HISTORY OF HEREDITARY NONPOLYPOSIS COLORECTAL CANCER OR “LYNCH SYNDROME”

Hereditary Nonpolyposis Colorectal Cancer (HNPCC or “Lynch syndrome”), involving pathogenic variants in the Mismatch Repair (MMR) genes, is the most common inherited condition that predisposed to colorectal adenomas and colorectal cancer. In this chapter I review the history of HNPCC, from early case reports, to more systematic clinical information and clinical criteria, and finally to the discovery of the MMR genes themselves in 1993, including the key feature of microsatellite instability. This central role for microsatellite analysis of colorectal cancers involves a growing trend toward “universal testing” for evidence of MSI, whether by PCR methods or by immunohistochemistry (IHC). Even though such universal testing has not been completely adopted around the world, we are already evolving toward more routine use of multi-gene “panels” for germline MMR mutation detection. Under these circumstances, one may reasonably ask whether understanding the historical unfolding of clinical features of HNPCC is even relevant. As this chapter hopes to demonstrate, an appreciation of the landscape of HNPCC would not be complete without such a historical perspective, including the important role of Dr Henry Lynch over a lifetime of work in the field.