Hereditary polyposis

There is a disease termed hereditary polyposis. Victims develop a very large number of polyps in their colons, sometimes several thousand. Since the development of a colon polyp is the first step on the road to colon carcinoma, they are at high risk of colon cancer. The associated mutation is in a gene known as the APC gene. 

A second example of inherited predisposition to cancer is provided by hereditary retinoblastoma. This is a rare tumor of the retina and, when it develops, it generally develops in one eye only. Nonetheless, in children with hereditary retinoblastoma, the cancer develops early in life and generally in both eyes. This is a striking example of the inherited predisposition to develop a tumor. As in the case of hereditary polyposis, the defect is in a tumor suppressor gene, in this case RBI. Here too patients have just one intact gene in each of their cells and a single mutation in that gene may be aU that is required to initiate tumor development. 

Familial adenomatous polyposis (FAP) 400 mg twice daily with food, as an adjunct to usual care. (FAP is a hereditary polyposis syndrome with a progression to colorectal cancer. Increased COX-2 protein was found in the polyp specimens from patients with FAP in a dose-dependent manner, early treatment with celecoxib significantly reduces the number of colorectal polyps in patients with FAP) [1]. 

All patients with upper gastrointestinal tract (GIT) symptoms are eligible for gastroscopy. Gastroscopy is also indicated in patients with symptoms of iron deficiency anaemia and/or clinical suspicion of enteropathy, and may be indicated in some asymptomatic patients i.e. healthy members of families with hereditary polyposis syndromes, most typically familial adenomatous polyposis (FAP). Finally, gastroscopy is indicated in follow-up programmes of ulcer treatment, cancer surveillance, dilation procedures, etc. 

Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC)... 

Non-steroidal anti-inflammatory agents, aspirin, and acetaminophen have been suggested for use in the prevention of different cancers, especially hereditary non-polyposis colon cancer.14 While there have been observational studies linked to a reduction of ovarian carcinoma risk, evidence is still lacking. Potential... 

Without regard to therapy, potentially valuable diagnostic tests are available for presymptomatic evaluation of risk of breast cancer due to predisposition from BRCA 1 or BRCA 2 and of colon cancer related to familial adenomatous polyposis (APC gene) or hereditary nonpolyposis mismatch repair genes (MSH 2). Genetic predisposition to Alzheimer disease associated with ApoE4 is neither sufficient nor necessary to lead to the clinical condition, and no definitive therapy is available. 

Chapters 11 and 31. Since cancers contain multiple mutations, they are complex diseases. However, many specific susceptibility loci are being located, including some for breast cancer (Box 11-D),392 prostate cancer,393 and familial adenomatous polyposis, a hereditary disease leading to colon cancer.388 394 Cancer has long been known to be associated with chromosome instability including deletion and insertion mutations at simple repeat sequences, frame-shift mutations,395 DNA breakage, translocation,396 and losses or gains of whole chromosomes 397... 

There are two major forms of hereditary susceptibility to colon cancer.00 Familial adenomatous polyposis is caused by defects in the APC gene (see Chapter 32). The more common hereditary nonpolyposis colorectal cancer (HNPCC), which includes many endometrial, stomach, and urinary tract tumors, results from defects in DNA mismatch repair. -)) The proteins hMSH2 and hMSLl are homologs of the E.coli MutS and MutL (main text). 

Inherited CRC syndromes initiate as a result of an inherited mutation in one of the genes involved in the CIN or MSI pathway. Although several CRC syndromes exist, the two most common are famUial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), Most interestingly, tumors in FAP kindreds and tumors displaying CIN more frequently are found in the distal part of the colon, whereas tumors in HNPCC families and tumors displaying MSI more commonly occur in the proximal part of the colon. ... 

Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, et al. Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary non-polyposis colon cancer. Nature 1994 368 258-61. 

Vasen HF, Mecldhi JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis CRC. (ICG-HNPCC). Dis Colon Rectum 1991 34 424-5. 

Colon cancer is one of the main causes of cancer mortality in Western societies [150]. About 15-20% of colorectal tumors are causally determined by inheritance of genetic alterations such as the hereditary nonpolyposis colorectal cancer (HNPCC) and the syndrome familial adenomatous polyposis (FAP) [151,152]. Microsatellite instability, a characteristic of HNPCC, is caused by mutations in the genes essential for mismatch repair. The loss of mismatch repair has several consequences most crucially, the loss of proofreading and correction of small deletions and insertions. FAP is a rare autosomal dominant syndrome caused by an inherited mutation in the APC gene. The disease is characterized by the development of multiple colorectal adenomas, numbering from a few polyps to several thousands. 

MSHl, MLH2, DNA mismatch repair hereditary non-polyposis... 

Lynch, H. M., Sinyrk, 1. C., Watson, R, Lanspa, I5 J.. Lynch, J. E. Lynch. R M-. Cavalieri, R. ].. and Boland, C R. 1993. Genetics, natural history, tumor spectrum, and pathology of hereditary non polyposis colorectal cancer An updated review. ( d.sfroe)itero/tigv 104 1535-1549. 

Hereditary non-polyposis colorectal cancer (HNPCC) is due to defects in mismatch repair (MMR) and thus to deficiencies in removing nucleotides mi-spaired by DNA polymerases as well as insertion/deletion loops (1-10 bases). This dramatically increases the mutation rate. The affected genes are MLHl (60%),MSH2 and MSH6. 

Muller, A., and R. Fishel. 2002. Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer Invest. 20 102-109. 

The protein products of these genes play roles in DNA repair, recombination, and regulation of transcription. A second example, HNPCC (hereditary non-polyposis colorectal cancer), was previously introduced in Chapter 13. It results from inherited mutations in enzymes involved in the DNA mismatch repair system. 

The intruder elements undergo random, single base substitutions these mutations are frequent (one to 10/10 base pairs), heterogenous, and become clonal. Best known are these mutations in the hereditary non-polyposis colon cancer Lynch syndrome [2098]. These somatic point mutations appear as repetitive sequences, which are mismatch-repaired. While the initial mutations as oncogenic pathways were of definitive causative effect, the additional somatic point mutations occur... 

Mismatched bases produced during DNA replication are those not conforming to or A=T base pairing. They are identified and corrected in the new strand by the mismatch-repair enzyme complex . The mismatched nucleotides are identified and excised, and the gap filled by DNA polymerase. Mutations in this complex result in failure to correct mismatched base pairs and cause hereditary non-polyposis colorectal cancer (HNPCC). 

Umar A, Risinger Jl, Hawk ET, Barrett JC (2004) Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 4 153-158... 

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