Genetic variation in the transforming growth factor‐β signaling pathway and survival after diagnosis with colon and rectal cancer

BACKGROUND: The transforming growth factor‐β (TGF‐β) signaling pathway is involved in many aspects of tumorigenesis, including angiogenesis and metastasis. The authors evaluated this pathway in association with survival after a diagnosis of colon or rectal cancer. METHODS: The study included 1553 patients with colon cancer and 754 patients with rectal cancer who had incident first primary disease and were followed for a minimum of 7 years after diagnosis. Genetic variations were evaluated in the genes TGF‐β1 (2 single nucleotide polymorphisms [SNPs]), TGF‐β receptor 1 ( TGF‐βR1 ) (3 SNPs), smooth muscle actin/mothers against decapentaplegic homolog 1 ( Smad1 ) (5 SNPs), Smad2 (4 SNPs), Smad3 (37 SNPs), Smad4 (2 SNPs), Smad7 (11 SNPs), bone morphogenetic protein 1 ( BMP1 ) (11 SNPs), BMP2 (5 SNPs), BMP4 (3 SNPs), bone morphogenetic protein receptor 1A ( BMPR1A ) (9 SNPs), BMPR1B (21 SNPs), BMPR2 (11 SNPs), growth differentiation factor 10 ( GDF10 ) (7 SNPs), Runt‐related transcription factor 1 ( RUNX1 ) (40 SNPs), RUNX2 (19 SNPs), RUNX3 (9 SNPs), eukaryotic translation initiation factor 4E ( eiF4E ) (3 SNPs), eukaryotic translation initiation factor 4E‐binding protein 3 ( eiF4EBP2 ) (2 SNPs), eiF4EBP3 (2 SNPs), and mitogen‐activated protein kinase 1 ( MAPK1 ) (6 SNPs). RESULTS: After adjusting for American Joint Committee on Cancer stage and tumor molecular phenotype, 12 genes and 18 SNPs were associated with survival in patients with colon cancer, and 7 genes and 15 tagSNPs were associated with survival after a diagnosis of rectal cancer. A summary score based on “at‐risk” genotypes revealed a hazard rate ratio of 5.10 (95% confidence interval, 2.56‐10.15) for the group with the greatest number of “at‐risk” genotypes; for rectal cancer, the hazard rate ratio was 6.03 (95% confidence interval, 2.83‐12.75). CONCLUSIONS: The current findings suggest that the presence of several higher risk alleles in the TGF‐β signaling pathway increase the likelihood of dying after a diagnosis of colon or rectal cancer. Cancer 2011;. © 2011 American Cancer Society.