Wednesday, June 27, 2012

Lynch Syndrome

Introduction


Lynch Syndrome is a genetic disease characterized by an increased risk of cancer of the lower digestive tract including the colon and rectum. Individuals who have Lynch syndrome are also predisposed to certain types of other cancers such as stomach, liver, pancreas, small intestine, urinary tract and brain. Women who have Lynch syndrome are at an increased risk of the ovaries and endometrium. Often referred to as hereditary nonpolyposis colorectal cancer (HNPCC), experts estimate that Lynch syndrome might be responsible for between two and seven percent of all colorectal cancers.

(Image from: Colon)


Lynch Syndrome often does not present with any clear symptoms until the individual is diagnosed with colorectal cancer at a young age (younger than 50 years old). Some individuals have a strong familial history of early onset colorectal cancers and might be directed by their primary care providers to a genetic counselor for confirmation of Lynch Syndrome. While literature previously indicated that those with Lynch Syndrome do not have colorectal polyps, more recent investigations indicate that not only do individuals with Lynch Syndrome have polyps; their polyps are more likely to develop into cancerous growths.

Knowing one's status regarding Lynch Syndrome and acting accordingly remains the leading method of prevention of colorectal cancer caused by heredity. Having Lynch Syndrome is not a confirmative diagnosis of cancer; it merely predisposes one to certain cancers, and early detection and removal of polyps is the best means of preventing a devastating cancer diagnosis.

Lynch Syndrome's Genetic Basis


Lynch Syndrome is a genetic condition that follows an autosomal dominant inheritance pattern, which means that only one of the affected individual's parents must pass the mutated allele on to the individual. While there are several potential gene mutations that indicate that the individual might have Lynch Syndrome, all the markers are mutations of the body's mismatch repair (MMR) genes. MMR genes protect the body from making mistakes in the DNA replication sequence.

In Lynch Syndrome, affected individuals have mutated MMR genes. The following four genes can be affected in individuals with Lynch Syndrome: MLH1, MSH2, MSH6 and PMS2. Genetic counseling can identify the MMR gene mutations, and while this will not prevent one from getting Lynch Syndrome, it can lead to early detection and life-saving excision of polyps or tumors.

The Role of MLH1


In particular, the expression of the MLH1 gene affects one's chances of developing cancers associated with Lynch Syndrome because of the unique role MLH1 plays in the process of DNA replication at the cellular level. When DNA replicates, the process ideally creates identical copies of itself. Sometimes, however, the DNA polymerase makes mistakes in the process that results in a mutated gene or genes in the DNA strand. DNA polymerase is responsible for arranging the base pairs at the replication fork of a DNA molecule. Typically these mistakes involve arranging bases in non-complementary pairings.

When DNA polymerase makes mistakes, the body's MLH1 genes are responsible for the repair of such mistakes. MLH1 in combination with other genes, codes for certain protein complexes that control the body's response to the mismatched base pairings. MLH1, therefore, is responsible for recognizing the mistakes that have been made in the replicated strand. This mismatch can be corrected by excising the incorrect part and replacing it with the correct part. MMR genes perform this task quickly, so that the mutated genes do not become expressed in the replicated cells.

When MLH1 becomes mutated, as can be seen in Lynch Syndrome, the body cannot recognize nor repair the damage to the mismatched base pairings quickly enough before cellular replication occurs. The cells with mutated DNA continue to grow and replicate themselves, mutations intact. This can lead to the proliferation of cells that contain irreversibly mutated DNA, which can lead to malignant tumors in the affected areas of the body.

Fortunately, genetic screenings can test individuals for the presence of the MMR gene mutations. Knowing that one has the genetic mutation, and knowing more specifically which gene is mutated, can greatly improve the prognosis for individuals with Lynch Syndrome. Armed with the knowledge that Lynch Syndrome is hereditary can also improve care provided to any offspring or family members who might also have Lynch Syndrome.

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