ABSTRACT
Objective To investigate the association between KRAS gene mutations and clinicopathological characteristics and prognosis of colorectal cancer (CRC) patients.Methods The retrospective casecontrol study was conducted.The clinicophathological data of 315 patients who underwent radical resection of CRC in the Yangpu Hospital Affiliated to Tongji University between January 2007 and July 2011 were collected.Nextgeneration sequencing was performed to identify KRAS gene mutations from surgical specimens.Observation indicators:(1) detection of KRAS gene;(2) association between KRAS gene mutations and clinicopathological characteristics of CRC patients;(3) follow-up and survival situations;(4) multivariate analysis of KRAS gene mutations in the prognosis of CRC patients.Follow-up using outpatient examination and telephone interview was performed to detect postoperative overall survival up to August 2016.Comparisons of count data were analyzed using the chi-square test.Measurement data with skewed distribution were described as M (interquartile range),and comparison between groups was analyzed using the nonparametric test.The survival rate was calculated using the Kaplan-Meier method,and survival was compared using the Log-rank test.The multivariate analysis was done using the COX regression model.Results (1) Detection of KRAS gene:all the 315 patients finished gene detection of surgical specimens,including 172 in wide-type mutations and 143 in mutant-type mutations (mutations at codon 12 and 13 of KRAS exon 2 and other mutant points were respectively detected in 80,24 and 40 patients,and 1 patient had simultaneous mutations at codon 12 and 13 of KRAS exon 2;missense and nonsense mutations were respectively detected in 141 and 2 patients).The major point mutations were at p.G12D and p.G13D.(2) Association between KRAS gene mutations and clinicophathological characteristics of CRC patients:tumors located in the proximal colon,distal colon and rectum were respectively detected in 34,48,90 patients with wild-type mutation and in 44,27,72 patients with mutant-type mutation,with a statistically significant difference (x2 =0.038,P＜0.05).(3) Follow-up and survival situation:315 patients were followed up for 3-115 months,with a median time of 78 months.The postoperative overall survival rate was 41.0％ in 172 patients with wild-type KRAS mutations,27.4％ in 80 patients with KRAS codon 12 mutations,26.3％ in 24 patients with KRAS codon 13 mutations and 48.2％ in 40 patients with other KRAS mutations,showing a statistically significant difference (x2=0.040,P＜0.05).(4) Multivariate analysis of KRAS gene mutations in the prognosis of CRC patients:the results of multivariate analysis showed that mutations at codon 12 of KRAS exon 2 was an independent factor affecting poor prognosis of CRC patients (Hazard ratio=1.543,95％ confidence interval:1.050-2.265,P＜0.05).Conclusions Most KRAS mutations of CRC patients are at codon 12 and 13 of KRAS exon 2,and the major point mutations are at p.G12D and p.G13D.KRAS gene mutations may be associated with tumor location.Mutations at codon 12 of KRAS exon 2 is an independent factor affecting poor prognosis of CRC patients.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate the impact of neutrophil-to-lymphocyte ratio(NLR) on the prognosis of patients with locally advanced colorectal cancer (LACRC).</p><p><b>METHODS</b>Clinicopathological data of 684 patients with stage II(-III( CRC undergoing radical resection at Shanghai Ruijin Hospital from January 2008 to December 2010 were analyzed retrospectively. NLR was calculated from neutrophil and lymphocyte counts on routine blood tests prior to surgery. The optimal cutoff value of NLR for predicting 5-year overall survival (OS) was determined through receiver operating characteristic (ROC) curve analysis. According to the cut-off value, patients were divided into high NLR and low NLR groups. Clinicopathological characteristics and prognosis were compared between two groups. Univariate and multivariate analyses were performed with Cox proportional hazards model to evaluate the impact of clinical factors on prognosis.</p><p><b>RESULTS</b>A total of 396 male and 288 female patients were included in the study, with a median age of 62 years(range 21-92).Among these patients, 335 had rectal cancers and 349 had colonic cancers; 328 were TNM stage II( and 356 were stage III(. The end of follow-up was January 2016. ROC curve showed that the optimal cut-off value of NLR was 3.0, then patients were divided into low NLR group (NLR≤3.0, n=481) and high NLR group (NLR>3.0, n=203). Compared with low NLR group, the high NLR group was more likely to be older (median 64 vs. 61, t=-2.412, P=0.016), presented higher ratio of colonic cancer [66.0%(134/203) vs. 44.7%(215/481), χ=25.945, P=0.000] and stage III( tumor [60.1%(122/203) vs. 48.6%(234/481), χ=7.499, P=0.007], but lower ratio of first-degree relative cancer history [8.9%(18/203) vs. 15.6%(75/481); χ=5.496, P=0.020]. However, no significant differences were observed between two groups in gender, smoking and drinking history, tumor differentiation grade, vessel invasion and nerve invasion (all P>0.05). The median follow-up time was 67 months (range 3-92), and the 5-year OS rates of high NLR and low NLR group were 59.6% and 73.2% respectively, with significant difference (P=0.001). Cox multivariate analysis revealed that age >65 years (HR=2.07, 95%CI=1.59-2.70, P=0.000), no first-degree relative cancer history (HR=2.01, 95%CI=1.23-3.28, P=0.005), poor differentiation grade (HR=1.65, 95%CI=1.26-2.15, P=0.000), positive vessel or nerve invasion (HR=1.92, 95%CI=1.35-2.71, P=0.000), high TNM stage(HR=2.10, 95%CI=1.59-2.77, P=0.000) and preoperative NLR>3.0(HR=1.51, 95%CI=1.14-2.00, P=0.004) were independent risk factors of prognosis for patients with LACRC.</p><p><b>CONCLUSIONS</b>Preoperative NLR can influence the prognosis of patients with LACRC receiving radical surgery. High NLR is associated with poor prognosis.</p>