Lynch syndrome

What is it?

Lynch syndrome, formerly known as "Hereditary Non-Polyposis Colorectal Cancer" (HNPCC), is an autosomal dominant inherited syndrome with medium to high penetrance. It can cause a variety of cancers, most frequently of the colorectum, uterus, stomach and small intestine. It can also predispose to cancer of the pancreas, urinary tract (kidneys, ureters, bladder), biliary tract, breast, ovary, prostate, and brain. Such neoplasms often have juvenile onset. It affects one in every 270 people, making it the leading cause of hereditary colorectal cancers. It is responsible for 3-5% of all colorectal cancers. Lynch syndrome is caused by a germline pathogenic variant (mutation) in one of these genes: MLH1, MSH2, MSH6, PMS2, or EPCAM. These genes are collectively called "mismatch repair" (MMR) genes, i.e. they are devoted to "mismatch repair". When DNA mutates, it accumulates mutations that lead to cancer.

Which are the symptoms?

Lynch syndrome predisposes to the development of various cancers. Risk varies by gene, age and organ. 
Referring to MLH1, for example, the risk of developing the following cancers is as follows:

  • Colon-rectum: risk increases from 10% at the age of 35 to 40% at the age of 50, 50% at the age of 55, and 70% at the age of 70.
  • Uterus: from 2% at the age of 40 to 48% at the age of 75.
  • Ovary: 11%
  • Prostate: 14%
  • Urinary tract: 4-5%
  • Stomach: 10-20%

How is it diagnosed?

Genetic testing is the main test for diagnosis and is performed by taking blood sample. DNA is extracted from the blood and sequenced to identify the presence of any mutations in genes associated with Lynch syndrome.
Sequencing is a molecular biology method to identify the presence of a pathogenic variant using two techniques called Next Generation Sequencing (NGS) and Multiplex ligation-dependent probe amplification (MLPA).
In suspected Lynch syndrome, analysis focuses on 5 major genes, called MLH1, MSH2, MSH6, PMS2 and EPCAM. If one (or more) of these genes is mutated, a diagnosis of Lynch syndrome is made.
Lynch syndrome is an undiagnosed disease. It is estimated that up to 90% of patients with Lynch syndrome do not receive the diagnosis. 

Suggested exams

How is it treated?

The first step toward treatment is to diagnose it in time. The indication to perform genetic testing is based on the oncological history of the patient and/or family members. Clinical criteria, histological criteria, and/or algorithms are used in this regard.

  • Clinical criteria: Amsterdam, Bethesta, and Kastrinos criteria. 
  • Histological criteria: immunohistochemistry for mismatch repair proteins, microsatellite instability, BRAF
  • Algorithms: PREMM5

In individuals with Lynch syndrome, preventive strategies are aimed at early identification of pre-neoplastic lesions. Prompt treatment of the latter will prevent the development of advanced neoplasia. Prevention consists therefore in the regular monitoring of the body districts at risk of developing the neoplasm, in particular the gastrointestinal tract and the uterine tract. Surveillance of other areas is evaluated on a case-by-case basis according to the clinical picture and/or familiarity for neoplasia in that area. In the era of precision medicine, Lynch syndrome requires careful, personalized, almost sartorial evaluation. The complexity of disease biology is integrated with personal and family history for determining the most appropriate methods and timing for oncologic surveillance of each individual.

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