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Hereditary Non-Polyposis Colon Cancer was first
described in 1913 by Aldred Scott Warthin (Ref.
1). Warthin's seamstress had told him that she would die at an early
age from colon cancer or cancer of the female organs. When Warthin inquired
about this prediction she said, "most of the members of my family die from
these cancers." (Ref. 3) The woman died, as
she predicted, of endometrial cancinoma, which prompted Warthin and his
colleagues to begin a study of her family. Warthin published information
about this family and a few others with multiple gastric and colorectal
cancers spanning three generations. (Ref. 8) |
The significance of Warthin's cancer prone families
was not appreciated until 1966 when Henry Lynch began his research.. Lynch
had discovered two other families and named the phenomenon Cancer Family
Syndrome (CFS). (Ref. 1) Lynch continued his
research and was the key investigator in much of the early characterization
of the disease. CFS was eventually split into two different inheritable
colon cancer diseases: Familial Adenomatous Polyposis (FAP) and Hereditary
Non-polyposis Colon Cancer (HNPCC). More recently HNPCC has been sub-divided
into Lynch syndrome I and Lynch syndrome II based on the location of cancer
development.
In 1993 the first of the HNPCC genes (MSH2) was discovered
on chromosome 2 by Lauri Aaltonen and Paivi Peltomaki who were part of
a multinational team researching the disease. (Ref.
9) Soon after, MLH1 was discovered on chromosome 3. It was determined
that mutations in these two genes accounted for 90% of the known HNPCC
families. (Ref. 7) Two other genes, PMS1 and
PMS2 were later determined to also be involved in HNPCC.
Timeline for the discovery of the genes associated with inheritable
colon cancer:
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1991 APC gene discovered (responsible for FAP)
-
1993 MSH2 discovered (responsible for 60% of all investigated
HNPCC cases)
-
1994 MLH1 discovered (responsible for 30% of all investigated
HNPCC cases)
-
1994 PMS1 discovered (responsible for <10% of all
investigated HNPCC cases)
-
1994 PMS2 discovered (responsible for <10% of all
investigated HNPCC cases)
Created by: April Bardes, Colin Connor, and Allison Niggemyer,
Biology Department, DePauw University, Bios 354: Molecular Genetics,
Spring 1998.