Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, originally was described as familial clustering of cancers at several sites including the colorectum, endometrium, stomach, ovary, ureters, brain,
Fig. 15.35 Familialadenomatouspolyposis.(A)Hundredsofsmallcolonicpolypsarepresentalongwithadominantpolyp(right). (B)Threetubularadenomasarepresentinthissinglemicroscopicfield.
small bowel, hepatobiliary tract, and skin. Colon cancers in patients with HNPCC tend to occur at younger ages than do sporadic colon cancers and often are located in the right colon (
Table 15.7 ). Adenomas are present in HNPCC, but excessive numbers (i.e., polyposis) is not. In many cases, sessile serrated adenomas are associated with HNPCC, and mucin production may be a prominent in the subsequent adenocarcinomas.
Just as identification of APC mutations in FAP has provided molecular insights into the pathogenesis of a majority of sporadic colon cancers, dissection of the defects in HNPCC has shed light on the mechanisms responsible for most of the remaining sporadic cases. HNPCC is caused by inherited germ line mutations in genes that encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication. At least five such mismatch repair genes have been recognized, but a majority of HNPCC cases involve either MSH2 or MLH1. Patients with HNPCC inherit one mutated DNA repair gene and one normal allele. When the second copy is lost through mutation or epigenetic silencing, defects in mismatch repair lead to the accumulation of mutations at rates up to 1000 times higher than normal, mostly in regions containing short repeating DNA sequences referred to as microsatellite DNA. The human genome contains approximately 50,000 to 100,000 microsatellites, which are prone to undergo expansion during DNA replication and represent the most frequent sites of mutations in HNPCC. The consequences of mismatch repair defects and the resulting microsatellite instability are discussed next in the context of colonic adenocarcinoma.
Adenocarcinoma of the colon is the most common malignancy of the gastrointestinal tract and is a major contributor to morbidity and mortality worldwide. By contrast, the small intestine, which accounts for 75% of the overall length of the gastrointestinal tract, is an uncommon site for benign and malignant tumors. Among malignant small-intestinal tumors, adenocarcinomas and carcinoid (neuroendocrine) tumors have roughly equal rates of occurrence, followed by lymphomas and sarcomas.
Each year in the United States, there are more than 130,000 new cases and nearly 50,000 deaths from colorectal adenocarcinoma. This represents nearly 15% of all cancer-related deaths, second only to lung cancer. Colorectal cancer incidence peaks at 60 to 70 years of age; less than 20% of cases occur before 50 years of age. Males are affected slightly more often than females. Colorectal carcinoma is most prevalent in the United States, Canada, Australia, New Zealand, Denmark, Sweden, and other (so-called) developed countries that share lifestyles and diet. The incidence of this cancer is as much as 30-fold lower in India, South America, and Africa. In Japan, where incidence was previously very low, rates have now risen to intermediate levels (similar to those in the United Kingdom), presumably as a result of changes in lifestyle and diet.
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