Lynch syndrome: genetics, natural history, genetic counseling, and prevention.
Abstract
Lynch syndrome is the most common hereditary form of colorectal cancer (CRC). Its natural history has been investigated extensively, so that highly targeted surveillance and management strategies, melded to its natural history, have proven effective in cancer control. Most important is the early age of onset of cancer (approximately 44 years), involving CRC and the several extracolonic cancers that are integral to the syndrome. With respect to CRC, approximately 70% of cases occur proximal to the splenic flexure. Synchronous and metachronous CRCs are extremely common. Full colonoscopy should be initiated when the patient is between the ages of 20 and 25, and because of the accelerated carcinogenesis of CRC, it should be performed every 1 to 2 years. The presence of initial CRC requires subtotal colectomy, given the mentioned increased frequency of metachronous cancer. Options available for germ-line mutation carriers, in addition to cancer screening, include prophylactic colectomy as well as prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy. The discovery of mismatch repair germ-line mutations (most commonly MSH2 or MLH1) has added significantly to the recognition of this disease as well as to the search for high-risk individuals throughout families who, with genetic counseling, may become candidates for germ-line mutation testing. Clearly, hereditary nonpolyposis colorectal cancer provides an excellent opportunity for learning about the etio-pathogenesis of cancer at the molecular and clinical levels and how this knowledge might ultimately be exploited for cancer control. A search for chemoprevention agents, such as cyclo-oxygenase 2 inhibitors, as well as for putative environmental effects and how they may interact with the genetic component in CRC etiology should abet this entire cancer control process.