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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


  1. Douglas JA et al. History and molecular genetics of Lynch syndrome in family G: a century later.JAMA. 2005 Nov 2;294(17):2195-202.
  2. Lynch HT, Lynch JF. What the physician needs to know about Lynch syndrome: an update. Oncology (Williston Park). 2005 Apr;19(4):455-63; discussion 463-4, 466, 469.

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