Inherited (germline) mutations in several genes involved in DNA mismatch repair are the major cause of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The syndrome shows autosomal dominant inheritance (only one copy of a mutation is necessary for expression of disease) and incomplete penetrance (not all mutation carriers will get the disease). At least five human genes (MLH1 ^{1, 2}, MSH2 ^{3, 4} , MSH6 ^{5, 8~13}, PMS1⁶ , PMS2 ⁶ ) have been implicated in HNPCC.

HNPCC comprises about 5-10% of all colon cancer and confers up to an 80% lifetime risk of developing colon cancer, a 35% risk for endometrial cancer, a 9% risk for ovarian cancer, and a small risk (<10%) for several other extracolonic cancers as well1. Alterations of the MLH1 and MSH2 genes account for approximately 90% of mutations in HNPCC ⁴. Alterations of the MSH6 are estimated to account for approximately 7-10% of mutations in HNPCC ^{5, 12, 14}. It has been sugggested that germline MSH6 mutations predispose a special subset of HNPCC individuals to primarily late-onset, familial colorectal or endometrial carcinomas that often do not fulfill classic criteria for HNPCC ^{9, 12, 13}. MSH6 mutations have also been detected in patients with tumors that show no or low microsatellite instability ^{10, 11}.

A characteristic of HNPCC tumors is microsatellite instability (MSI). Detection of microsatellite instability in a tumor sample will increase the probability of detecting a germline mutation in a DNA mismatch repair gene from the patient sample. Thus, MSI analysis is usually performed prior to proceeding with full mutation analysis of the mismatch repair genes, MLH1, MSH2, and/or MSH6. Immunohistochemistry (IHC) performed on a tumor sample may detect the absence of one or more of these mismatch repair proteins and thus suggest a candidate gene for full mutation analysis. Please also see our assay summary about MSI and IHC.

To open a printable assay summary in a new window, click the links below.

HNPCC - Genes Assay Summary
HNPCC - MSI IHC Assay Summary
(in portable document format (pdf) which requires Adobe® Acrobat® Reader™ to view or print; download latest version free)

Please submit the Test Request Form (TRF) and the HNPCC Patient Information Form when ordering this test.

References
1. Bronner, C.E. et al (1994). Nature 368:258-261.
2. Papadopoulos, N. et al. (1994). Science 263:1625-1629.
3. Fishel, R. et al. (1993). Cell 75:1027-1038.
4. Leach, F. S. et al. (1993). Cell 75:1215-1225.
5. Miyaki, M. et al. (1997). Nat. Genet. 17:271-272.
6. Nicolaides, N. C. et al. (1994). Nature 371:75-80.
7. Umar, A.. et al. (2004). J.Natl.Cancer Inst. 96:261-268.
8. Edelmann, W. et al. (1997). Cell 91:467-477.
9. Kolodner, R.D. et al. (1999). Cancer Res. 59:5068-5074.
10.Wu, Y. et al. (1999). Am. J. Hum. Genet. 65:1291-1298.
11.Parc, Y.R. et al. (2000). Cancer Res. 60: 2225-2231.
12.Berends, M.J.W. et al. (2002). Am. J. Hum. Genet. 70: 26-37.
13.Plaschke, J. et al. (2004). J. Clin. Oncol. 22: 4486-4494.
14. Peltomarki P. et al. (2003) J. Cli. Oncol. 21:1174-9.

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