When Genes Lose Their "Spell Check"

Manuel Perucho, Ph.D.

Manuel Perucho, Ph.D. Professor and Program Co-Director, Tumor Development

While working on the chromosomal alterations common to colon cancer, Dr. Manuel Perucho’s team stumbled upon another kind of genomic alteration—subtle mutations in some very abundant repetitive sequences called microsatellites. This microsatellite instability led to the identification of the genes responsible for Hereditary Nonpolyposis Colorectal Cancer (HNPCC), the most common syndrome of hereditary colon cancer.


We all have genes that encode proteins that preserve the integrity of our genome. These genes can be likened to computer spell-check programs, which detect errors and correct them. When these genes are not working properly, they become “mutator” genes, causing mutations to accumulate rapidly. Most of these random mutations are harmless, but when mutations occur in certain cancer genes, they lead to cancer development. These mutations can be particularly dangerous in intestinal cells, which are among the fastest proliferating cells. As a result, they are highly susceptible to mutations during a person’s lifetime.

Cancer mutations

For those afflicted with HNPCC syndrome, early screening enhances detection even before symptoms appear, greatly improving prognosis. This is a case of predictive and preventive medicine already benefiting patients.

Some mutator genes are not activated by genetic mutations but by epigenetic changes. Epigenetic modifications of the DNA are additions to the genetic code that affect the expression of genes without changing their sequence. Dr. Perucho has discovered a link between aging and cancer through the gradual, age-associated accumulation of epigenetic alterations that may play an important role in increasing the probability of chromosomal changes.

Research - Cancer - Your Health: When Genes Lose their "Spell Check"
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