Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States.
OBJECTIVE
Lynch syndrome is caused by germ-line mismatch repair gene mutations. We examined the phenotypic differences between MLH1 and MSH2 gene mutation carriers and whether mutation type (point versus large rearrangement) affected phenotypic expression.


METHODS
This is a cross-sectional prevalence study of 1,914 unrelated probands undergoing clinical genetic testing for MLH1 and MSH2 mutations at a commercial laboratory.


RESULTS
Fifteen percent (285 of 1,914) of subjects had pathogenic mutations (112 MLH1, 173 MSH2). MLH1 carriers had a higher prevalence of colorectal cancer (79% versus 69%, P = 0.08) and younger mean age at diagnosis (42.2 versus 44.8 years, P = 0.03) than MSH2 carriers. Forty-one percent of female carriers had endometrial cancer and prevalence was similar in both groups. Other cancers were more frequent in MSH2 carriers (24% versus 9%, P = 0.001) and their families (P < 0.001). Multivariable analyses confirmed these associations. Of the 1,016 subjects who underwent Southern blot analysis, 42 had large rearrangements (7 MLH1, 35 MSH2). There were no phenotypic differences between carriers with large rearrangements and point mutations.


CONCLUSIONS
In this large study of mismatch repair gene mutation carriers from the United States, MLH1 carriers had more colorectal cancer than MSH2 carriers whereas endometrial cancer prevalence was similar. Large genomic rearrangements were more frequent in the MSH2 gene. MSH2 carriers and their relatives have more extracolonic nonendometrial Lynch syndrome-associated cancers and may benefit from additional screening.
Kastrinos
Fay
F
Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, Boston, MA 02115, USA.
Stoffel
Elena M
EM
Balmaña
Judith
J
Steyerberg
Ewout W
EW
Mercado
Rowena
R
Syngal
Sapna
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D003430:Cross-Sectional Studies; D053843:DNA Mismatch Repair; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D015995:Prevalence; D014481:United States
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein