Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published August 22, 2018


What are the mismatch-repair genes affected in patients with the Lynch syndrome?

The Lynch syndrome is the most common inherited syndrome associated with colorectal cancer, accounting for 3% of new diagnoses. Colorectal cancer occurs at a younger age among patients who have the Lynch syndrome than among patients who have sporadic colorectal cancer (45 to 60 vs. 69 years of age), although the age at onset varies according to genotype. Read the latest NEJM Clinical Practice here

Clinical Pearls

Q: What is the mechanism by which Lynch syndrome–associated cancers occur?

A: The Lynch syndrome phenotype is characterized by a predominance of cancers on the right side of the colon and a propensity for synchronous and metachronous colorectal cancers. These tumors typically show poor differentiation that may include mucinous features or a medullary growth pattern, as well as abundant infiltrating lymphocytes in the tumor that represent a response to neoantigens generated by a high mutational burden. Hypermutation results from deficient mismatch repair that compromises the ability to repair base-pair mismatches in DNA, which in turn confers a predisposition to colorectal cancer and other cancers over the course of a person’s lifetime.

Q: What cancers other than colorectal cancer are associated with the Lynch syndrome?

A: Although colorectal cancer is the most common cancer associated with the Lynch syndrome, extracolonic cancers, including cancers of the endometrium (the most common), small bowel, ureter and renal pelvis, stomach, hepatobiliary tract, and ovary, can occur.

Morning Report Questions

Q: What are the mismatch-repair genes affected in patients with the Lynch syndrome?

A: The diagnosis of the Lynch syndrome is made by identification of a germline mutation in a mismatch-repair gene (MLH1, MSH2, MSH6, or PMS2) or a germline deletion in EpCAM (epithelial-cell adhesion molecule) (which leads to epigenetic inactivation of MSH2). When one of the mismatch-repair genes is mutated in the germline, there is a high probability that a second “hit” of somatic mutation will occur in the other copy of that gene that disables mismatch-repair function and can lead to cancer. Resultant deficient mismatch repair leads to microsatellite instability in cancers, which is characterized by alterations in lengths of repetitive regions within DNA known as microsatellites. The risk of cancer depends on the affected gene. Mutations in MLH1 or MSH2 have been reported to account for 60 to 80% of all Lynch syndrome–associated cancers. Recently, guidelines supported by multiple organizations have recommended universal testing of all patients with newly diagnosed colorectal cancer for deficient mismatch repair or microsatellite instability to determine whether the cancer is associated with the Lynch syndrome.

Q: What are the guidelines for screening family members of a person with the Lynch syndrome?

A: Once the diagnosis of the Lynch syndrome is confirmed in a proband by the identification of a germline mutation in a mismatch-repair gene, genetic testing is recommended for at-risk family members, beginning with first-degree relatives. The Lynch syndrome can be identified or ruled out by analysis of a blood sample for the specific mutation identified in the proband. Persons with the mutation, regardless of whether cancer develops in them, have a 50% chance of passing the mutation on to their offspring. For family members who lack an identified germline mutation, routine screening for colorectal cancer is recommended according to guidelines for the general population. For carriers of the mutation, colonoscopy every 1 to 2 years is recommended beginning at 20 to 25 years of age or 2 to 5 years before the youngest age at which colorectal cancer was diagnosed in the family if the diagnosis occurred before 25 years of age; for carriers of MSH6 or PSM2, colonoscopy every 1 to 2 years should begin at 30 years of age and 35 years of age, respectively.

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