Colorectal cancer inherited

A second group of inherited colon cancers are termed hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC may account for 5% of all colon cancer cases and can be caused by mutations in any of five different genes. All of these genes encode proteins involved in DNA mismatch repair (Fig II-5-3). As with inherited breast cancer, fiiulty DNA repair leads to mutated cells capable of producing tumors. 

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, with about 5% of cases associated with inherited mutations linked to colon cancer syndromes. The molecular basis of sporadic and inherited CRC involves two distinct pathways, one of chromosomal instability and one associated with microsateUite mstabifity. The original model of chromosome instability proposed in 1990 to explain the pathogenesis of most sporadic tumors (-85%) has been further characterized to reveal a complex chain of events whereby normal colon fining (mucosa) is transformed... 

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. ... 

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. 

Multiple factors are associated with the development of colorectal cancer, including acquired and inherited genetic susceptibility, environmental elements, and lifestyle choices. Overall, about 37% of... 

Familial colon cancer represents the least understood pattern of colorectal cancer. Up to 25% of patients who develop colorectal cancer will have a family history of colorectal cancer. In these famihes, the frequency of colorectal cancer is too high to be considered sporadic, but the pattern is not consistent with an inherited syndrome. First-degree relatives of patients diagnosed with colorectal cancer have an increased risk of the disease that is at least two to four times that of persons in the general population without a family history. ... 

The development of a colorectal neoplasm is a multi-step process of several genetic and phenotypic alterations of normal bowel epithelium structure and function, leading to unregulated cell growth, proliferation, and tumor development. Since the majority of colorectal cancers develop sporadically, with no inherited or familial disposition, efforts have been directed toward identifying these alterations and learning whether detection of such changes may lead to improved cancer detection and/or treatment outcomes. 

Loss of these systems correlates with Increased risk for cancer. For example, humans who inherit mutations in genes that encode a crucial mismatch-repair or excision-repair protein have an enormously Increased probability of developing certain cancers (Table 23-1). Without proper DNA repair, people with xeroderma pigmentosum or hereditary nonpolyposis colorectal cancer have a propensity to accumulate mutations in many other genes, including those that are critical in controlling cell growth and proliferation. 

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. 

Chmiel, N. H., Livingston, A. L., and David, S. S. (2003). Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer Complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E. coli enzymes. J. Mol. Biol. 327, 431-443. 

Katoh T, Boissy R, Nagata N, Kitagawa K, Kuroda Y, Itoh H> et al. Inherited polymorphism in the N-acetyltransferase 1 (NATl) and 2 (NAT2) genes and susceptibility to gastric and colorectal adenocarcinoma. Int J Cancer 2000 85 46-9. 

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