Hereditary nonpolyposis cancer HNPCC

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

Mismatched base (Gj) DNA replication errors A mutation on one of two genes, hMSH2 or hMLHl, initiates defective repair of DNA mismatches, resulting in a condition known as hereditary nonpolyposis colorectal cancer— HNPCC. DNA polymerase DNA ligase... 

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. 

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). 

PMSl). The DNA located between the nick and the mismatch is removed by 3 to 5 or 5 to 3 exonucleases depending on whether the nick is 3 or 5 to the mismatch. The gap is then filled by DNA Pol III in E. coli (Fig. 10) by DNA Pol 5 in humans and is ligated. Mismatch repair increases the spontaneous mutation rate in E. coli and yeast. Humans defective in mismatch repair exhibit a cancer-prone syndrome called hereditary nonpolyposis colon cancer (HNPCC), and sporadic mutations of mismatch repair genes are also associated with up to 50% of all human cancers (42 4). 

Microsatellite instability is found to be a common feature of nearly all tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) (4,16). The majority of HNPCC cases arise through germline mutations in two genes, hMSH2 and hMLHl on chromosomes 2 and 3, which encode the human homologs of bacterial mismatch repair genes, MutS and MutL (17,18). Cells which display microsatellite instability are termed as having an RER+ phenotype, which stands for replication error (5). Such RER+ tumor cells have been shown to have defects in mismatch repair and possess a mutator phenotype (19). 

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. ... 

Peltomaki P, Vasen HF, and the ICG-HNPCC. Mutations predisposing to hereditary nonpolyposis colorectal cancer database and results of a collaborative study. Gastroenterology 1997 113 1146-58. 

Vasen HFA, Watson P, Mecklin JP, Lynch HT and The International Collaborative Group on HNPCC. New clinical criteria for Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999 116 1453-6. 

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. 

Several human DNA mismatch repair genes are associated with hereditary nonpolyposis colon cancer (HNPCC). One of these mismatch repair genes (hMSH2) is located on the short arm of chromosome 2 others are located on chromosome 3. Defects in any of these DNA repair genes predispose individuals to colon cancer as well as to other cancers. 

Patients with hereditary nonpolyposis colon cancer [HNPCC (114500)] have genes with microsatellite instability, that is, many regions containing abnormal, small loops of unpaired DNA. This is a result of a mutation affecting... 

HNPCC hereditary nonpolyposis colorectal cancer IFL irinotecan plus fluorouracil plus leucovorin IMPACT International Multicentre Pooled Analysis of Colon Cancer Trials... 

The tumors may arise sporadically or in patients with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.Current experience is too limited to determine their biologic behavior and prognosis however, in one study, the patients were found to have an improved survival rate relative to those with DAs. ° Immunohistochemically, the epithelioid cells are labeled by antibodies to cytokeratins whereas trypsin, chymotrypsin, lipase, chromogranin, and synaptophysin are usually negative. CD3 antibody highlights the presence of numerous intratumoral T lymphocytes. Rare examples also contain Epstein-Barr virus RNA. ... 

As discussed earlier in this chapter, Lynch syndrome or hereditary nonpolyposis colon cancer syndrome (HNPCC) is a cancer predisposition syndrome caused by mutation of a mismatch repair gene. Immunohistochemistry can be used to screen for mutations in... 

Hereditary breast-ovarian cancer syndrome (HBOC) accounts for the vast majority (85%-90%) of all hereditary ovarian cancers [5]. The site-specific ovarian cancer syndrome with only ovarian cancer accounts for 10%-15% of hereditary ovarian cancers. In hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which is also known as Lynch syndrome II, patients present with colon, endometrial, breast, ovarian and other cancers [6],... 

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