Prediction of germline mutations and cancer risk in the Lynch syndrome.
BACKGROUND
Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.


OBJECTIVE
To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.


METHODS
External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.


METHODS
Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.


RESULTS
In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.


CONCLUSIONS
MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.
Chen
Sining
S
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md 21205, USA. sichen@jhsph.edu
Wang
Wenyi
W
Lee
Shing
S
Nafa
Khedoudja
K
Lee
Johanna
J
Romans
Kathy
K
Watson
Patrice
P
Gruber
Stephen B
SB
Euhus
David
D
Kinzler
Kenneth W
KW
Jass
Jeremy
J
Gallinger
Steven
S
Lindor
Noralane M
NM
Casey
Graham
G
Ellis
Nathan
N
Giardiello
Francis M
FM
Offit
Kenneth
K
Parmigiani
Giovanni
G
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000465:Algorithms; D002352:Carrier Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000453:epidemiology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000453:epidemiology; D005260:Female; D005817:Genetic Counseling; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011336:Probability; D012306:Risk
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein