Significance of mutations in TGFBR2 and BAX in neoplastic progression and patient outcome in sporadic colorectal tumors with high-frequency microsatellite instability.
The mutator pathway implied in the development of colorectal cancer is characterized by microsatellite instability (MSI), which is determined by alterations of mismatch repair (MMR) genes. Defects in MMR genes affect repetitive DNA tracts interspersed mostly between coding sequences, and therefore it cannot be expected that they play a role during tumor progression. Genes containing repetitive sequences within their coding regions could be targets for MSI tumorigenesis, but this does not necessarily imply a causal role for the affected gene, because most are probably passenger mutations. We analyzed MSI and TGFBR2 and BAX frameshift mutations to further clarify the relationships between inactivation of the two genes and genomic instability in sporadic colorectal cancer (CRC), and to address how mutations in these genes influence the development of tumors and, eventually, patient outcome. One hundred and fifty-five patients with sporadic CRC were classified according to their MSI status. Frameshift mutations in the two genes were recurrent in high-frequency MSI (MSI-H) tumors, but these tended to be more common in poorly differentiated tumors. A high rate of mutations of TGFBR2 was found in tumors at Dukes' B stage, showing a greater extent of vascular invasion. Finally, in MSI-H tumors, mutations of either gene were associated with a significant decrease in survival. Our results contribute to the understanding of how the TGFBR2 and BAX gene mutations contribute to tumor progression in the mutator phenotype pathway for MSI colorectal cancers.
Fernández-Peralta
Antonia M
AM
Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid, Spain.
Nejda
Nargisse
N
Oliart
Soledad
S
Medina
Vicente
V
Azcoita
Mariano Moreno
MM
González-Aguilera
Juan J
JJ
D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D018125:Receptors, Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II