Cancer Genetics

The estimated general population lifetime risk for colorectal cancer is 2%-6%, affecting approximately one in every 17 people, including both men and women. Most colon cancers occur sporadically, or cluster in susceptible families. However, several genes have been identified which are associated with hereditary colorectal cancer syndromes. Researchers have currently identified two main forms of hereditary colon cancer: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP represents less than 1% of all colorectal cancer cases diagnosed by doctors each year, and HNPCC represents about 5%.

Clinical criteria can be utilized to help identify patients and families considered to be at-risk for a hereditary colorectal cancer syndrome. These criteria include a strong family history of colorectal cancer (or other types of cancers associated with known cancer predisposition syndromes), early onset colorectal cancer, colon cancer and multiple other primary cancer sites, or a personal and/or strong family history of colorectal polyps.

Polyps
Familial Adenomatous Polyposis (FAP) and Attenuated FAP (AFAP)
Medical Management of FAP and AFAP
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Microsatellite Instability
Immunohistochemical Staining
Medical Management of HNPCC

Colorectal polyps are areas of tissue overgrowth in the colon or rectum. Hyperplastic polyps are benign polyps that have developed in the mucosa, and rarely develop into a malignancy. Two other types of benign polyps are hamartomatous polyps (containing a disorganized mixture of normal cells) and inflammatory polyps (consisting of an inflammatory epithelial reaction).

Adenomatous polyps are considered to be pre-malignant, have glandular tissue at the head of the polyp, and may have stalks composed of fibrosis tissue. Polyps with a distinct stalk are called pedunculated, while those without a stalk (flat adenomas) are termed sessile lesions. Adenomatous polyps may be classified as villous (velvety, cauliflower-like appearance, comprised of epithelial tissues), tubular (because of the branch-like tubules extending from the stalk), or tubulovillous (containing features of both types of polyps). Tubular adenomas are the most common type of adenomatous polyps, and are the least likely to develop into cancer. Villous polyps are the least common adenomatous polyp, but have the greatest potential to develop into a malignancy. Tubulovillous polyps have an intermediate cancer risk; a greater risk to develop into a malignancy than tubular polyps, but not as high of a risk for malignancy as villous polyps.

Gardner syndrome, familial polyposis coli, adenomatous polyposis coli

Familial Adenomatous Polyposis (FAP) and Attenuated FAP (AFAP) are two major hereditary polyposis syndromes associated with germline mutations in the APC gene. The APC gene is located on chromosome 5q21, and codes for a protein involved in signal transduction and cell adhesion. The risk for colon cancer with an inherited mutation in the APC gene is almost 100%. Individuals with an APC gene mutation are at increased risk to develop colon cancer at a significantly younger age than individuals in the general population.

Individuals with mutations in the APC gene are also at increased risk for extracolonic cancers, including duodenal, hepatobilliary, gastric, pancreatic, thyroid and brain cancer. In addition, there is an increased risk for other extracolonic manifestations, including desmoid tumors, CHRPE (congenital hypertrophy of the retinal pigment epithelium), osteomas, and dental abnormalities. Identification of at-risk individuals is valuable in that it allows for early screening to be implemented and the option of preventative surgery may preclude the development of a malignancy.

The main distinguishing factor between these two hereditary syndromes is the number of adenomatous colon polyps that develop in individuals with FAP as compared to individuals with AFAP. Individuals with classic FAP are likely to develop hundreds to thousands of colon polyps as early as the second decade of life, whereas individuals with AFAP will develop fewer polyps, (between 20 and 100), and tend to have a later age at onset of polyp development or colon cancer. These polyps tend to be throughout the colon in FAP, creating what is typically referred to as a "carpet" of polyps. Individuals with attenuated FAP tend to form polyps more proximally in the colon than individuals with classic FAP. Also, although some of the extracolonic manifestations may be present in individuals with AFAP (upper gastrointestinal polyps and cancers), the presence of CHRPE and desmoid tumors are rare.

Most individuals with typical or classic FAP have a mutation in the APC gene that results in truncation of the APC protein in the beginning of the gene. Attenuated FAP is associated with truncating mutations further down the length of the gene. The amount of functional protein may affect the development of polyps (density) and the presentation of the condition (presence or absence of extracolonic features). There is also a relatively high rate of new (de novo) mutations in the APC gene. Approximately 30% of individuals will be the first in their family to have a mutated germline APC gene. Although these individuals did not inherit the new mutation from their parents, they are at risk for passing the mutation on to their own offspring. Familial APC gene mutations are inherited in an autosomal dominant pattern, meaning each child of an affected individual has a 50% chance of inheriting the same mutation.

MEDICAL MANAGEMENT OF FAP AND AFAP

For individuals diangosed with FAP, colectomy is recommended, usually by the age of 25, to prevent a colon cancer from developing. Following colectomy, the NCCN (National Comprehensive Cancer Network) recommends a signoidoscopy every 6 months for three years in patients whose rectum has not been removed, an upper endoscopy every 4 years, and a physical exam annually. Because of the potential of early onset of cancer, individuals who are identified as being at-risk for FAP but who do not have any symptoms or polyps diagnosed have typically been offered annual flexible sigmoidoscopy beginning in early puberty (as early as age 10) and continuing until the age of 24. Between ages 24 and 34, sigmoidoscopy should be performed every two years, then every three years until age 44. After 44 years of age, at-risk individuals should have a sigmoidoscopy every 3-5 years until the age of 50-55, when that individual (without any clinical symptoms) may revert to population-based screening recommendations.

HEREDITARY NON-POLYPOSIS COLON CANCER (HNPCC)

Lynch Syndrome, Family Cancer Syndrome

HNPCC is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. These genes function to maintain the integrity of DNA during replication and are inherited in an autosomal dominant pattern. Several genes have been associated with HNPCC, including hMLH1 (chromosome 3p21), hMSH2 (2p16), hPMS1 (2q31), hPMS2 (7q11), hMSH6 (2p16) and hMSH3 (5q11.2-q13.2). Clinical testing for hMLH1 and hMSH2 mutations is readily accessible, and is thought to be associated with approximately 70% of DNA mismatch repair mutations in HNPCC families. Research testing is available for DNA analysis of the less commonly found mutations in the other DNA repair genes. Vogelstein's multistep model of colon tumorigenesis suggests that inherited mutations in DNA repair genes (such as hMLH1 and hMSH2) cause global genomic instability and result in increased mutation rates in other genes.

HNPCC differs significantly from FAP in that affected individuals are likely to have only a few adenomatous polyps. Despite the smaller number of polyps though, individuals with an HNPCC mutation still have a 70-80% lifetime risk to develop colon cancer (as compared to a 100% risk for individuals with FAP). The average age at colon cancer diagnosis is younger in individuals with HNPCC than in the general population. Individuals with HNPCC are more likely to develop colon cancer on the right side of the colon, proximal to the splenic flexure than in any other part of the colon. Individuals with HNPCC who have already had colon cancer are also at increased risk for metachronous and synchronous colon cancers.

Individuals who have HNPCC are at risk for other cancers in addition to colon cancer. Women with HNPCC are at significant risk for endometrial cancer (up to 40% lifetime risk). There also appears to be an earlier age of onset of endometrial cancer in the HNPCC population, with diagnoses averaging 15 years earlier than in the general population. Other cancers associated with HNPCC mutations include ovarian cancer, gastric cancer, cancer of the small bowel, ureter, or renal pelvis.

Clinical criteria, termed the Amsterdam Criteria, for the diagnosis of HNPCC were established in 1991 to facilitate consistency in research. If a family history is consistent with these requirements it is highly suggestive of HNPCC. However, due to the explicit nature of these criteria guidelines, additional criteria, referred to as the Bethesda criteria, were put forth in an aim to establish a more comprehensive guideline for identifying families with HNPCC. The Bethesda criteria are less restrictive than the Amsterdam criteria, but accordingly, less specific.

Risk assessment for HNPCC utilizes the above criteria as tools for discussing the options related to genetic testing for HNPCC. Microsatellite analysis and immunohistochemistry testing of tumor specimens of at-risk individuals can help identify those individuals for whom DNA analysis is warranted and potentially informative. Some genetics professionals view these laboratory tests as being more cost-effective and less intrusive than DNA analysis.

MICROSATELLITE ANALYSIS

The accumulation of genetic errors caused by mutations in any of the mismatch repair genes can often be seen in small genetic segments called microsatellites that are present throughout the genome. Although their function is unknown, microsatellites are repeating sequences of nucleotide bases within the genome. Microsatellites do not cause a malignancy to develop, but fluctuations in the length of microsatellites (termed instability) can mean that mismatch repair genes are not functioning correctly. Testing can be performed to determine if a tumor exhibits microsatellite instability (MSI) by comparing the microsatellites in the tumor specimen to normal tissue from that individual. If the tumor specimen exhibits alterations within the microsatellite regions, it is indicative of a probable defect in the mismatch repair genes. MSI testing demonstrating instability in the tumor specimen is suggestive of HNPCC, although not diagnostic since 10-15% of sporadic colon cancers will also exhibit MSI.

IMMUNOHISTOCHEMICAL STAINING

Immunohistochemistry (IHC) is a technique for identifying antigens by means of the antibody-antigen interactions. Immunohistochemical staining for hMSH2 and hMLH1 utilizes monoclonal antibodies for the hMLH1 and hMSH2 proteins. Loss of protein expression in a tumor specimen is also suggestive of a mutation in the specific mismatch repair. An abnormal IHC test provides information as to which gene is not functioning properly so that additional testing may be performed to try to determine the specific mutation in that gene.

MEDICAL MANAGEMENT OF HNPCC

Several expert panels have recommended surveillance guidelines for individuals with HNPCC, or individuals considered to be at-risk for HNPCC. Sigmoidoscopy is not useful in individuals with HNPCC because of the propensity to develop right-sided colon cancers, thus colonscopy or double contrast barium enemas are preferentially recommended for screening individuals with HNPCC. The NCCN recommends that individuals with HNPCC consider colonoscopy starting at age 25 or 5 years younger than the earliest cancer diagnosis in the family, whichever comes first, and then yearly from that point on.

Women with HNPCC should consider having transvaginal ultrasound or endometrial biopsies annually beginning at ages 25-35. For individuals at- risk for HNPCC, colonoscopy is recommended beginning around the age of 25 every one to two years, then yearly after the age of 40. Currently there is no consensus regarding screening recommendations for these other HNPCC-related cancers in at-risk individuals. Individuals with a family history of HNPCC or who are known to have HNPCC should have a discussion with a physician familiar with HNPCC regarding other medical management options, such as prophylactic surgeries, urinalysis, CT scans, etc.