Syndromic colon cancer: Lynch syndrome and familial adenomatous polyposis

Colon cancer, the third leading cause of mortality from cancer in the United States, afflicts about 150,000 patients annually. More than 10% of these patients exhibit familial clustering [1]. The most common and well characterized of these familial colon cancer syndromes is hereditary nonpolyposis colon cancer syndrome (HNPCC or Lynch syndrome), which accounts for about 2% to 3% of all cases of colon cancer in the United States [1]. Lynch syndrome, an autosomal dominant condition with incomplete penctrance, was initially defined by clinical and family history criteria, known as the Amsterdam criteria (Box 1). Subsequently, genetic mutations in six distinct DNA mismatch repair genes have been identified, and testing for three of these genes (MLH1, MSH2, MSH6) has become widely available to clinicians. Lynch syndrome now refers to patients who have mutations in one of four DNA mismatch repair (MMR) genes-MLH1, MSH2, MSH6, and PMS2-regardless of whether the Amsterdam criteria for family history are met [2,3]. About I in 1000 to I in 3000 Americans are carriers for MMR gene mutations [4,5], and 100,000 to 300,000 Americans have Lynch syndrome. Genetic testing for these mutations is now used for the diagnosis, although genetic testing is limited by its cost of more than $2000 and concerns regarding privacy. Patients may be reluctant to be identified as a carrier of a cancer-causing genetic mutation that may limit their ability to obtain insurance, home mortgage loans, or employment. This aversion to being identified, potentially publicly, as a cancer gene carrier, has impeded the diagnosis of Lynch syndrome even in European countries where nationalized health care renders concerns about insurability irrelevant [6].