PURPOSE: Immunohistochemistry for mismatch repair proteins has shown utility in the identification of Lynch syndrome, but majority of tumors with loss of MLH1 expression 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 MLH1 germline 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.
PURPOSE: Immunohistochemistry for mismatch repair proteins has shown utility in the identification of Lynch syndrome, but majority of tumors with loss of MLH1 expression 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 MLH1 germline 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. BRAFV600E 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 BRAFV600E. 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.
Authors: Steven L Gibson; Amelie Boquoi; Tina Chen; Norman E Sharpless; Colleen Brensinger; Greg H Enders Journal: Cancer Biol Ther Date: 2005-12-09 Impact factor: 4.742
Authors: R Jover; P Zapater; A Castells; X Llor; M Andreu; J Cubiella; V Piñol; R M Xicola; L Bujanda; J M Reñé; J Clofent; X Bessa; J D Morillas; D Nicolás-Pérez; A Payá; C Alenda Journal: Gut Date: 2005-11-18 Impact factor: 23.059
Authors: Daniel J Weisenberger; Kimberly D Siegmund; Mihaela Campan; Joanne Young; Tiffany I Long; Mark A Faasse; Gyeong Hoon Kang; Martin Widschwendter; Deborah Weener; Daniel Buchanan; Hoey Koh; Lisa Simms; Melissa Barker; Barbara Leggett; Joan Levine; Myungjin Kim; Amy J French; Stephen N Thibodeau; Jeremy Jass; Robert Haile; Peter W Laird Journal: Nat Genet Date: 2006-06-25 Impact factor: 38.330
Authors: Shuji Ogino; Takako Kawasaki; Mohan Brahmandam; Mami Cantor; Gregory J Kirkner; Donna Spiegelman; G Mike Makrigiorgos; Daniel J Weisenberger; Peter W Laird; Massimo Loda; Charles S Fuchs Journal: J Mol Diagn Date: 2006-05 Impact factor: 5.568
Authors: Wade S Samowitz; Hans Albertsen; Jennifer Herrick; Theodore R Levin; Carol Sweeney; Maureen A Murtaugh; Roger K Wolff; Martha L Slattery Journal: Gastroenterology Date: 2005-09 Impact factor: 22.682
Authors: Heather Hampel; Wendy Frankel; Jenny Panescu; Janet Lockman; Kaisa Sotamaa; Daniel Fix; Ilene Comeras; Jennifer La Jeunesse; Hidewaki Nakagawa; Judith A Westman; Thomas W Prior; Mark Clendenning; Pamela Penzone; Janet Lombardi; Patti Dunn; David E Cohn; Larry Copeland; Lynne Eaton; Jeffrey Fowler; George Lewandowski; Luis Vaccarello; Jeffrey Bell; Gary Reid; Albert de la Chapelle Journal: Cancer Res Date: 2006-08-01 Impact factor: 12.701
Authors: S Ogino; M Cantor; T Kawasaki; M Brahmandam; G J Kirkner; D J Weisenberger; M Campan; P W Laird; M Loda; C S Fuchs Journal: Gut Date: 2006-01-11 Impact factor: 23.059
Authors: Heather Hampel; Wendy L Frankel; Edward Martin; Mark Arnold; Karamjit Khanduja; Philip Kuebler; Hidewaki Nakagawa; Kaisa Sotamaa; Thomas W Prior; Judith Westman; Jenny Panescu; Dan Fix; Janet Lockman; Ilene Comeras; Albert de la Chapelle Journal: N Engl J Med Date: 2005-05-05 Impact factor: 91.245
Authors: S Forbes; J Clements; E Dawson; S Bamford; T Webb; A Dogan; A Flanagan; J Teague; R Wooster; P A Futreal; M R Stratton Journal: Br J Cancer Date: 2006-01-30 Impact factor: 7.640
Authors: Kaori Shima; Katsuhiko Nosho; Yoshifumi Baba; Mami Cantor; Jeffrey A Meyerhardt; Edward L Giovannucci; Charles S Fuchs; Shuji Ogino Journal: Int J Cancer Date: 2011-03-01 Impact factor: 7.396
Authors: Leticia Moreira; Francesc Balaguer; Noralane Lindor; Albert de la Chapelle; Heather Hampel; Lauri A Aaltonen; John L Hopper; Loic Le Marchand; Steven Gallinger; Polly A Newcomb; Robert Haile; Stephen N Thibodeau; Shanaka Gunawardena; Mark A Jenkins; Daniel D Buchanan; John D Potter; John A Baron; Dennis J Ahnen; Victor Moreno; Montserrat Andreu; Maurizio Ponz de Leon; Anil K Rustgi; Antoni Castells Journal: JAMA Date: 2012-10-17 Impact factor: 56.272