Loss of control over telomere length may also contribute to cancer by affecting the cell cycle. Recall that telomeres, or chromosome tips, protect chromosomes from breaking. Human telomeres consist of the DNA sequence TTAGGG repeated thousands of times. The repeats are normally lost from the telomere ends as a cell matures, from 15 to 40 nucleotides per cell division. The more specialized a cell, the shorter its telomeres. The chromosomes in skin, nerve, and muscle cells, for example, have short telomeres. Chromosomes in a sperm cell or oocyte, however, have long telomeres. This makes sense—as the precursors of a new organism, gametes must retain the capacity to divide many times. In normal, specialized cells, telomerase is turned off and telomeres shrink, signaling a halt to cell division when they reach a certain size. In cancer cells, telomerase is turned back on. Telomeres extend, and this releases the normal brake on rapid cell division. As daughter cells of the original abnormal cell continue to divide uncontrollably, a tumor forms, grows, and may spread. Usually the longer the telomeres in cancer cells, the more advanced the disease. However, turning on telomerase production in a cell is not sufficient in itself to cause cancer. A proto-oncogene may not only move next to another gene, but also be transcribed and translated with it as if they are one gene. The double gene product, called a fusion protein, activates or lifts control of cell division. For example, in acute promyelocytic leukemia, a translocation between chromosomes 15 and 17 brings together a gene coding for the retinoic acid cell surface receptor and an oncogene called myl. The fusion protein functions as a transcription factor, which, when overexpressed, causes cancer. The nature of this fusion protein explains why some patients who receive retinoid (vitamin A-based) drugs recover. Their immature, dedifferentiated cancer cells, apparently stuck in an early stage of development where they divide frequently, suddenly differentiate, mature, and die. Perhaps the cancer- causing fusion protein prevents affected white blood cells from getting enough retinoids to specialize, locking them in an embryonic-like, rapidly dividing state. Supplying extra retinoids allows the cells to resume their normal developmental pathway. Looking at cancer at a population level reveals the interactions of genes and the environment. For example, researchers examined samples of non-Hodgkin's lymphoma tumors from 172 farmers, 65 of whom had a specific chromosomal trans- location. The 65 farmers were much more likely to have been exposed for long times to toxic insecticides, herbicides, fungicides, and fumigants, compared to the farmers with lymphoma who did not have the translocation.
Determining precisely how an environmental factor such as diet affects cancer risk can be complicated.
Consider the cruciferous vegetables, such as broccoli and brussels sprouts, which are associated with decreased risk of developing colon cancer. These vegetables release compounds called glucosinolates, which in turn activate "xenobiotic metabolizing enzymes" that detoxify carcinogenic products of cooked meat called heterocyclic aromatic amines. With a vegetable-poor, meaty diet, these amines accumulate. They cross the lining of the digestive tract and circulate to the liver, where enzymes metabolize them into compounds that cause driver mutations for colon cancer
The discovery that many children with RB have deletions in the same region of the long arm of chromosome 13 led researchers to the RB1 gene and its protein product, which linked the cancer to control of the cell cycle. The RB1 protein normally binds transcription factors so that they cannot activate genes that carry out mitosis. It normally halts the cell cycle at G1. When the RB1 gene is mutant or missing, the hold on the transcription factor is released, and cell division ensues.
For many years, the only treatment for retinoblastoma was removal of the affected eye. Today, children with an affected parent or sibling, who have a 50 percent chance of having inherited the mutant RB1 gene, can be monitored from birth so that noninvasive treatment (chemotherapy) can begin early. Full recovery is common.
Mutations in the RB1 gene cause other cancers. Some children successfully treated for retinoblastoma develop bone cancer as teens or bladder cancer as adults. Mutant RB1 genes have been found in the cells of patients with breast, lung, or prostate cancers, or acute myeloid leukemia, who never had the eye tumors. Expression of the same genetic defect in different tissues may cause these cancers.