This is heriditary non polyposis colorectal cancer (HNPCC ). It is another rare form of familial colorectal cancer. However it is not characterised by as many adenomatous polyps as are found in (FAP). Adenomatous polyps do occur at an increased frequency compared to the general population though. There is a higher rate of mucinous tumors and a higher rate of tumors affecting the right colon. There is also a high rate of synchronous and metachranous tumours.
Extra-colic tumors are common in HNPCC , indeed the original descritption of this syndrome was as the Cancer Family Syndrome. Lynch syndrome I is used to describe those families who mostly get colonic cancer at a young age and Lynch syndrome II, those who get both colorectal and extracolinic cancer. The common extracolinic tumors are endometrial, ureteric, renal pelvis and small bowel.
One early difficulty with this condition was that there no simple marker, like the multiple polyps seen in the various types of familial adenomatous polyposis coli (FAP), was evident. However, even though this condition is termed (non polyposis) it must be remembered that adenomatous polyps are more common in families with HNPCC than in the rest of the population.
The condition is inheritied in an autosomal dominant fashion.
At least six differnet genes have been identified, and they all are involved in correction of defects in DNA replication, mismatch repair mechanism.
| hMLH1 |
| hMSH2 |
| hMSH3 |
| hMSH6 |
| hPMSI |
| hPMS2 |
The presence of defective DNA mismatch repair can be seen by looking for microsatteline instability. The microsattelites are short repeated motifs in DNA such as (CA) which may be repeated 10-15 times thus;
Normal genotype 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' Mutator genotype 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3' 5'GATC-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-CA-GATC3'
A sample of the patient's tissue is taken and the DNA isolated. This is then amplified using the polymerase chain reaction (PCR ). The primers used target one of a number of identified microsattelites. The PCR product is then denatured and run on a polyacrylamide gel to see the variability in the length of the microsattelite. A person with the mutator phenotype will show a number of different PCR product lengths due to lengthening and shortening of the microsattelite sequence that have occured from errors in DNA replicaiton which have not been fixed. Usually a panel of 5 microsattelites is tested and if more than two show instability the patient is considered for germ line testing. Alternative names for patients with this variation in the lengths of microsattelites are microsattelite instability, replication error phenotype and the mutator phenotype.
When HNPCC was discovered it was necessary to define criteria to select patients who may have HNPCC these patients could then be screened for the mutator phenotype, and subsequently more detailed molecular analysis; the first set of internationally agreed criteria were defined in Amsterdam in 1990, and are termed the Amsterdam 1 criteria. These were felt to be too restrictive and were modified in 1999 as the Amsterdam 2 criteria.