Hereditary cancer colorectal without polypose

The hereditary cancer colorectal without polypose (syndrome of Lynch) is a susceptibility increased to develop a Cancer Côlon and a cancer of the endometer, ovary, stomach, small intestine, liver, urinary tract higher, brain and skin. The colonist is free from polyps.

The people carrier of this syndrome have a risk of 80% to develop a cancer of the colonist of which two thirds occur on the right colonist with an Middle Age of 44 years diagnosis. The women carrier of this syndrome have a risk from 20 to 60% to develop a cancer of the Endomètre with an Middle Age of 46 years diagnosis. The cancer of the ovary appears in a third of the cases before 40 years.

Incidence & prevalence

Standardized annual incidence colonist: from 25,9 to 45,8/100.000 men and of 17,4 to 28,4/100.000 women.

Subjects with colorectal cancer risk:

prone at the average risk: individuals of more than 50 years.
prone at the high risk (risk 2 to 5 times higher than for the average population at risk): personal antecedent of cancer colorectal, antecedent of adenoma (polyp) higher than 1 cm, antecedents family with the 1° degree of cancer colorectal and adenoma higher 1 ulcéro-hemorrhagic cm, antecedents of rectocolite and wide disease of Crohn. (Colorectal Cancer risk from 10 to 25% with the courses of the life).
prone at the risk very high in the hereditary forms (3% of colorectaux cancers): polypose adénomateuse family and syndrome of cancer colic without polypose (syndrome of Lynch). Close to an individual on two will be reached of a cancer colorectal in these families.

Causes

The causes of syndrome HNPCC are genetic. they are due to changes on the genes MR. (MisMatch Repair), i.e. the genes implied in the repair of the DNA at the time of the replication. These genes are:

The change is autosomale dominant and increases in an important way the predisposition to cancer of the colonist. If the change is present at a man, it has a risk from 70% to 80% to develop a cancer colorectal before 70 years. If the change is present at a woman, it has a risk from 30 to 40% to develop a cancer colorectal, and from 30 to 40% to develop a cancer of the endometer, before 70 years. These people have also a risk to develop other cancers in relation to syndrome HNPCC, but with a much lower frequency. It is thus essential to know that it is not because one carries a change associated with the syndrome HNPCC which one will develop with certainty a cancer during his life.

Diagnosis

The discovery of a syndrome HNPCC cannot be correlated which has a genetic tracking of coordination with the study of the family medical past.

The clinical diagnosis, except declaration of proven cancer, can be done only by coloscopy. The addition of carmine an Indigo dye decreases the risk for the expert to pass beside a tumor hnpcc.

Except family framework hnpcc, the prevalence is that of the normal population.

In the event of genetic diagnosis clearly proven on people having had a cancer of the colonist and on 3 subjects reached in the family, a genetic tracking can be considered, after consultation with a geneticist. A simple blood test allow to confirm the change or not. However a follow-up pseychologic can be considered according to the patient

Treatment & assumption of responsibility

There does not exist current treatment for syndrome HNPCC. Only the prevention makes it possible to avoid the cancer of the colonist.

A coloscopy every 2 years is enough.

However plusiseurs ways of research for treatments are under studies, such as the vaccines against the HNPCC and the use of aspirine associated starch in the test CAPP2 has whose results should be published in 2007 or 2008.

Genetic diagnosis

at the time of a cancer of the colonist with an obvious family past, the withdrawn tumor of the patient then is cut out in fine layer then fixed on a paraffin blade. The cuts can be thus preserved during several years. From these blades, one can extract the tumoral DNA from the tumoral cells. On this DNA, initially, one studies the stability of microsatellites definite according to international criteria. There exist 2 possible statutes:

MSI-L (MicroSatellite Instability Low): The microsatellites all are is stable or far from unstable.
MSI-H (MicroSatellite Instability High): The microsatellites are very unstable.

By convention, a patient is definite MSI-H when 40% of the microsatellites are unstable.

The microsatellites are short sequences of DNA of the chromosomes formed of the repetition of a reason itself made up for one to four bases. The most studied are the repetitions (CA) N. Very polymorphic, they are good markers for the genetic cartography. The studied microsatellites are:

BAT25
BAT26
NR40
D5S346
D2S123
D17S250
NR21
NR22
NR24

Bat25, BAT26 are mononucleotidic repetitions and are quasimonomorphic. The unstable microsatellites are those whose replication of the repeated sequences badly was held. The DNA polymerase has difficulties in retort nucleotide repetitions in particular Poly A. If protein MLH1 or MSH2 is transferred, it there not correction of the replication. In rule general, the sequences of microsatellite are shortened.

According to the schools and the various opinions of the biologists, only 5 microsatellites can suffir to define a statute MSI-H. According to a publication of Richard Hamelin, Multipopulation Analysis off Polymorphisms in Five Mononucleotide Repeats Used to Determine the Microsatellite Instability Status off Human Tumors , only BAT25, BAT26, NR21, NR24 and NR27 is enough to define statute MSI.

When a patient is MSI-H, in rule general one launches the sequencing of the gene hMLH1 and hMLH2 in first, because they are the genes most often transferred.

The localization known gene MLH1 is in 3p21.3, i.e. on the small arm of chromosome 3. It is composed of 19 exons and 18 will introns. It makes 57359 pairs of bases. One then compares tumoral gene of origin with a gene of reference.

Sources

Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MANDELEVIUM. MIM Number: 120435 * Wendy Kohlmann, Stephen B Gruber, Hereditary Non-Polyposis Colonist Cancer in GeneTests: Medical Genetics Information Resource (database online). Copyright, University off Washington, Seattle. 1993-2007

References

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