Test ID: HNPCC
Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Screen

Identification of individuals at high risk for having hereditary nonpolyposis colon cancer (HNPCC)/Lynch syndrome

Both microsatellite instability (MSI) and immunohistochemistry (IHC) testing of tumor tissue from an affected individual are performed to screen individuals for possible HNPCC/Lynch syndrome.

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant inherited cancer syndrome that predisposes individuals to the development of colorectal, endometrial, gastric, upper urinary tract, and other cancers. Individuals with HNPCC/Lynch syndrome have a germline mutation in 1 of several genes involved in DNA mismatch repair. The majority of mutations associated with HNPCC/Lynch syndrome occur in MSH2 and MLH1; however mutations in MSH6 and PMS2 have also been identified.

There are several strategies for evaluating individuals whose personal and/or family history of cancer is suggestive of HNPCC/Lynch syndrome. Testing the tumors from individuals at risk for HNPCC/Lynch syndrome for microsatellite instability (MSI) demonstrates the presence or absence of defective DNA mismatch repair within the tumor. Individuals whose tumors demonstrate the presence of defective DNA mismatch repair in the form of microsatellite instability are more likely to have a germline mutation in one of the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Tumors from affected individuals usually demonstrate an MSI-H phenotype (MSI >30% of microsatellites examined), whereas tumors from individuals who do not have HNPCC/Lynch syndrome usually have an MSS/MSI-L phenotype (MSI at <30% of microsatellites examined). Immunohistochemistry (IHC) is a complementary testing strategy to MSI testing. In addition to identifying tumors with defective DNA mismatch repair, IHC analysis is helpful for identifying the gene responsible for the defective DNA mismatch repair within the tumor, because the majority of MSI-H tumors show a loss of expression of at least 1 of the 4 mismatch repair genes described above.  

Testing is typically first performed on the tumor of an affected individual and in the context of other risk factors, such as young age at diagnosis or a strong family history of HNPCC/Lynch syndrome-related cancers. If defective DNA mismatch repair is identified within the tumor, mutation analysis of the involved gene can be performed to identify the causative germline mutation and allow for predictive testing of at risk individuals.

Of note, MSI-H phenotypes and loss of protein expression by IHC have also been demonstrated in various sporadic cancers, including those of the colon, endometrium, and stomach. Absence of MLH1 and PMS2 protein expression within a tumor, for instance, is most often associated with a somatic alteration in individuals with an older age of onset of cancer than typical HNPCC/Lynch syndrome families. Therefore, an MSI-H phenotype or loss of protein expression by IHC within a tumor does not distinguish between somatic and germline mutations. Genetic testing of the gene indicated by IHC analysis can help to distinguish between these two possibilities. In addition, when absence of MLH1/PMS2 are observed, MLBRF/87931 MLH1 Hypermethylation and BRAF Mutation Analyses, Tumor or MLH1H/87978 MLH1 Hypermethylation Analysis, Tumor may also help to distinguish between a sporadic and germline etiology.

It should be noted that this HNPCC screen is not a genetic test, but rather stratifies the risk of having an inherited cancer predisposition syndrome, and identifies patients who might benefit from subsequent genetic testing.

See Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm in Special Instructions for additional information.

An interpretive report will be provided.

The report will include specimen information, assay information, and interpretation of test results. Microsatellite stable (MSS) is reported as MSS/MSI-L (0 or 1 of 5 markers demonstrating instability) or MSI-H (2 or more of 5 markers demonstrating instability).

Owing to the sensitive and complicated nature of cancer risk stratification testing, it is strongly recommended that testing be performed in conjunction with appropriate pre- and post-test counseling.

The finding of tumor MSI or the absence of protein expression for MSH2, MSH6, MLH1, or PMS2 does not distinguish between somatic and germline mutations.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given to us is inaccurate or incomplete.

Over 1,000 patients who have colon cancer have been evaluated for these genetic alterations (1/2006).

1. Baudhuin LM, Burgart LJ, Leontovich O, Thibodeau SN: Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch Syndrome. Fam Cancer 2005;4(3):255-265

2. Terdiman JP, Gum JR Jr, Conrad PG, et al: Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 2001 January;120(1):21-30

• Molecular Genetics-Inherited Cancer Syndromes Patient Information Sheet
• Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm