Characterization of rare transforming KRAS mutations in sporadic colorectal cancer

• Published in: Cancer biology & therapy Vol. 15; no. 6; pp. 768 - 776
• Main Authors: Tong, Joanna HM, Lung, Raymond WM, Sin, Frankie MC, Law, Peggy PY, Kang, Wei, Chan, Anthony WH, Ma, Brigette BY, Mak, Tony WC, Ng, Simon SM, To, Ka Fai
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-06-2014; Landes Bioscience
• Subjects: Adenocarcinoma - epidemiology; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Animals; Base Sequence; colorectal cancer; Colorectal Neoplasms - epidemiology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA Mutational Analysis; Female; Genetic Association Studies; HEK293 Cells; Humans; INDEL Mutation; KRAS; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Mutation, Missense; Neoplasm Transplantation; NIH 3T3 Cells; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Research Paper; Sex Distribution; Signal Transduction; targeted therapy; Young Adult; targeted therapy; KRAS; colorectal cancer
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.28550

KRAS mutational status has been shown to be a predictive biomarker of resistance to anti-EGFR monoclonal antibody (mAb) therapy in patients with metastatic colorectal cancer. We report the spectrum of KRAS mutation in 1506 patients with colorectal cancer and the identification and characterization of rare insertion mutations within the functional domain of KRAS. KRAS mutations are found in 44.5% (670/1506) of the patients. Two cases are found to harbor double mutations involving both codons 12 and 13. The frequencies of KRAS mutations at its codons 12, 13, 61, and 146 are 75.1%, 19.3%, 2.5%, and 2.7%, respectively. The most abundant mutation of codon 12 is G12D, followed by G12V and G12C while G13D is the predominant mutation in codon 13. Mutations in other codons are rare. The KRAS mutation rate is significantly higher in women (48%, 296/617) than in men (42.1%, 374/889, P = 0.023). Tumors on the right colon have a higher frequency of KRAS mutations than those on the left (57.3% vs. 40.4%, P < 0.0001). Two in-frame insertion mutations affect the phosphate-binding loop (codon 10-16) of KRAS are identified. One of them has never been reported before. Compared with wild-type protein, the insertion variants enhance the cellular accumulation of active RAS (RAS-GTP) and constitutively activate the downstream signaling pathway. NIH3T3 cells transfected with the insertion variants show enhanced anchorage-independent growth and in vivo tumorigenicity. Potentially these mutations contribute to primary resistance to anti-EGFR mAb therapy but the clinical implication requires further validation.