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. than in men (42.1%, 374/889, = 0.023). Tumors on the right colon have a higher frequency of mutations than those around the left (57.3% vs. 40.4%, 0.0001). Two in-frame insertion mutations affect the phosphate-binding loop (codon 10C16) of are identified. One of them has never been reported before. Compared with wild-type protein, the insertion variants enhance the CCNU 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. mutation which accounting for 30C40% of non-responsive cases.4-7 mutation status is now considered to be a predictive biomarker of resistance to anti-EGFR mAbs treatment for mCRC patients. KRAS is one of the RAS superfamily of proto-oncoproteins which is usually small signal switch molecule called GTPase, cycling between inactive GDP-bound (RAS-GDP) and active GTP-bound (RAS-GTP) forms, to regulate cellular growth and differentiation. 8 Activating mutations of RAS proto-oncogenes constantly elevate the cytoplasmic RAS-GTP level. Oncogenic signaling pathways, such as Raf-MEK-ERK and PI3K/AKT cascades, are then constitutively activated in an EGFR activation-independent manner and therefore promote cell cycle progression.6,8 mutation is found in 40% of CRCs and missense point mutation is the most common mutation. The majority of the point mutation sites of in CRC patients are located at codons 12 and 13 (~80% and ~17%, respectively), together with rare mutations at codons 61 and 146 (~1C4%).3,9-11 Most clinical studies of mutation in CRC were conducted in western countries. However, mutation rate or spectrum in CRCs may partially depends on the population studied.12 It has been reported that mutations were identified in CRC patients from the UK, Switzerland, and Spain, Alisertib enzyme inhibitor for 27.4%, 38%, and 41% respectively.12 This epidemiological variation indicates the essence of establishment of a local CRC mutation data in different populations. There has been a dramatic increase in reported incidence of colorectal cancer in Asian.12 It is of paramount importance to investigate the mutation spectrum in our locality in view of the implication in using anti-EGFR targeting therapy. We aim to analyze the mutation status and the clinical correlation in Chinese patients with CRC in Hong Kong. Here we report the spectrum of mutation in a large cohort of colorectal cancer and the identification and characterization of a novel insertion mutation within the function domain name of KRAS. Results Clinical characteristics of the patients We tested a total of 1506 patients with colorectal cancer. Of them 889 (59%) were males and 617 (41%) were females. The median age at presentation was 61 11.3 y (range 21C89 y). The clinical characteristics were in keeping with other reported populations of colorectal cancer.11 The age of female patients were slightly younger than males (59 12.1 vs 61 11.2, = 0.014). There was significantly higher frequency of left colon tumor (75.8%) than the right side (24.2%, 0.0001). However, the right side tumors were more common in females (28.7%) compared with males (21.1%, = 0.001). When rectal tumor was considered a separate entity, female patients had a higher frequency of right side tumor whereas the rectal tumors were more commonly found in male patients ( 0.0001). The Alisertib enzyme inhibitor clinical characteristics of the patients tested were summarized in Table 1. Table Alisertib enzyme inhibitor 1. Clinical characteristics of 1506 patients tested for status value=1506617 (41%)889 (59%)?Age61 11.359 12.161 11.20.014Tumor site (right vs left)??0.001Right365 (24.2%)177 (28.7%)188 (21.1%)?Left1141 (75.8%)440 (71.3%)701 (78.9%)?Tumor site (right vs left vs rectum)?? 0.0001Right365 (24.2%)177 (28.7%)188 (21.1%)?Left538 (35.7%)228 (40.0%)310 (34.9%)?Rectum603 (40.1%)212 (34.3%)391 (44.0%)? Open in a separate window Status of mutation mutations on codons 12, 13, 61 and 146 were analyzed by PCR-direct sequencing using microdissected FFPE tumor tissues from 1506 patients. A total of 672 mutations were identified from 670 patients (44.5%, 670 out of 1506, Table 2). Two cases were found to harbor double mutations. Both cases involved codon 12 and Alisertib enzyme inhibitor codon 13 of gene. One case harbored.