KRAS c.35G>T (p.G12V) and c.34G>C (p.G12R) Mutations Predict Shorter Survival in 1925 Colorectal Cancers
Yu Imamura, Charles Fuchs, Shuji Ogino. Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital, Boston, MA
Background: KRAS mutation test has become routine for colorectal cancer. Experimental evidence indicates stronger oncogenic effects of KRAS c.35G>T (p.G12V) and c.34G>C (p.G12R) mutations, compared to other codon 12 and 13 mutations. We hypothesized that colorectal cancers with KRAS c.35G>T and c.34G>C mutations might behave more aggressively than tumors with other KRAS mutations and wild-type KRAS.
Design: We sequenced KRAS codons 12 and 13 in 1925 colorectal cancers, including 1267 stage I-IV colorectal cancers (cohort A) and a validation set of 658 stage III colon cancers in a clinical trial (cohort B). Patient survival was assessed by Kaplan-Meier method, and by Cox proportional hazards model, which was adjusted for other variables, including stage and status of MSI and BRAF mutation.
Results: KRAS mutations were detected in 684 (36%) of 1925 tumors. In cohort A, Kaplan-Meier and multivariate Cox regression analyses showed that c.35G>T mutants (N=93) and c.34G>C mutants (N=8) were associated with significantly high colorectal cancer-specific mortality.
|KRAS||N||Univariate HR (95% CI)||P value||Multivariate HR (95% CI)||P value|
|Wild-type||635||1 (reference)||1 (reference)|
|c.34G>A (p.G12S)||12||2.61 (1.15-5.91)||0.022||1.03 (0.44-2.44)||NS|
|c.34G>C (p.G12R)||8||4.22 (1.72-10.4)||0.002||3.39 (1.28-9.00)||0.014|
|c.34G>T (p.G12C)||44||1.70 (1.01-2.85)||0.045||1.56 (0.92-2.65)||NS|
|c.35G>A (p.G12D)||155||1.47 (1.07-2.04)||0.019||1.08 (0.76-1.51)||NS|
|c.35G>C (p.G12A)||19||1.36 (0.60-3.08)||NS||0.56 (0.24-1.30)||NS|
|c.35G>T (p.G12V)||93||1.84 (1.28-2.64)||0.001||2.00 (1.38-2.90)||0.0003|
|c.38G>A (p.G13D)||103||1.33 (0.90-1.96)||NS||0.88 (0.59-1.30)||NS|