Hereditary nonpolyposis colorectal cancer pathophysiology

Characteristics of HNPCC-associated colon cancers
In the United States, about 160,000 new cases of colorectal cancer are diagnosed each year. Hereditary nonpolyposis colorectal cancer is responsible for approximately 2 percent to 7 percent of all diagnosed cases of colorectal cancer. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome.

HNPCC defects in DNA mismatch repair lead to microsatellite instability, also known as MSI-H, which is a hallmark of HNPCC. Three major groups of MSI-H cancers can be recognized by histopathological criteria:
 * (1) right-sided poorly differentiated cancers
 * (2) right-sided mucinous cancers
 * (3) adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)

MSI is identifiable in cancer specimens in the pathology laboratory.

Genetic basis of Lynch syndrome
HNPCC is known to be associated with mutations in genes involved in the DNA mismatch repair pathway Up to 39% of families with mutations in an HNPCC gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many patients at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article.

HNPCC is inherited in an autosomal dominant manner. Most people with HNPCC inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all patients with an HNPCC gene mutation have a parent who had cancer. Some patients develop HNPCC de-novo in a new generation, without inheriting the gene. These patients are often only identified after developing an early-life colon cancer. Parents with HNPCC have a 50% chance to pass the gene on to each child.