A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening.
OBJECTIVE
Mismatch repair (MMR) deficiencies are the hallmark of tumors arising in Lynch syndrome, however, in approximately 15% of sporadic colorectal cancers (CRC) these deficiencies most often are associated with somatic methylation of the MMR gene MLH1. Recently, an oncogenic mutation in the BRAF gene has been involved in sporadic CRC showing MMR deficiencies as a result of MLH1 promoter methylation. The aim of this study was to evaluate the contribution of BRAF V600E mutation analysis in the identification of MSH2/MLH1 gene mutation carriers in newly diagnosed CRC patients.


METHODS
BRAF V600E mutation was analyzed in CRC patients with MMR deficiencies (microsatellite instability and/or lack of MLH1/MSH2 protein expression) in the EPICOLON population-based study. The effectiveness and efficiency of different strategies were evaluated with respect to the presence of MSH2/MLH1 germline mutations.


RESULTS
MMR deficiencies were detected in 119 of the 1222 CRC patients with tumors showing either microsatellite instability (n = 111) or loss of protein expression (n = 81). BRAF mutation was detected in 22 (18.5%) of the patients. None of the patients with unambiguous germline mutation had BRAF mutation. Regardless of the strategy used to identify MSH2/MLH1 gene carriers, the introduction of BRAF analysis in these patients slightly improves their effectiveness. The introduction of BRAF mutation analysis as a step before germline genetic testing in patients with MMR deficiencies achieved a significant reduction in costs per mutation detected.


CONCLUSIONS
Detection of BRAF V600E mutation could simplify and improve the cost effectiveness of genetic testing for hereditary nonpolyposis colorectal cancer, especially in patients whose family history is incomplete or unknown.
Bessa
Xavier
X
Department of Gastroenterology, Hospital del Mar, Barcelona, Catalonia, Spain. 93281@imas.imim.es
Ballesté
Belen
B
Andreu
Montserrat
M
Castells
Antoni
A
Bellosillo
Beatriz
B
Balaguer
Francesc
F
Castellví-Bel
Sergi
S
Paya
Artemio
A
Jover
Rodrigo
R
Alenda
Cristina
C
Titó
Llúcia
L
Martinez-Villacampa
Mercedes
M
Vilella
Angels
A
Xicola
Rosa M
RM
Pons
Elisenda
E
Llor
Xavier
X
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000172:deficiency; D009687:Nuclear Proteins / Q000172:deficiency; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins