This article is a comprehensive review of
genetic testing for hereditary colorectal cancer detection. There is no longer
any doubt that hereditary factors contribute to an increased risk of colon
cancer. It remains to be seen how great their contribution is, how best to
identify high-risk groups, and how best to care for carriers of the mutated
genes. Approximately 25% of colorectal cancers occur in younger individuals or
those with a family history of the disease, suggesting a heritable
The recent identification and cloning of the genes responsible
for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal
cancer (HNPCC), along with other colon cancer genes, has led to the availability
of genetic testing for hereditary colorectal cancer. Identifying individuals
with FAP and HNPCC may result in individually tailored surveillance programs and
consideration of prophylactic surgery to prevent the development of tumors.
The clinical presentation and endoscopic appearance of FAP is
fairly classical, and diagnosis is usually straightforward. Because the clinical
findings of HNPCC can be subtle, an experienced gastrointestinal pathologist
knowledgeable of the characteristics of HNPCC will help screen more patients for
potential genetic testing. Colorectal cancer arising in HNPCC patients is
typically characterized by mucinous or signet-ring cell carcinoma, poor cellular
differentiation, and the presence of peritumoral lymphocytic infiltration.
The histopathologic features of adenomas in HNPCC families
usually include a villous component and show more high-grade dysplasia,
supporting the hypothesis that they can progress to cancer more frequently and
more rapidly then sporadic adenomas. The fact that over 90% of HNPCC-related
cancers demonstrate microsatellite instability suggests that screening tumors
for high-frequency microsatellite instability is one way of selecting
individuals for HNPCC testing.
Indications for Genetic Testing
There must be a suspicion of hereditary colon cancer before it
can be tested for, diagnosed, or treated surgically. Among the clues pointing to
hereditary colon cancer are a family history, early age of cancer onset,
multiple primary tumors, multifocal cancers, and cancer in combination with
congenital abnormalities. Physicians continue to miss high-risk patients,
despite the obvious phenotype of FAP patients. In 1990, Arvanitis et al
demonstrated that the majority (59%) of patients with FAP die of metastatic
colorectal cancer. Genetic counseling should be offered to persons with an
increased risk of FAP due to family history or the presence of multiple colonic
Genetic counseling of patients newly diagnosed with FAP and
their families is essential. Patients with clinical FAP and no family history
should also undergo genetic testing, as these patients represent the 30% with
new germ-line mutations. Attenuated FAP can be particularly difficult to
diagnose clinically because affected patients may have only one or two small,
right-sided adenomas, and colorectal cancer, when it develops, tends to occur 10
to 15 years later than classic FAP.
Determining when genetic testing is indicated for HNPCC is a far
more difficult problem. Unlike FAP, patients with HNPCC do not have a unique
phenotype. As in FAP, affected individuals should be tested first. The Amsterdam
criteria have traditionally been used to determine eligibility for HNPCC
testing; however, these guidelines have been criticized as being both too
restrictive and too lax. The Amsterdam criteria ignore several important
characteristics of HNPCC, such as the occurrence of extracolonic cancers. For
the criteria to be met, a detailed family history is needed, and it is often
Genetic counseling generally serves two functions: (1) to help
the patient and family understand the medical and genetic information about FAP
and HNPCC, and (2) to provide emotional and psychological support as the family
copes with the new information and the burdens that such information can impose.
The pretest counseling should include patient education on the risks,
prophylactic procedures, and intervention options, and should address all
potential consequences of genetic testing, including insurance and employability
issues. Genetic testing for hereditary colon cancer is expensive and not
uniformly covered by insurance companies. Furthermore, up-front copay costs and
concern over insurance discrimination sometimes discourage high-risk patients
from undergoing genetic testing.
Implications of Genetic Testing
Genetic testing results can alter the risk for index case family
members from the standard 50% to essentially 0% or 100%. Once an index-affected
individual is identified, presymptomatic genetic testing of at-risk family
members can be performed quickly, accurately, and inexpensively. Family members
testing negative do not have an increased risk of colon cancer and can avoid
intense screening programs. Those testing positive are likely to improve their
compliance for long-term screening programs and consider prophylactic surgery.
If the genetic test fails to identify the genetic alteration in
the index person, no statement can be made regarding the individual gene carrier
status of all family members. The specific gene mutation is undetectable in 20%
of hereditary colon cancer families, and thus a negative genetic testing result
could represent a false-negative.
The goals of chemoprevention are to reduce cancer risk and
improve quality of life. Potential benefits associated with the use of an active
chemoprevention agent in hereditary colon cancer would be a decline in the
frequency of surveillance procedures, surgical resections, cancer incidence, and
Many investigators have examined the role of nonsteroidal
anti-inflammatory drugs (NSAIDs) in the regression and prevention of adenomas in
animal and human studies. Recent research has shown sulindac (Clinoril), a
cyclooxygenase (COX)-2 inhibitor, to be quite effective at causing prevalent
adenomas to regress or modulating proliferative markers, generally yielding
noticeable results within 2 to 8 months after initiation. The long-term
efficacy of sulindac seems to require prolonged therapy, because adenomas have
frequently recurred soon after discontinuation of the agent. Several ongoing
chemoprevention trials are looking at the role of selective COX-2 inhibitors in
polyp regression in hereditary colon cancer patients.
In conclusion, the authors present an excellent overview of the
current issues surrounding hereditary colorectal cancer. Patients at risk for
this disease should undergo a comprehensive evaluation at institutions with
dedicated geneticists, surgeons, gastroenterologists, social workers, and
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