genetics
Last reviewed 05/2021
Lynch syndrome is a genetic condition caused by germ line mutations or alterations in any one of the four genes known as mismatch repair (MMR) genes
- MMR genes are essential to maintain the integrity of the DNA, checking
for and correcting mistakes that if not repaired have the potential for tumor
formation and cancer development
- the four MMR genes implicated in the Lynch syndrome are MLH1, MSH2, MSH6, and PMS2
- of these four, MLH1 and MSH2 account for approximately 80%-90% of Lynch syndrome cases
- MSH6 accounts for approximately 10%-15% and PMS2 accounts for a small proportion of cases
Lynch syndrome is transmitted in a mendelian autosomal-dominant (AD) pattern of inheritance whereby individuals with Lynch syndrome have a 50% chance of transmitting the genetic mutation to each of their offspring. Individuals with Lynch syndrome are born with a normal functioning gene (wild type allele) on one chromosome and a mutated gene on the other chromosome
- despite the presence of a Lynch syndrome-associated gene mutation at birth
(known as the 'first hit'), cancer does not arise unless there is a loss of
function (or acquired somatic mutation) on the remaining chromosomal gene
or allele (second hit)
- this acquired mutation is likely because of gene/environment interaction and leads to a 'second hit' that disables the remaining wild-type allele. The second hit leads to the development of cancer due to the loss of the protective repair mechanisms of the MMR genes
- the requirement for the second hit illustrates why some individuals with the genetic mutation might not develop Lynch syndrome-associated cancers
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