Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Colon Carcinoma, familial, non-polypous (HNPCC) [C18.9] [Z80.0]

OMIM numbers: 609310, 120436 (MLH1), 120435, 609309 (MSH2), 614350, 600678 (MSH6), 614337, 600259 (PMS2)

Dr. biol. hum. Stefanie Kühner, Dr. med. Dagmar Wahl,
Dr. med. Imma Rost

Scientific Background

The colorectal carcinoma (CRC) is one of the most common tumor diseases in the Western developed countries. In approximately 10%, familial clustering is observed which is usually characterized by manifestation prior to age 50. There are two major forms of familial, primarily genetic colorectal diseases: hereditary non-polypous colon carcinoma (HNPCC or Lynch syndrome, approx. 2–3% of all CRC cases), caused by mutations in the DNA repair genes, and the group of rare syndromes characterized by colorectal polyposis such as familial adenomatous polyposis (FAP) (approx. 0.5% of all CRC cases).

The age of manifestation in HNPCC is usually under 50 (average age 45 years). The majority of all colorectal carcinomas are located in the right hemicolon. Histologically they tend to be poorly differentiated with abundant mucin and marked lymphocytic infiltration. Carriers of a mutation in one of the four responsible DNA mismatch repair genes are also at a higher lifetime risk of other tumors, mainly endometrial, ovarian, gastric, urothelial, bile duct carcinomas and carcinomas of the small intestine.

HNPCC (Hereditary Nonpolyposis Colorectal Cancer) follows an autosomal dominant inheritance pattern caused by mutations in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6 and PMS2. The germline mutation, usually inherited from one parent, is present in every somatic cell while the second, functioning allele suffices to keep the repair system intact. A random mutation event (somatic mutation) causes the so far intact allele to lose its function as well; the cell exhibits a repair defect (Knudson multiple-hit hypothesis). Inactivating point mutation in MLH1 and MSH2 make up approximately 60% and 30% of all MMR gene mutations respectively, 7–10% are MSH6 mutations and less than 5% are PMS2 mutations. The MMR system recognizes and corrects errors during DNA replication. Mutations in the MMR genes result in defective DNA replication during the cell division in the tumor tissue and thus to accumulation of mutations and altered protein expression. This is also explains the immune response in form of lymphocytic infiltration in the tumor tissue.

The diagnosis HNPCC is established clinically, when the Amsterdam criteria are fulfilled (see indication). The Amsterdam criteria, however, are frequently not fulfilled due to the low number of family members or incomplete penetrance of the HNPCC syndrome. Therefore, the revised Bethesda guidelines were formulated to identify further HNPCC patients (see indication).

The HNPCC diagnostic procedure involves several steps: If HNPCC is suspected (according to the Amsterdam or revised Bethesda criteria) a microsatellite (MSI) analysis as well as immunohistochemical analysis (IHC) from tumor material is carried out.

If a patient fulfills the Amsterdam or Bethesda criteria, HNPCC is suspected. Clarification regarding whether the disease is present involves several steps. Initially, an affected individual (index patient) should be examined, just like in the case of any tumor disease. The tumor tissue is analyzed by immunohistochemistry (IHC) or microsatellite instability (MSI) (see chapter molecular Oncology – Pathology). HNPCC is confirmed if the absence of protein expression of one of the MMR genes or high microsatellite instability is detected. In dependence of the IHC result, a blood sample of the patient can then be tested for germline mutations of the MMR genes. If the index patient has a pathogenic germline mutation in one of the four MMR genes, other, so far healthy family members can undergo targeted mutation analysis. This falls under the category of predictive diagnostics; therefore, genetic counseling has to be carried out prior to testing as well as after having received the result (§10, section 2, GenDG). Carriers of a mutation in one of the MMR genes should attend a comprehensive medical prevention program, including annual coloscopy starting from the age of 25.