1. ¹Department of Preventive Medicine, Creighton University School of Medicine, Omaha, NE, USA
2. ²Division of Gastroenterology, Baylor University Medical Center, Dallas, TX, USA
3. ³Division of GI Oncology, MD Anderson Cancer Center, Houston, TX, USA
4. ⁴Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
5. ⁵Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

Correspondence: Dr HT Lynch, Department of Preventive Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA. Tel: +1 402 280 2942; Fax: +1 402 280 1734. E-mail: htlynch@creighton.edu

Received 12 July 2005; Revised 22 November 2005; Accepted 28 December 2005; Published online 15 February 2006.

Abstract

Lynch syndrome is the most common form of hereditary colorectal cancer (CRC). This review covers the cardinal features of Lynch syndrome with particular emphasis upon its diagnostic criteria, molecular genetics, natural history, genetic counseling, surveillance and management. Considerable attention has been given to the etiologic role of mismatch repair (MMR) genes as well as low penetrance alleles and modifier genes. The American founder mutation, a deletion of exons 1–6 of MSH2, is discussed in some detail, owing to its high frequency in the US (19 000–30 000 carriers). Genetic counseling is essential prior to patients' undergoing DNA testing and again when receiving their test results. Families with a lower incidence of CRC and extracolonic cancers, in the face of being positive for Amsterdam I criteria but who do not have MMR deficiency by tumor testing, are probably not Lynch syndrome, and thereby should preferably be designated as familial CRC of undetermined type. Patients who are either noncompliant or poorly compliant with colonoscopy, and who are MMR mutation positive, may be candidates for prophylactic colectomy, while MMR mutation-positive women who are noncompliant with gynecologic surveillance may be candidates for prophylactic hysterectomy and bilateral salpingo-oophorectomy.