Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening.
BACKGROUND
The identification of individuals who should undergo hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing remains a critical issue. The Bethesda guidelines were developed to preselect patients for microsatellite instability (MSI) testing before germline mutation screening. These criteria have been revised, and a new set of recommendations, the revised Bethesda guidelines, has been proposed.


OBJECTIVE
To evaluate the performance of these revised guidelines for identifying patients with HNPCC in a series of unselected consecutive patients and compare this revised guidelines-based approach with a molecular strategy (MSI testing for all tumors, followed by exclusion of MSI-positive sporadic cases from mutational testing).


METHODS
The study included 214 patients with newly diagnosed colorectal cancer. The MSI analysis was performed for all tumors. Germline testing, guided by immunohistochemical staining for mismatch repair proteins, was performed for patients with MSI-positive tumors. Sporadic MSI-positive tumors were identified by screening for BRAF mutation and MLH1 promoter methylation.


RESULTS
Ninety patients (42.1%) met the revised guidelines. Twenty-one patients (9.8%) had MSI-positive tumors. Germline testing identified eight mutations (3.7%) (MSH2 N = 5, MLH1 N = 2, MSH6 N =1). The revised guidelines failed to identify 2 of the 8 probands (aged 67 and 81 yr, both with no family history). In contrast, the molecular strategy identified all patients requiring testing for germline mutation. The percentages of patients selected for germline testing by the revised guidelines and the molecular strategy were 4.2% and 5.1%, respectively.


CONCLUSIONS
The revised Bethesda guidelines did not identify all HNPCC cases in our series. The molecular approach identified all HNPCC patients with MSI-positive tumors, increasing the workload for germline testing only slightly.
Julié
Catherine
C
Service d'Anatomie et de Cytologie Pathologiques, Hôpital Ambroise Paré, AP-HP, Université Versailles-Saint Quentin en Yvelines, Boulogne, France.
Trésallet
Christophe
C
Brouquet
Antoine
A
Vallot
Céline
C
Zimmermann
Ute
U
Mitry
Emmanuel
E
Radvanyi
François
F
Rouleau
Etienne
E
Lidereau
Rosette
R
Coulet
Florence
F
Olschwang
Sylviane
S
Frébourg
Thierry
T
Rougier
Philippe
P
Nordlinger
Bernard
B
Laurent-Puig
Pierre
P
Penna
Christophe
C
Boileau
Catherine
C
Franc
Brigitte
B
Muti
Christine
C
Hofmann-Radvanyi
Hélène
H