By Miriam Komaromy, MD

Reviewed by Peggy Conrad, MS, CGC and Jonathan Terdiman, MD
Last updated August 1, 2000

Although doctors have been aware of the inherited cancer syndrome hereditary nonpolyposis colorectal cancer (HNPCC) for some time, in the past no diagnostic tests existed for the syndrome. The only way doctors could detect HNPCC was by analyzing a family's medical history. In recent years, however, scientists have pinpointed five specific genes (and they think there are more) that when altered, or mutated, are linked to HNPCC. With this knowledge, they have been able to develop commercially available DNA tests that can determine whether an individual has inherited a mutated copy of two genes found most commonly in families with HNPCC.

Mode of Inheritance

HNPCC syndrome occurs when an individual inherits a mutated, or defective, copy of one of five specific genes from either parent.

HNPCC syndrome occurs when an individual inherits a mutated, or defective, copy of one of five specific genes from either parent. The syndrome is passed down in what is called autosomal dominant fashion. At conception, each of us inherits gene pairs that are formed when one copy of each of our mother's genes is matched with one copy of each of our father's genes. In other words, we have two versions of each gene. If a mutation in a particular gene is inherited in a dominant fashion, you need only inherit one mutated version of the gene (rather than two) to develop its associated trait. In other words, you only have to inherit one mutated version of an HNPCC-associated gene to have the associated high risk for cancer.

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The Genes

Although neither HNPCC syndrome itself nor the mutations connected with it cause cancer directly, they can predispose individuals to cancer by allowing multiple mutations in other important genes to go undetected and unrepaired.

As our cells age and die, new cells must be made to replace them. For this to happen, each of the 3 billion letters of DNA found within every cell has to be copied one letter at a time. Not surprisingly, mistakes can occur. When this happens, a gene might be switched off, or the product that it makes (the protein) might cease to function normally. To ensure that such mistakes don't permanently damage our genes, our body has special proteins — called mismatch repair proteins — that check for and then correct mistakes in the newly made DNA. The genes that produce these special proteins are called mismatch repair genes. In five of these genes that researchers have discovered the mutations linked with HNPCC.

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When a mismatch repair gene becomes altered, it can stop producing the mismatch repair protein, or the mismatch repair protein it produces may no longer work properly. But the consequences are the same: Those inevitable DNA copying mistakes are not being caught and corrected. When such mistakes occur in genes whose function is to prevent a cell from becoming cancerous, cancer can develop.

References

Peltomaki, P. and H. Vasen (1997). International collaborative group on hereditary nonpolyposis colorectal cancer: mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroeneterology 113: 1146-1158.

Lynch, H. and de la Chapelle, A. (1999). Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 36: 801-818.