title: Characterization of rare transforming KRAS mutations in sporadic colorectal cancer.
abstract: 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.
authors.affiliation: Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China.
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China.
authors.forename: Raymond W M
authors.initials: RW
authors.lastname: Lung
authors.affiliation: Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China.
authors.forename: Frankie M C
authors.initials: FM
authors.lastname: Sin
authors.affiliation: Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China.
authors.forename: Peggy P Y
authors.initials: PP
authors.lastname: Law
authors.affiliation: Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China.
authors.forename: Anthony W H
authors.initials: AW
authors.lastname: Chan
authors.affiliation: Sir Y.K. Pao Cancer Center; Hong Kong SAR, PR China; Department of Clinical Oncology; The Chinese University of Hong Kong; Hong Kong SAR, PR China.
authors.forename: Brigette B Y
authors.initials: BB
authors.lastname: Ma
authors.affiliation: Department of Surgery; The Chinese University of Hong Kong; Hong Kong SAR, PR China.
authors.forename: Tony W C
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China; Department of Surgery; The Chinese University of Hong Kong; Hong Kong SAR, PR China.
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
authors.affiliation: Department of Anatomical and Cellular Pathology; State Key Laboratory in Oncology in South China; Prince of Wales Hospital; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Institute of Digestive Disease; Partner State Key Laboratory of Digestive Disease; The Chinese University of Hong Kong; Hong Kong SAR, PR China; Li Ka Shing Institute of Health Science; Hong Kong SAR, PR China.
authors.forename: Ka Fai
authors.initials: KF
authors.lastname: To
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D017678:Sex Distribution; D015398:Signal Transduction; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: KRAS; colorectal cancer; targeted therapy