American founder mutation for Lynch syndrome. Prevalence estimates and implications.
BACKGROUND
Recently, a new founder mutation, an exon 1-6 deletion in a mismatch repair gene (MMR), MSH2, in nine kindreds with Lynch syndrome was reported. In 3 of the kindreds this mutation was traced by genealogy through 11-12 generations to a common founder, and thus termed the American Founder Mutation (AFM). Since then, 13 additional 'unrelated' kindreds with AFM were detected by a recently designed single polymerase chain reaction. This test might serve as first-line screening for Lynch syndrome mutations, provided AFM was prevalent, which is assessed in the current study.


METHODS
The number of current AFM carriers and the incidence of Lynch syndrome caused by AFM were estimated based on population growth of mutation carriers derived from genealogy data. For cross-checking, its annual incidence was also estimated based on published epidemiology data.


RESULTS
There are 18,981 (5th and 95th percentiles, 6038 and 34,466, respectively) expected current AFM carriers, or 160 (range 51-290) Lynch syndrome cases diagnosed per year due to AFM estimated based on genealogy data. The incidence estimate closely overlaps with that based on published epidemiology data, which is 114-400 cases per year.


CONCLUSIONS
A large number of AFM carriers are likely to exist in the U.S., which harbors significant implications for cancer control. Given the ease of detection, testing for AFM not only among members of the existing AFM families, but also among all patients with Lynch syndrome in the U.S. is proposed.
Lynch
Henry T
HT
Department of Preventive Medicine and Public Health, Creighton University, Omaha, Nebraska 68178, USA. htlynch@creighton.edu
de la Chapelle
Albert
A
Hampel
Heather
H
Wagner
Anja
A
Fodde
Riccardo
R
Lynch
Jane F
JF
Okimoto
Ross
R
Clark
Mary Beth
MB
Coronel
Stephanie
S
Trowonou
Abdon
A
Fu
Yun-Xin
YX
Haynatzki
Gleb R
GR
Gong
Gordon
G
D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation; D015995:Prevalence; D014481:United States