Wenwei Fan

Background: The occurrence, progression, and prognosis of colorectal cancer (CRC) are regulated by EGFR-mediated signaling pathways. However, the relationship between the core genes ( KRAS / NRAS / BRAF / PIK3CA ) status in the signaling pathways and clinicopathological characteristics of CRC patients in Hakka population remains controversial. Methods: Patients were genotyped for KRAS (codons 12, 13, 61, 117, and 146), NRAS (codons 12, 61, 117, and 146), BRAF (codons 600), and PIK3CA (codons 542, 545 and 1047) mutations. Clinical records were collected, and clinicopathological characteristic associations were analyzed together with mutations of studied genes. Results: Four hundred and eight patients (256 men and 152 women) were included in the analysis. At least one mutation in the four genes was detected in 216 (52.9%) patients, while none was detected in 192 (47.1%) patients. KRAS, NRAS, BRAF , and PIK3CA mutation status were detected in 190 (46.6%), 11 (2.7%), 10 (2.5%), 34 (8.3%) samples, respectively. KRAS exon 2 had the highest proportion (62.5%). Age, tumor site, tumor size, lymphovascular invasion, and perineural invasion were not associated with gene mutations. KRAS mutations (adjusted OR 1.675, 95% CI 1.017– 2.760, P =0.043) and NRAS mutations (adjusted OR 5.183, 95% CI 1.239– 21.687, P =0.024) appeared more frequently in patients with distant metastasis. BRAF mutations (adjusted OR 7.224, 95% CI 1.356– 38.488, P =0.021) and PIK3CA mutations (adjusted OR 3.811, 95% CI 1.268– 11.455, P =0.017) associated with poorly differentiated tumor. Conclusion: KRAS/NRAS mutations are associated with distant metastasis and BRAF/PIK3CA mutations are associated with poor tumor differentiation in CRC. And the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients. Keywords: colorectal cancer, KRAS , NRAS , BRAF , PIK3CA , clinicopathological feature

1121 Objectives To radiosynthesize and evaluate a molecular imaging probe, termed [11C]SU11274 ([11C]14), for quantification of MET receptors in human cancers in vivo. Methods (3-[3,5-dimethyl-4-(4-methyl-piperazine-carbonyl)-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chlorophenyl)-methyl amide (14) was radiolabelled with C-11 through radiomethylation of 3-[3,5-dimethyl-4-(piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihyro-1H-indole-5-sulfonic acid (3-chlorophenyl)-methyl amide hydrochloride (13) that was designed as the precursor. For in vivo microPET studies, two human lung cancer xenograft models were established using MET-positive NCI-H1975 and MET- negative NCI-H520. MRI (9.4T) studies were performed right after microPET to co-register with microPET images. In vitro histological studies were further conducted after microPET and MRI imaging. Results The synthesis of 13 was achieved in 10 steps with a total yield of 9.7%. [11C]14 was obtained in a range of 5-10 % radiochemical yield and over 95% radiochemical purity after HPLC preparation. Quantitative microPET study showed that the tumor uptake of the [11C]14 in the NCI-H1975 xenograft was significantly higher than that in the NCI-H520 xenograft, which is consistent with their corresponding immunohistochemical tissue staining patterns of MET receptors from the same animals. Conclusions These studies demonstrated that [11C]14-PET is an appropriate imaging marker for quantification of MET receptor in vivo and can facilitate efficacy evaluation in the clinical development of MET targeted cancer therapeutics