individuals at high risk of Lynch has been found to reduce risk of colorectal cancer by about 60 percent. Genetic testing for MMR gene mutations can identify individuals with Lynch syndrome. Identifying Lynch syndrome in newly diagnosed colorectal patients and offering testing to relatives of patients with Lynch could identify relatives with Lynch syndrome before they develop cancer and allow them to reduce their risk through screening. Potentially, more than 2,500 cases of colorectal cancer could be prevented each year if all individuals with Lynch were identified and screened early (Baglietto et al., 2009; EGAPP, 2009; Horner et al., 2009; Palomaki et al., 2009; Stoffel et al., 2009; U.S. Cancer, 2009; U.S. Preventive Services Task Force, 2008).

Test Purpose

Screening: a test to identify patients with colorectal cancer who should be offered confirmatory molecular testing.

Diagnostic: a test to confirm that the person has a specific genetic condition.

Test Description

DNA analysis of 4 major MMR genes (MLH1, MSH2, MSH6, and PMS2) is the standard test for Lynch (Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009). Because of the cost of MMR testing, 3 preliminary tests on tumors may be considered in patients with colorectal cancer in order to determine whom to test for MMR mutations. Microsatellite instability (MSI) testing identifies tumors demonstrating abnormalities of DNA mismatch repair. Patients with a high instability score can be offered DNA sequencing of the 4 MMR genes. Immunohistochemical (IHC) staining tests of tumors identify proteins produced by MMR genes. Patients with no staining of a specific protein can be offered DNA analysis of the MMR gene identified by IHC. About 30 percent of tumors that lack staining for the MLH1 protein have a somatic mutation in BRAF (V600E) or MLH1 promoter hypermethylation, neither of which is associated with Lynch syndrome. BRAF gene testing and MLH1 promoter hypermethylation may be done for patients who have no IHC staining for MLH1. Patients who do not have the BRAF mutation or MLH1 promoter hypermethylation can be offered DNA analysis of MLH1. MLH1 promoter hypermethylation was not considered in the published evidence reviews. Other test combinations are sometimes used (Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009).

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