper" genes that block cell replication and force the cell to commit suicide ("apoptosis"). The role of DNA repair and gate-keeper genes is to ensure genomic integrity as cells advance through their replication cycle ("cell cycle"). However, occasional non-lethal alterations escape detection, repair, or blockade and are transmitted from a replicating cell to its daughter cells.

Transmitted alterations of DNA sequences outside of genes, called "polymorphism", are neither beneficial nor harmful to the cell or the host. Conversely, transmitted alterations within gene sequences, called "mutations", are responsible for approximately 4,000 human diseases, including cancer. When mutations affect an egg or a sperm, they can be transmitted to future generations, resulting in familial predisposition to diseases such as hemophilia, and to some cancers such as retinoblastoma. At present, the genetic fingerprints of most cancers are not known mainly because insensitive detection techniques of the pre-genomic era uncovered mostly structural chromosomal abnormalities visible by light microscopy that are seldom disease-specific. While diagnostically and prognostically valuable in the clinical setting, such gross abnormalities seldom provide insight into the genetic defects responsible for the development, growth, and dissemination of cancer.