TY - JOUR
T1 - Utility of p16 immunohistochemistry for the identification of Lynch syndrome
AU - Payá, Artemio
AU - Alenda, Cristina
AU - Pérez-Carbonell, Lucía
AU - Rojas, Estefanía
AU - Soto, José Luis
AU - Guillén, Carmen
AU - Castillejo, Adela
AU - Barberá, Victor M.
AU - Carrato, Alfredo
AU - Castells, Antoni
AU - Llor, Xavier
AU - Andreu, Montserrat
AU - Koh, Jim
AU - Enders, Greg H.
AU - Benlloch, Susana
AU - Jover, Rodrigo
PY - 2009/5/1
Y1 - 2009/5/1
N2 - Purpose: Immunohistochemistry for mismatch repair proteins has shown utility in the identification of Lynch syndrome, but majority of tumors with loss of MLH1expression are due to sporadic hypermethylation of the MLH1 promoter. These tumors can also show epigenetic silencing of other genes, such as p16. The aim of our study is to evaluate the utility of p16 immunohistochemistry in the prediction of MLH1germline mutations. Experimental Design: p16 immunohistochemistry was appropriately evaluated in 79 colorectal cancers with loss of MLH1 expression. Methylation of MLH1 and p16 were quantitatively studied using real-time PCR assay Methylight. BRAF V600E mutation in tumor tissue was also investigated. Genetic testing for germline mutation of MLH1 was made on 52 patients. Results: Loss of p16 expression was seen in 21 of 79 samples (26.6%). There was found statistically significant association between p16 expression and p16 methylation (P < 0.001), MLH1 methylation (P < 0.001), and BRAF mutation (P < 0.005). All tumors with loss of p16 expression showed hypermethylation of p16 (21 of 21), 95.2% (20 of 21) showed MLH1 methylation, and 71.4% (15 of 21) were mutated for BRAF V600E. Mutational analysis showed pathogenic germline mutations in 8 of the patients, harboring 10 tumors. All 10 of these tumors showed normal staining of p16 in the immunochemical analysis. Conclusions: p16 immunohistochemistry is a good surrogate marker for p16 and MLH1 epigenetic silencing due to hypermethylation, and is useful as screening tool in the selection of patients for genetic testing in Lynch syndrome.
AB - Purpose: Immunohistochemistry for mismatch repair proteins has shown utility in the identification of Lynch syndrome, but majority of tumors with loss of MLH1expression are due to sporadic hypermethylation of the MLH1 promoter. These tumors can also show epigenetic silencing of other genes, such as p16. The aim of our study is to evaluate the utility of p16 immunohistochemistry in the prediction of MLH1germline mutations. Experimental Design: p16 immunohistochemistry was appropriately evaluated in 79 colorectal cancers with loss of MLH1 expression. Methylation of MLH1 and p16 were quantitatively studied using real-time PCR assay Methylight. BRAF V600E mutation in tumor tissue was also investigated. Genetic testing for germline mutation of MLH1 was made on 52 patients. Results: Loss of p16 expression was seen in 21 of 79 samples (26.6%). There was found statistically significant association between p16 expression and p16 methylation (P < 0.001), MLH1 methylation (P < 0.001), and BRAF mutation (P < 0.005). All tumors with loss of p16 expression showed hypermethylation of p16 (21 of 21), 95.2% (20 of 21) showed MLH1 methylation, and 71.4% (15 of 21) were mutated for BRAF V600E. Mutational analysis showed pathogenic germline mutations in 8 of the patients, harboring 10 tumors. All 10 of these tumors showed normal staining of p16 in the immunochemical analysis. Conclusions: p16 immunohistochemistry is a good surrogate marker for p16 and MLH1 epigenetic silencing due to hypermethylation, and is useful as screening tool in the selection of patients for genetic testing in Lynch syndrome.
UR - http://www.scopus.com/inward/record.url?scp=65649090603&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-08-3116
DO - 10.1158/1078-0432.CCR-08-3116
M3 - Artículo
C2 - 19383812
AN - SCOPUS:65649090603
SN - 1078-0432
VL - 15
SP - 3156
EP - 3162
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -