Genetics
HNPCC defects in DNA mismatch repair lead to microsatellite instability, also known as MSI-H, which is a hallmark of HNPCC. MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...).
HNPCC is known to be associated with mutations in genes involved in the DNA mismatch repair pathway
| OMIM name | Genes implicated in HNPCC | Frequency of mutations in HNPCC families | Locus | First publication |
|---|---|---|---|---|
| HNPCC1 (120435) | MSH2 | approximately 60% | 2p22 | Fishel et al., 1993 |
| HNPCC2 (609310) | MLH1 | approximately 30% | 3p21 | Papadopoulos et al., 1994 |
| HNPCC5 | MSH6 | 7-10% | 2p16 | |
| HNPCC4 | PMS2 | relatively infrequent, <5% | 7p22 | |
| HNPCC3 | PMS1 | case report | 2q31-q33 | |
| HNPCC6 | TGFBR2 | case report | 3p22 | |
| HNPCC7 | MLH3 | disputed | 14q24.3 |
Patients with MSH6 mutations are more likely to be Amsterdam criteria II-negative. The presentation with MSH6 is slightly different than with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it.
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 of passing the genetic mutation on to each child.
Read more about this topic: Hereditary Nonpolyposis Colorectal Cancer