[685] KRAS Codon 12, 13, 61 and 146 Mutations in 1267 Colorectal Cancers: Clinicopathological, Molecular, and Survival Analyses

Xiaoyun Liao, Yu Imamura, Shuji Ogino. Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital, Boston, MA

Background: KRAS mutations status is increasingly important for management of colorectal cancer patients. KRAS mutations typically occur in codons 12, 13, 61 and 146. There has been no large-scale study which has comprehensively examined clinicopathologic, molecular, and prognostic associations of KRAS codon 61 and 146 mutations in colorectal cancer.
Design: We performed PCR and pyrosequencing of KRAS codons 12, 13, 61 and 146 in 1267 colorectal cancers. We characterized other molecular features [BRAF and PIK3CA mutations; MGMT promoter methylation and loss of expression; microsatellite instability (MSI) status] Proportional hazards model was used to compute mortality hazard ratio (HR) and 95% confidence interval (CI), adjusting for potential confounders, including stage, BRAF mutations, and MSI.
Results: We found 505 (40% of 1267) KRAS-mutated colorectal cancers, including 19 cases (1.5%) in codon 61 mutations, 40 cases (3.2%) in codon 146 mutations, and 12 cases (0.9%) with two or more KRAS mutations.

KRAS mutations in 1267 colorectal cancers
CodonNo.Proportion in 1267 tumors
Any50540%
1234427%
131159.1%
61191.5%
146403.2%
There are cases with more than one KRAS mutations.

In codons 61 and 146, we found c.182A>G (p.Q61R; N=2), c.182A>T (p.Q61L; N=4), c.183A>C (p.Q61H; N=7), c.180_181delinsAA (p.G61K; N=4), c.436G>A (p.A146T; N=21), c.436G>C (p.A146P; N=3), and c.437C>T (p.A146S; N=11). Regardless of codon, KRAS mutations appeared to be associated with cecal tumor location (P <0.001), and PIK3CA mutations (P <0.001). MGMT loss was associated with KRAS G:C>A:T mutations (P <0.001). Patients who had colorectal cancers with KRAS codon 61 and 146 mutations survived similarly (multivariate HR =0.86; 95% CI, 0.31-2.35; and multivariate HR =0.95; 95% CI, 0.42-1.74; respectively) to KRAS wild-type cases.
Conclusions: KRAS codon 61 and 146 mutations occur approximately 5% of colorectal cancers. Clinicopathologic and molecular features of colorectal cancers with KRAS codon 61 and 146 mutations appear to be similar to KRAS codon 12 and 13 mutations. Additional studies are necessary to determine clinical utility of KRAS codon 61 and codon 146 testing in colorectal cancer.
Category: Gastrointestinal

Monday, March 4, 2013 1:00 PM

Poster Session II # 140, Monday Afternoon

 

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