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Chapter 15 · Part 8 of 8
  1. Chapter overview
  2. 1How mutations change a polypeptide
  3. 2Where a mutation strikes
  4. 3What causes mutations
  5. 4Repairing damaged DNA
  6. 5How cancer develops
  7. 6Oncogenes
  8. 7Tumor-suppressor genes
  9. 8Silenced suppressors and the many steps to cancer

Silenced suppressors and the many steps to cancer

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A tumor-suppressor gene protects a cell only while it is expressed. Cancer cells find several ways to shut these genes off, and a cancer usually needs many such changes, built up one at a time.

Three ways to silence a tumor-suppressor gene

Way What happens
Gene mutation A mutation in the gene itself stops it from making a working protein
Chromosome loss The cell loses the whole chromosome that carries the gene
Epigenetic change The gene’s chromatin is altered so it isn’t transcribed, though its sequence is unchanged

A mutation can silence the gene in several ways you’ve already seen. It might destroy the promoter, so the gene is never transcribed, or it might be a nonsense mutation that puts an early stop codon in the coding sequence. Either way, no functional protein is made.

Chromosome loss is cruder. When a cell loses a whole chromosome, every tumor-suppressor gene on it goes too.

The third way leaves the DNA sequence untouched. An epigenetic change is a change in chromatin structure that alters gene expression without changing the base sequence. A common example is DNA methylation, which you met in Chapter 14: methyl groups are attached to cytosines in the CpG islands near a gene’s promoter, and transcription shuts down. Many tumors have abnormally methylated tumor-suppressor genes.

Check yourselfSequencing shows that a tumor’s p53 gene has a perfectly normal base sequence, yet no p53 protein is made. What could explain this?

An epigenetic change, such as methylation of the DNA near the p53 promoter. Methylation can block transcription without altering the base sequence.

Cancer takes many changes

A single mutation rarely causes cancer. Most cancers need multiple genetic changes in the same cell lineage, perhaps 10 or more. These include changes that activate oncogenes and changes that inactivate tumor-suppressor genes.

The order of the changes isn’t fixed, but they take time to accumulate. That’s why cancer is mostly a disease of older people, and why cutting exposure to mutagens such as cigarette smoke throughout life lowers the risk. Even after a tumor becomes malignant, it keeps gathering changes that make its cells divide faster or invade more readily, so it becomes harder to treat.

Researchers estimate that about 300 human genes, roughly 1.5% of our protein-coding genes, can promote cancer when altered by mutation or epigenetic change.

How lung cancer progresses

Lung cancer shows the step-by-step path clearly, and most cases are caused by smoking. Most lung cancers are carcinomas, cancers of epithelial cells, the cells that line body surfaces. In the airways, the epithelium includes ciliated cells that sweep out mucus and trapped particles, and basal cells beneath them.

  1. Mutations build up in a lineage of basal cells, which multiply and thicken the epithelium. This overgrowth is hyperplasia.
  2. The crowding basal cells push out the ciliated cells, so the airway loses its ability to clear mucus.
  3. More mutations give the basal cells abnormal shapes, a stage called dysplasia. The cells are precancerous, and if smoking stops, they are likely to disappear.
  4. If smoking continues, the cells gain further changes and lose the ability to stop dividing. They have become a carcinoma.
  5. The tumor breaks through the basement membrane, the sheet of extracellular matrix between the epithelium and the bloodstream, and its cells can metastasize.

Until the cancer cells cross the basement membrane, they haven’t spread. Removing the whole tumor at that stage should cure the patient. Once cells have metastasized, the cancer usually proves fatal, and lung cancer is often found only at this late stage.

Check yourselfWhy can a lung tumor that hasn’t penetrated the basement membrane be cured by surgery, while one that has usually can’t?

Until the basement membrane is breached, the cancer cells can’t reach the bloodstream, so they haven’t metastasized and removing the tumor removes all of them. Once they cross it, cells may already have spread to other parts of the body.

Practice questions

  1. 1 of 2

    In the early stages of lung cancer, a lineage of mutant basal cells multiplies and thickens the airway lining. What is this overgrowth called?

  2. 2 of 2

    A lung tumor’s cells have not yet crossed the basement membrane. What does that tell the doctor?