Role of bax mutations in apoptosis in colorectal cancers with microsatellite instability.
Half of colorectal tumors with microsatellite instability contain frameshift mutations in the (G)8 tract of bax, a major apoptosis effector, but their functional significance remains unclear. We studied the role of bax mutations on bax expression and apoptosis in 59 primary colorectal cancers of which 41 were microsatellite unstable. Tumors were screened for bax(G)8 mutations and evaluated immunohistochemically for bax, bcl-2, and p53 protein expression and apoptotic (M30 cytoDEATH) and proliferative (Ki-67) indexes. We identified bax(G)8 mutations in 20 (49%) of 41 unstable tumors; the mutations were associated significantly with proximal, poorly differentiated, or mucinous adenocarcinomas. Most bax-mutated cases displayed a bax-immunonegative zone in all or part of the tumor that was proved to correspond to biallelic bax(G)8 mutations by microdissection and to confer growth advantage to the tumor by decreasing apoptosis compared with adjacent bax-immunopositive tumor. Biallelic bax(G)8 mutations are subject to positive selection pressure and might disable apoptosis in colorectal cancer.
Miquel
Catherine
C
Department of Pathology and the French National Center for Scientific Research--Unit 2169 Genetic Instability and Cancer, Institut Gustave Roussy, Villejuif, France.
Borrini
Francesco
F
Grandjouan
Sophie
S
Aupérin
Anne
A
Viguier
Jérôme
J
Velasco
Valérie
V
Duvillard
Pierre
P
Praz
Françoise
F
Sabourin
Jean-Christophe
JC
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D042282:Microdissection; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein