Clinical Information

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is an inherited cancer syndrome caused by a germline mutation in 1 of several genes involved in DNA mismatch repair (MMR), including MLH1, MSH2, MSH6 and PMS2. There are several laboratory-based strategies that help establish the diagnosis of HNPCC/Lynch syndrome, including testing tumor tissue for the presence of microsatellite instability (MSI-H) and loss of protein expression for any 1 of the MMR proteins by immunohistochemistry (IHC). It is important to note, however, that the MSI-H tumor phenotype is not restricted to inherited cancer cases; approximately 20% of sporadic colon cancers are MSI-H. Thus, MSI-H does not distinguish between a somatic (sporadic) and a germline (inherited) mutation, nor does it identify which gene is involved. Although IHC analysis is helpful in identifying the responsible gene, it also does not distinguish between somatic and germline defects.

Defective MMR in sporadic colon cancer is most often due to an abnormality in MLH1, and the most common cause of gene inactivation is promoter hypermethylation (epigenetic silencing). A specific mutation in the BRAF gene (V600E) has been shown to be present in approximately 70% of tumors with hypermethylation of the MLH1 promoter. Importantly, the V600E mutation has not been identified to date in cases with germline MLH1 mutations. Thus, direct assessment of MLH1 promoter methylation status and testing for the BRAF V600E mutation can be used to help distinguish between a germline mutation and epigenetic/somatic inactivation of MLH1. Tumors that have the BRAF V600E mutation and demonstrate MLH1 promoter hypermethylation are almost certainly sporadic, whereas tumors that show neither are most often caused by an inherited mutation.

Although testing for the BRAF V600E mutation and MLH1 promoter hypermethylation are best interpreted together, they are also available separately to accommodate various clinical situations and tumor types. These tests can provide helpful diagnostic information when evaluating an individual suspected of having HNPCC/Lynch syndrome, especially when testing is performed in conjunction with MSIHC / Microsatellite Instability (MSI)/Immunohistochemistry (IHC) Profile-Lynch/Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Screen, which includes MSI and IHC studies. It should be noted that these tests are not genetic tests, but rather stratify the risk of having an inherited cancer predisposition and identify patients who might benefit from subsequent genetic testing. See Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm in Special Instructions. Also, see Hereditary Colorectal Cancer: Hereditary Nonpolyposis Colon Cancer (November 2005, Communique') in Publications.

Assessment for the BRAF V600E mutation has alternative clinical utilities. BRAF is part of the epidermal growth factor receptor (EGFR) signaling cascade, which plays a role in cell proliferation. Dysregulation of this pathway is a key factor in tumor progression. Targeted therapies directed to components of this pathway have demonstrated some success (increased progression-free and overall survival) in treating patients with certain tumors. Effectiveness of these therapies, however, depends in part on the mutation status of the pathway components.