COLORECTAL CANCER GENETICS AND FAMILY HISTORY (page 1 of 6)
Sheila Solomon, M.S.
Geneticist, Allegheny Cancer Center

Colorectal cancer (CRC) affects nearly 150,000 people per year in the United States.1
Of these cases, approximately 5 to 10 percent are related to inherited cancer susceptibility. For families with hereditary-based CRC, genetic counseling and testing are important components in determining hereditary cancer risk, strategies for cancer prevention and early detection, all while attending to the emotional and psychological needs of the family.
This brief review will address clinical issues relating to two common hereditary CRC predisposition syndromes and methods for identifying at-risk patients for referral to genetic counseling and
testing.

Hereditary Non-Polyposis Colon Cancer syndrome (HNPCC)
HNPCC accounts for 3 to 4 percent of hereditary CRC. HNPCC predisposes to early-onset CRC with an average age at diagnosis of 45 years, and the lifetime risk of CRC is 82 percent. Tumors predominate in the proximal colon and exhibit distinct pathological and molecular features. HNPCC-associated CRC tends to show mucinous and signet ring features. HNPCC syndrome predisposes
patients to extra-colonic tumors, including cancer of the endometrium (60 percent lifetime risk), stomach (13 percent),
ovary (12 percent), bladder/ureter/urethra (4 percent), brain, kidney and biliary tract (<4 percent).2

Like most cancer predisposition syndromes, HNPCC is inherited in an autosomal dominant manner, whereby both sexes can inherit and pass on the mutated gene. There is a 50 percent chance for all first-degree relatives of an affected family member to inherit the mutated gene. To date, there are five known genes that, when mutated, cause HNPCC. These genes — MLH1, MSH2, MSH6, PMS1 and PMS2 — code for the DNA mismatch repair mechanism in cells. Mutations in MLH1 and MSH2 are responsible for the majority of HNPCC. Mismatch repair genes fix errors in the genetic code of various genes in the cell. When a mutation is present in a mismatch repair gene, other mutations can accumulate without being corrected in the genome (including tumor suppressor genes), resulting in tumor development. Another feature of HNPCC tumors is microsatellite instability (MSI). Microsatellites are sequences of DNA that occur between active genes. Because mismatch repair genes do not work properly in individuals with HNPCC, changes in microsatellite DNA can be seen in HNPCC-related tumors. MSI is found in 95 percent of tumors associated with HNPCC and can be an indication that HNPCC-related mutation is found in a family even if genetic blood testing does not reveal a gene mutation.3

Suspicion of HNPCC can be clarified using the Amsterdam criteria, a set of clinical conditions in a family history listed below:4
1. Three or more relatives with CRC or
HNPCC-associated tumor, AND

2. Two or more affected generations, with one
of the relatives as an immediate family member
to the other two, AND

3. One relative must have CRC or HNPCCassociated
tumor diagnosed under age 50, AND

4. Familial Adenomatous Polyposis (FAP) must
be ruled out.