The study of genetics in cancer has become extremely important as new ways to assess and identify risk of the disease become evident.1 Although the lifetime risk of colorectal cancer (CRC) in the general population is approximately 5% to 6%, patients with a familial risk make up almost 20% of all patients with CRC.2 There are several forms of hereditary CRC, but the main forms of this type of CRC are:
- Hereditary nonpolyposis colorectal cancer (HNPCC), also known as the Lynch syndrome, often appearing in the proximal area of the colon, usually with diploid DNA, mutations in mismatch-repair genes, and less aggressive behavior
- Accounts for 2% to 3% of all CRC
- Polyp formation rarely seen with this syndrome2
- Familial adenomatous polyposis (FAP) occurring in the distal colon, more likely to have aneuploid DNA, with mutations in APC, TP53, and K-ras genes, and more aggressive behavior2
- Accounts for less than 1% of the annual CRC patient population
- Usually presents with literally hundreds to thousands of polyps2
- Peutz-Jeghers syndrome: autosomal dominant inherited condition in which intestinal hamartomatous polyps occur at the same time with mucocutaneous melanocytic macules. The intestinal growths are usually hamartomas; however, patients with Peutz-Jeghers syndrome have a 15-fold increased risk of developing intestinal cancer compared with that of the general population3
- Juvenile polyposis: rare syndrome with autosomal dominant inheritance and the most common cause of colonic polyposis in children4
- Gardner’s syndrome: considered a variant of FAP; patients usually present with literally hundreds to thousands of polyps and probably have the same genotype as FAP coli4
- Cowden disease: hamartomatous polyposis syndrome in which colonic hamartomatous polyps and benign and neoplastic tumors can appear on the thyroid, breast, uterus, and skin2
- Bannayan-Ruvalcaba-Riley syndrome: rare variant in which patients have microcephaly, fibromatosis, hamartomatous polyposis, and hemangiomas2
Genetics of Hereditary CRC
Lynch syndrome (or HNPCC) is the most common hereditary CRC.5 Mutations in 4 mismatch-repair (MMR) genes in the germlines specific to Lynch syndrome have been discovered.5 These mutations are in the following genes: MSH2, MLH1, PMS2, and MSH6. These patients have an 80% risk of being diagnosed with CRC by age 75.1 This syndrome also puts patients at risk for the development of tumors in additional sites, such as the stomach, ovary, small intestine, ureter, and kidney. The risk of endometrial cancer in these patients is approximately 30% to 60%, compared with the general risk for endometrial cancer at 3%.1 Although the significance of microsatellite instability (MSI) in patients with HNPCC is not entirely known, research has shown that MSI is characteristic of patients with Lynch syndrome.6-8 The microsatellites are genomic areas that contain short DNA sequences or repeated single nucleotides and exist by the thousands in the human genome.2 During replication of the DNA, mutations occur in some of the microsatellites, which then are repaired by mismatch-repair proteins. In some tumors, repair may be inadequate, with insufficient proteins.2
FAP is also caused by mutations, but these changes occur in the APC (adenomatous polyposis coli) gene, which is located on chromosome 5q21-q22. The less severe form of FAP is called attenuated FAP, and these patients may present with fewer than 100 colorectal adenomas, occurring in proximal locations for the most part. However, this form of FAP also has a very high risk of colon cancer, with 80% of patients developing the disease by age 70.1,9 There is usually 100% penetrance, and almost all patients risk a diagnosis of CRC by the age of 40 unless preventive surgery is performed.9 Some recent research has shown that a small percentage of patients with an FAP phenotype may have no APC mutation but that they instead show a biallelic germline mutation in the base-excision-repair gene MYH. This group has an autosomal recessive pattern of inheritance.9 They are also at risk for other primary adenomas and carcinomas of the duodenum and rectum, as well as other tumors.1
When someone is diagnosed with a hereditary CRC syndrome, suitable relatives should be notified, with appropriate individuals receiving genetic counseling and testing.2 For HNPCC, the Amsterdam II criteria has been used to help clinicians determine which patients might have the syndrome.10
Amsterdam II criteria for HNPCC10
At least 3 members of the family must have been diagnosed with a cancer associated with HNPCC (colon, endometrium, small bowel, ureter, or renal pelvis); all the following should be present:
- One of the 3 family members must be a first-degree relative (parent, offspring, or sibling) of the other 2 members
- At least 2 successive generations of the family should be affected
- At least 1 of these relatives must have been diagnosed with cancer before age 50
- FAP must be ruled out as the cause of colon cancer in the family
- Tumors should be verified whenever possible
Recommendations for Surveillance2
- Annual full colonoscopy, initiated between the ages of 20 and 25 years, is recommended for patients with strong evidence of HNPCC or documented germline mutations in MLH1, LSH2, or MSH6
- Extracolonic screening, especially of the endometrium and ovary, is indicated, with transvaginal ultrasonography and endometrial aspiration begun at the age of 30 years and repeated annually
- Ovarian ultrasonography and serum CA-125 screening should begin at the age of 30 years
- Patients with an APC mutation or who have one or more first-degree relatives with FAP or an identified APC mutation (or both) are at high risk and should be screened with flexible sigmoidoscopy by the age of 10 to12 years
- Patients with colonic polyps, a positive APC germline mutation, or both will need annual endoscopic examination
- With advanced disease, as seen frequently in the late teens and early 20s, polypectomy may be too difficult to achieve (with literally hundreds to thousands of polyps to remove), and consideration of prophylactic subtotal colectomy and continued annual endoscopy of the remaining rectal tissue is recommended
Pharmacologic Treatment of FAP
Although the use of nonsteroidal anti-inflammatory medications has been studied in FAP patients), and has shown a significant reduction in the size and number of polyps in some patients (leading to the approval of celecoxib in this setting), researchers have reported that after a period of time, polyps can return.2,11 The use of these agents as chemoprevention continues to be studied, and at this time, these drug strategies should not replace adequate screening for the development of cancer in these high-risk patients.2
Oncology nurses need to be aware of hereditary colon cancer syndromes. In this age of increasing awareness regarding genetic cancer syndromes, clinicians should understand the most common inherited forms of CRC and the need to identify patients who are at high risk. Because early identification and intervention can help to prevent the development of colon cancer, heightened awareness is especially important. Screening and surveillance recommendations should be discussed with appropriate patients, with oncology nurses playing a role in this important endeavor; referrals to appropriate specialists or participation in national registries can also play a role in the care of these patients.10
- Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. 2005;23: 276-292.
- Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919-932.
- Mukherjee S, Duchini A, Carethers JM. Peutz-Jeghers syndrome. EMedicine. Available at: http://www.emedicine.com/med/topic1807.htm. Accessed December 14, 2010.
- Khan AN, Macdonald S. Colon, polyposis syndromes. EMedicine. Available at: http://www.emedicine.com/radio/topic567.htm. Accessed December 14, 2010.
- Hendriks YM, de Jong AE, Morreau H, et al. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin. 2006;56:213-225.
- Kim GP, Colangelo LH, Wieand S, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study. J Clin Oncol. 2007;25:767-772
- Boland CR. Clinical uses of microsatellite instability testing in colorectal cancer: an ongoing challenge. J Clin Oncol. 2007;25:754-756
- Pucciarelli S, Agostini M, Viel A, et al. Early-age-at-onset colorectal cancer and microsatellite instability as markers of hereditary nonpolyposis colorectal cancer. Dis Colon Rectum. 2003;46:305-312.
- Guillen JG, Wood WC, Moley, JF, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol. 2006;24:4642-4660.
- Vasen HF. Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol. 2000;18:(21 suppl):81s-92s.
- Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946-1952
- Griffin-Sobel JP. Biology, prevention, and screening. In Griffin-Sobel JP, ed. Gastrointestinal Cancers. Pittsburgh, PA: Oncology Nursing Society; 2007:19-30.
HCCA: the official web site of the Hereditary Colon Cancer Association. Available at: http://www.hereditarycc.org/index.html. Accessed December 14, 2010.
Memorial Sloan-Kettering Cancer Center. Hereditary Colorectal Cancer Family Registry. Available at: http://www.mskcc.org/mskcc/html/14539.cfm. Accessed December 14, 2010.
National Institutes of Health. Genetics home reference. Available at: http://ghr.nlm.nih.gov/condition=hereditarynonpolyposiscolorectalcancer. Accessed December 14, 2010.
Genetic Health. How is colon cancer inherited? Available at: http://www.genetichealth.com/CRC_Colon_Cancer_Does_Colon_Cancer_Run_in_Families.shtml. Accessed December 14, 2010.
Amsterdam II criteria—the International Collaborative Group (ICG) met in Amsterdam in 1990 to establish criteria for identifying individuals at risk for familial inherited CRC known as (classic Amsterdam criteria). Over time, the range of cancers that can present in HNPCC families were identified. The ICG revised the criteria in 1999, which are now known as Amsterdam II criteria.
aneuploid DNA—a cell with too many or too few chromosomes. Cancer cells are aneuploid.
APC, TP53, and K-ras gene mutations—proposed genetic model for suggesting sequential accumulation of mutations in the genes for CRC. This sequence drives healthy colonic epithelia dysplastic adenoma to become CRC. Griffin-Sobel12 (Figure 3-2, page 21) illustrates these mutations.
autosomal dominant—1 copy of a mutant allele and 1 normal allele, meaning there is a 50-50 chance of passing on the mutant allele and disorder. In autosomal recessive diseases, the individual has 2 copies of the mutant allele
base-excision-repair gene MYH—carries the message to cells to repair the DNA. Polyposis results if both MYH inherited genes are mutated
biallelic germline—both copies of 1 gene; 1 from the mother and 1 from the father
diploid DNA—genetic material with paired chromosomes: one chromosome from each parent; 46 chromosomes in the diploid human genome
MSH2, MLH1, PMS2, and MSH6 gene mutations—responsible for HNPCC having different chromosome locations