Recent studies have demonstrated the cancer-related role of genes that function in the repair of DNA damage. In hereditary nonpolyposis colorectal cancer (HNPCC), an inherited mutation in one of the mismatch repair (MMR) genes appears to be a critical factor. MMR genes normally produce proteins that identify and correct sequence mismatches that can occur during DNA replication. A mutation that inactivates an MMR gene leads to the accumulation of cell mutations that greatly increase the likelihood of malignant transformation and cancer. Five MMR genes have been implicated in HNPCC, but the majority of mutations seem to be found in three genes: MLH1, MSH2, and MSH6.⁴⁵

Colorectal cancers associated with hereditary nonpolyposis colorectal cancer (HNPCC) seem to be biologically different from sporadic colorectal cancers. Compared with sporadic colorectal cancer, HNPCC-associated tumors are more common on the right side of the colon, with about two-thirds of the cancer found proximal to the splenic flexure.²⁸ Several studies have also reported better survival rates in HNPCC-associated colorectal cancer than sporadic colorectal cancer when matched by cancer stage.⁷

Even though HNPCC is the most common hereditary colon cancer, accounting for up to five percent of all cases, awareness of the disease among the public and health care providers is low.³⁴ One reason may be that HNPCC lacks the dramatic features of the less-common familial adenomatous polyposis (FAP). In this form of hereditary colon cancer, hundreds to thousands of polyps may be found carpeting the colon.³²

By contrast, in HNPCC, the number of precursor polyps (or adenomas) appears to be no greater than the number found in the general population. However, these polyps are thought to progress more rapidly to cancer²² and form at earlier ages. These polyps lead to an increased risk of colorectal cancer in HNPCC—at least 25 percent by age 50 and up to 82 percent by age 70.^{1, 28} HNPCC is also linked to other primary cancers. Females with HNPCC have up to a 71 percent risk of developing endometrial cancer by age 70.⁵⁰ All patients with HNPCC are at increased risk for other cancers as well, including cancers of the ovary, stomach, ureter/renal pelvis, biliary tract, small bowel, pancreas, brain and sebaceous adenomas.⁵¹

Although the clinical characteristics of HNPCC are less striking than those of FAP, the patient's personal and family medical history can reveal that a predisposition to the disease exists. When assessing hereditary cancer risk, a patient's comprehensive family history remains an essential part in determining if there is a possibility of HNPCC. However, genetic testing is the most accurate way to diagnose patients with HNPCC.

» Identifying Patients at Risk for HNPCC

A genetic test for hereditary nonpolyposis colorectal cancer (HNPCC)