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Familial polyposis

Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps are benign, they may become malignant, predisposing patients to colorectal cancer. more...

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Signs and symptoms

From the age of 16 onward, patients develop hundreds to thousands of polyps. These may bleed, leading to admixture of blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemia due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or even with metastasis in the liver or elsewhere.

The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the duodenum and stomach. Other signs that may point at FAP are pigmented lesions of the retina ("congenital hypertrophy of the retinal pigment"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner syndrome (with or without abnormal scarring).

Diagnosis and treatment

In patients with a strong family of colorectal cancer and symptoms suggestive of polyposis, colonoscopy is indicated, with biopsy of a number of polyps (especially of those that appear dysplastic). In severe cases, a full or partial colectomy is required.

Blood tests (liver enzymes) and ultrasound of the abdomen are often performed to rule out metastasis to the liver.

Genetic testing provides the ultimate diagnosis in 95%; genetic counseling is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to have the FAP mutation.


FAP is due to mutations in the APC gene, which is located on the fifth chromosome (5q21-q22), or in the MUTYH gene located on chromosome 1 (p34.3-p32.1).

APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.

Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. Often, the remaining "normal" allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53 or KRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.

The normal function of the APC gene product is still being investigated; it is present both the cell nucleus and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton organization.


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Genetic markers improve colorectal screen - test to predict development of adenomatous polyposis, a condition that often precedes colorectal cancer
From Science News, 2/16/91 by Wendy Gibbons

Genetic markers improve colorectal screen

A rare genetic defect causes tiny polyps -- sometimes hundreds of them -- to grow in the large intestine. Without surgery to remove the polyp-ridden section of the colon, cancer eventually results. Now researchers have developed a genetic test to predict a person's risk of developing the precancerous condition, known as familial adenomatous polyposis (FAP).

People who have a parent with FAP run a 50-50 chance of inheriting the gene and developing the disorder, which often emerges during adolescence. To detect FAP in time to stop its progression to cancer, physicians typically begin checking for polyps when youngsters in families carrying the gene reach their teens, repeating the exams annually and watching for additional symptoms such as bony growths on the head.

Used in conjunction with standard diagnostic methods, the new genetic screen for members of FAP-prone families should reduce the need for frequent colorectal exams among those who don't inherit the gene while increasing the chance of identifying those who do, says study leader Malcolm G. Dunlop of the Medical Research Council Human Genetics Unit in Edinburgh, Scotland.

Scientists have yet to find the gene for FAP, but they have founds a number of DNA probes, or "markers," positioned on the chromosome very close to it. Dunlop and his colleagues, who describe their work in the Feb. 9 LANCET, used six previously identified markers to screen blood samples from 41 members (including children, teens and adults) of seven families with a history of FAP.

The screen revealed a high risk of FAP in four adults who had stopped having annual colon exams in their 30s or late 20s because their results had consistently come up negative. Upon subsequent examination, one showed cancerous growths and the other three showed polyps that probably would have progressed to cancer if not detected, Dunlop says. All four underwent colorectal surgery.

For 18 of the study's 41 participants, the blood test indicated a very low probability of carrying the FAP gene. "That's obviously pretty important, because that means they don't have to be [examined! so often," Dunlop says.

The researchers suggest that people from affected families who show a low risk on the genetic test and also test negative for clinical symptoms at age 15 need undergo only one additional exam at about age 30. Teenagers showing a moderate genetic risk should receive colorectal exams every two to three years, they recommend, while high-risk test results call for yearly exams.

Dunlop cautions, however, that the six markers yielded inconclusive results for nearly a third of the study group. Until researchers improve the technique's accuracy by finding markers for additional DNA sequences linked to the FAP gene, physicians using the test must combine it with clinical exams, he says.

Scientists could develop a better screen for FAP by identifying the DNA sequence of the culprit gene. But even then, the linked markers used in Dunlop's study would "undoubtedly prove useful," says Bert Vogelstein of the Johns Hopkins School of Medicine in Baltimore, who directs a search for the gene. Because the FAP gene's apparently large size allows for many defect sites, researchers could never be sure that their DNA probes uncovered every possible glitch along its length -- but by incorporating markers near the gene, they could boost the odds of detection, Dunlop says.

Although FAP is uncommon -- underlying fewer than 1 percent of all colon cancers -- colorectal cancer itself ranks as the second leading cancer in the United States. Understanding the genetics of FAP may help clarify the causes of colon cancer in people who have not inherited the defect, Dunlop suggests. "The exciting thing," he says, "is that this gene might be involved in ordinary [colorectal! cancer," perhaps by mutating at some later point in life.

COPYRIGHT 1991 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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