Identification of Lynch syndrome among patients with colorectal cancer.
BACKGROUND
Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.


OBJECTIVE
To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.


METHODS
Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.


RESULTS
Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).


RESULTS
Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.


CONCLUSIONS
Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.
Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Leticia
L
Moreira
Francesc
F
Balaguer
Noralane
N
Lindor
Albert
A
de la Chapelle
Heather
H
Hampel
Lauri A
LA
Aaltonen
John L
JL
Hopper
Loic
L
Le Marchand
Steven
S
Gallinger
Polly A
PA
Newcomb
Robert
R
Haile
Stephen N
SN
Thibodeau
Shanaka
S
Gunawardena
Mark A
MA
Jenkins
Daniel D
DD
Buchanan
John D
JD
Potter
John A
JA
Baron
Dennis J
DJ
Ahnen
Victor
V
Moreno
Montserrat
M
Andreu
Maurizio
M
Ponz de Leon
Anil K
AK
Rustgi
Antoni
A
Castells
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005190:Family; D005260:Female; D005387:Finland; D005820:Genetic Testing / Q000592:standards*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009820:Ohio; D012042:Registries / Q000706:statistics & numerical data; D012680:Sensitivity and Specificity
D045643:DNA Repair Enzymes