BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer.

The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers. To that end, we performed VE1 immunohistochemistry and BRAF sequencing in a series of 91 MSI-H colorectal cancer specimens from patients tested for Lynch syndrome. Concordance of VE1 immunohistochemistry and molecular BRAF mutation status was observed in 90 of 91 (98.9%) MSI-H samples. All 11 tumors classified as BRAF V600E mutation-positive by Sanger sequencing were immunopositive, and 79 (98.8%) of 80 tumors classified as BRAF wild type showed negative staining. All VE1-positive tumors were MLH1- and PMS2-negative by immunohistochemistry. None of the tumors from mismatch repair (MMR) gene germline mutation carriers (n = 28) displayed positive VE1 staining, indicating that BRAF V600E mutation-specific immunostaining has a low risk of excluding Lynch syndrome patients from germline mutation analysis. In conclusion, implementation of VE1 immunohistochemistry was able to detect BRAF-mutated MSI-H colorectal cancers with a sensitivity of 100% and a specificity of 98.8%. Among MLH1-negative colorectal cancers, the rate of VE1-positive lesions was 21%, offering the exclusion of these patients from MMR germline testing. Therefore, we suggest the integration of VE1 immunohistochemistry into the diagnostic panel of Lynch syndrome.

Capper D ，Voigt A ，Bozukova G ，Ahadova A ，Kickingereder P ，von Deimling A ，von Knebel Doeberitz M ，Kloor M ... -  《-》

Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.

Lagerstedt Robinson K ，Liu T ，Vandrovcova J ，Halvarsson B ，Clendenning M ，Frebourg T ，Papadopoulos N ，Kinzler KW ，Vogelstein B ，Peltomäki P ，Kolodner RD ，Nilbert M ，Lindblom A ... -  《-》

Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer.

Loughrey MB ，Waring PM ，Tan A ，Trivett M ，Kovalenko S ，Beshay V ，Young MA ，McArthur G ，Boussioutas A ，Dobrovic A ... -  《Familial Cancer》

BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines.

Molinari F ，Signoroni S ，Lampis A ，Bertan C ，Perrone F ，Sala P ，Mondini P ，Crippa S ，Bertario L ，Frattini M ... -  《-》

Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR.

Bettstetter M ，Dechant S ，Ruemmele P ，Grabowski M ，Keller G ，Holinski-Feder E ，Hartmann A ，Hofstaedter F ，Dietmaier W ... -  《CLINICAL CANCER RESEARCH》