ARLTS1 variants and melanoma risk

Variants in the tumor suppressor gene ARLTS1 (ADP-ribosylation factor-like tumor-suppressor gene 1) have been shown to influence familial cancer risk. Both Cys148Arg and Trp149Stop were associated with an increased risk of familial or high-risk familial breast cancer, respectively. We studied the impact of these gene variants on melanoma risk, investigating 351 melanoma patients and 804 control subjects. While ARLTS1 Trp149Stop did not influence melanoma risk (OR = 0.83, 95% CI = 0.37-1.88, p = 0.65), Cys148Arg revealed a statistically significant association with an increased risk for heterozygous carriers (OR = 1.43, 95% CI = 1.05-1.95, p = 0.02). An additional risk enhancement, though statistically non-significant, was observed in individuals with multiple melanomas (OR = 2.33, 95% CI = 0.87-6.26, p = 0.08).     

Genetic variants in frizzled-related protein (FRZB) and the risk of colorectal neoplasia

Objective  The Wnt/APC/β-catenin signaling pathway, which includes frizzled-related protein (FRZB), plays a critical role in the development of colorectal cancer, and recent evidence suggests that the functional polymorphism, FRZB Arg324Gly, may be associated with risk for this disease. To determine if this finding could be replicated, we investigated the association between two FRZB polymorphisms (Arg324Gly and Arg200Trp) and the risk of colorectal adenoma and cancer in nested case–control studies. Methods  Participants consisted of 1,709 adenoma cases, 620 cancer cases, and 1,849 controls within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the associations with colorectal neoplasia. Results  No association was observed for either polymorphism or any haplotypes with colorectal adenoma or colorectal cancer (p > 0.05 for all). Conclusion  Our study does not support the previously observed association between the FRZB 324Gly variant and colorectal cancer risk. However, further study of additional genetic variants within this pathway is still warranted, given the important role of the Wnt signaling pathway in colorectal carcinogenesis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association between polymorphisms in long non-coding RNA PRNCR1 in 8q24 and risk of colorectal cancer

Background

Genome-wide association studies have identified that genetic variants in 8q24 confer susceptibility to colorectal cancer (CRC). Recently, a novel lncRNA (PRNCR1) that located in the 8q24 was discovered. Single nucleotide polymorphisms (SNPs) in the lncRNAs may influence the process of splicing and stability of mRNA conformation, resulting in the modification of its interacting partners. We hypothesized that SNPs in the lncRNA PRNCR1 may be related to the risk of CRC.

Methods

We conducted a case–control study and genotyped five tag SNPs in the lncRNA PRNCR1 in 908 subjects including 313 cases with CRC and 595 control subjects using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay.

Results

In overall analyses, we found that the rs13252298 and rs1456315 were associated with significantly decreased risks of CRC. In stratification analyses, we found that CRC patients carrying the rs1456315G were likely to have a tumor size of greater than 5 cm (G vs. A: adjusted OR = 1.56, 95% CI: 1.10-2.23). Additionally, patients with the rs7007694C and rs16901946G had decreased risks to develop poorly differentiated CRC, whereas patients with the rs1456315G had an increased risk to develop poorly differentiated CRC.

Conclusion

These findings suggest that SNPs in the lncRNA PRNCR1 may contribute to susceptibility to CRC.     

Comparison of visual and automated assessment of tumour inflammatory infiltrates in patients with colorectal cancer

BackgroundCancer-associated inflammation is increasingly recognised to be an important determinant of oncological outcome. In colorectal cancer, the presence of peri-tumoural inflammatory/lymphocytic infiltrates predicts improved survival. To date, these infiltrates, assessed visually on haematoxylin and eosin (H&E) stained sections, have failed to enter routine clinical practice, partly due to their subjective assessment and considerable inter-observer variation. The present study aims to develop an automated scoring method to enable consistent and reproducible assessment of tumour inflammatory infiltrates in colorectal cancer.Methods154 colorectal cancer patients who underwent curative resection were included in the study. The local inflammatory infiltrate was assessed using the method described by Klintrup–Makinen. H&E tumour sections were uploaded to an image analysis programme (Slidepath, Leica Biosystems). An image analysis algorithm was developed to count the inflammatory cells at the invasive margin. The manual and automated assessments of the tumour inflammatory infiltrates were then compared.ResultsThe automated inflammatory cell counts assessed using the freehand annotation method (p < 0.001) and the rectangular box method (p < 0.001) were significantly associated with both K–M score (p < 0.001) and K–M grade (p < 0.001). The inflammatory cell counts were divided using quartiles to group tumours with similar inflammatory cell densities. There was good agreement between the manual and automated scoring methods (intraclass correlation coefficient (ICC) = 0.82). Similar to the visual K–M scoring system, the automated K–M classification of the inflammatory cell counts, using quartiles, was significantly associated with venous invasion (p < 0.05) and modified Glasgow Prognostic Score (mGPS) (p ⩽ 0.05). On univariate survival analysis, both automated K–M category (p < 0.05) and automated K–M grade (p < 0.005) were associated with cancer-specific survival.ConclusionThe results of the present study demonstrate that automated assessment effectively recapitulates the clinical value of visual assessment of the local inflammatory cell infiltrate at the invasive margin of colorectal tumours. In addition, it is possible to obtain an objective assessment of tumour inflammatory infiltrates using routinely stained H&E sections. An automated, computer-based scoring method is therefore a workable and cost-effective approach to clinical assessment of local immune cell infiltrates in colorectal cancer.     

Start codon polymorphisms in the vitamin D receptor and colorectal cancer risk

The expression of the nuclear vitamin D receptor (VDR), which is involved in regulating cell growth and proliferation, may contribute to the development of colorectal cancer. Polymorphisms in the VDR gene (OMIM 601769) may influence the expression or function of the VDR protein. A population-based, case-control study of VDR start codon, intron, and exon polymorphisms, haplotypes for these polymorphisms, and the relationships between these polymorphisms and clinicopathological parameters in 190 colorectal cancer patients and 318 controls was conducted. The start codon variant VDR 27823*C/*C genotype was associated with an increased risk for colorectal cancer, while the 27823*T/*T genotype was associated with a decreased risk. In addition, the VDR 61888*G/*G genotype was associated with reduced colorectal cancer risk. The intron 8 60880G>A and exon 9 61968T>C polymorphisms were not associated with colorectal cancer risk. The VDR 27823*C-60890*G-61888*T-61968*T haplotype was associated with an increased risk of colorectal cancer, whereas the VDR 27823*T-60890*G-61888*G-61968*T haplotype was associated with a decreased risk of colorectal cancer. Moreover, the 27823*C/*C genotype was more frequently identified in patients with preoperative serum carcinoembryonic antigen (CEA) levels over 6ng/mL. These results suggest that the VDR start codon 27823*C allele may be linked to high risk for colorectal cancer, especially in a subset of colorectal cancers showing specific biological behaviors.     

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk

Recently, ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) has been identified as a tumor suppressor gene, playing a major role in apoptotic signaling. The ARLTS1 Trp149Stop mutation has been shown to predispose to general familial cancer and high-risk familial breast cancer (BC), provoking the attenuation of apoptotic function. We studied the impact of the ARLTS1 Pro131Leu and Cys148Arg variants on high-risk familial and familial BC risk, investigating 482 familial BC cases (including 305 high-risk cases) and 530 control individuals. Unlike ARLTS1 Pro131Leu, Cys148Arg revealed a significant association with an increased risk of high-risk familial BC (odds ratio (OR)=1.47, 95% confidence interval (95% CI)=1.04-2.06, p=0.03) in a dose-dependent manner (ptrend=0.007). The genotype distribution of Cys148Arg in familial cases was similar, indicating significance as well (OR=1.48, 95% CI=1.10-1.99, p=0.009; ptrend=0.003). On the basis of the small number of 46 cases, we additionally showed an association between the Trp149Stop mutation and an increased risk of bilateral BC (OR=4.11, 95% CI=1.27-13.31, p=0.011).     

两种风险评估模型在结直肠癌筛查中应用效果的比较研究

目的 比较两种风险评估模型在结直肠癌早期筛查中的应用效果,探讨更适用于我国居民结直肠癌早期筛查的评估模型。方法 以2017—2019年参加深圳市南山区城市癌症早诊早治项目的40~74岁常住居民为研究对象,采用两种风险评估模型对同一人群进行结直肠癌风险评估,比较不同模型的筛查效果和预测价值。结果 共纳入4 141例研究对象,平均年龄(56.4±9.0)岁。模型一、模型二的初筛阳性率分别为15.2%和21.3%,总体一致率为93.50%(Kappa值=0.784,P＜0.001)。702例肠镜检查者中,肠炎、息肉、腺瘤、肠癌、其他肠道病变的检出率分别为12.5%、12.0%、15.8%、0.7%、30.7%,两种模型初筛阳性者的肠镜检查结果分布无统计学差异(χ²=8.679,P=0.123)。模型一的灵敏度为 45.7%,低于模型二(61.2%);而模型一的特异度(64.8%)、阳性预测值(76.7%)、Kappa值(0.081)、约登指数(0.103)均高于模型二(41.7%、72.6%、0.026、0.029)。两种模型的ROC曲线下面积分别为0.660(95% CI:0.618~0.702)和0.675(95% CI:0.634~0.715),两者之间无统计学差异(P=0.584)。结论 两种风险评估模型对结直肠癌早期诊断均具有一定的预测能力和优势,但在筛查准确度和筛查效益方面,模型一稍优于模型二,在大规模人群筛查中,建议两种模型取长补短,综合应用。     

Extramural venous invasion (EMVI) in colorectal cancer is associated with increased cancer recurrence and cancer-related death

IntroductionColorectal cancer (CRC) outcomes vary depending on tumour biology, with several features used to predict disease behaviour. Extramural venous invasion (EMVI) is associated with negative outcomes and its presence has been established as an indicator of more aggressive disease in CRC.MethodsA prospectively maintained database was examined for patients undergoing curative resection for non-metastatic CRC between 2012 and 2018 in a tertiary institution. Clinicopathological factors were compared to assess their impact on recurrence, all-cause mortality and cancer-related death. Kaplan Meier analysis of the association between EMVI and these endpoints was performed, and univariable and multivariable analysis was carried out to establish the relationship of predictive factors in oncological outcomes.ResultsEighty-eight (13.5%) of 654 patients developed recurrence. The mean time to recurrence was 19.8 ± 13.5 months. There were 36 (5.5%) cancer-related deaths at a mean duration of follow-up of 46.3 ± 21.6 months. Two hundred and sixty-six patients had extramural venous invasion (40.7%). EMVI was significantly associated with reduced overall recurrence-free survival, systemic recurrence-free survival, and increased cancer-related death on univariate analysis (p < 0.001 for all, Fig. 1), and multivariable analysis (OR 1.8 and 2.1 respectively, p < 0.05 for both).ConclusionEMVI is associated with a poor prognosis, independent of stage, nodal status and other histopathological features. The presence of EMVI should be strongly considered as an indication for adjuvant therapy.     

Association of Caveolin-1 polymorphisms with colorectal cancer susceptibility in Taiwan

AIM: To investigate the association of Caveolin-1 (Cav-1) polymorphisms with colorectal cancer (CRC) risk in a central Taiwanese population.METHODS: Three hundred and sixty-two patients with colorectal cancer and the same number of recruited age- and gender-matched healthy controls were genotyped. And only those matches with all single nucleotide polymorphisms data (case/control = 362/362) were selected for final analyzing.RESULTS: There were significant differences between CRC and control groups in the distributions of their genotypes (P = 1.6 × 10^-12 and 3.0 × 10^-4) and allelic frequencies (P = 2.3 × 10^-13 and 4.0 × 10^-5) in the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms respectively. As for the haplotype analysis, those who had GG/AT or GG/AA at Cav-1 G14713A/T29107A showed a 0.68-fold (95% CI: 0.48-0.98) decreased risk of CRC compared to those with GG/TT, while those of any other combinations were of increased risk. There were joint effects of Cav-1 G14713A and T29107A genotype with smoking status on individual CRC susceptibility.CONCLUSION: This is the first report providing evidence of Cav-1 being involved in CRC and it may be novel useful genomic markers for early detection of CRC.     

A case-control study on risk of changing food consumption for colorectal cancer

Objectives. To investigate the relative risk factor of food items for colorectal cancer in four time periods through a case-control study in a Chinese rural area.

Methods. Colorectal cancer patients diagnosed at a county cancer center, Hebei Province, China, and non-cancer outpatients with similar age, sex, and place of residence were selected for cases and controls, respectively. There were 102 (93.6%) colorectal cancer patients and 99 (90.8%) outpatients being the cases and controls, respectively in the present investigation, who agreed to be interviewed about their food intake, during a 20-year period, through a food frequency questionnaire. The risks of intake of different food items and lifestyle for colorectal cancer were compared between cases and controls.

Results. During the 20-year period, diets of both cases and controls changed with increase in intake of animal foods and fruits, and alcohol consumption tended to increase. In the food items, milk intake showed a protective effect in both males and females, and the odds ratios were 0.38 (95% CI 0.16-0.90) and 0.28 (95% CI 0.10-0.81) for males and females, respectively. A reduced risk of fruit intake could be seen in males, while a reduced risk of vegetables could be observed in females. Meat intake and saturated fats were the prominent risk factors for colorectal cancer in males and females, respectively. A comparison of life habits, showed that tea drinking had a consistent protective effect in females, and the odds ratios were 0.21 (0.08-0.58), 0.23 (0.08-0.67), 0.25 (0.10-0.64), and 0.11 (0.04-0.30) for periods of 20-, 10-, 5-years ago, and current time, respectively.

Conclusions. These findings indicate that change in food consumption is strongly associated with a change in risk of colorectal cancer, and dietary meat has increased the risk of colorectal cancer. Increase in the consumption of milk and fruits may be a significant measure for colorectal cancer prevention in low-incidence areas.     

Coding region polymorphisms in the CHFR mitotic stress checkpoint gene are associated with colorectal cancer risk

CHFR was recently identified as an early mitotic checkpoint that delays transition to metaphase in response to mitotic stress. Although studies have shown that CHFR is relevant to tumorigenesis, no previous report has investigated whether polymorphisms in the CHFR gene are associated with the risk of cancer development. Here, we genotyped polymorphisms in the CHFR gene and analyzed the possible associations of single polymorphisms and haplotypes with the risk and clinicopathological characteristics of colorectal cancer. Six coding SNPs in the CHFR gene were genotyped in 462 colorectal cancer patients and 245 healthy normal controls, using either the TaqMan assay or direct sequencing. Our results revealed that the V539M polymorphism was significantly associated with a lower risk of colorectal cancer (P = 0.03; OR, 0.533; 95% CI, 0.302–0.94), and significantly correlated with no distant metastasis (M0 stage), different TNM stage, and microsatellite instability (MSI) among the colorectal cancer patients. Among the five tested haplotypes, hap 10 (TGACTA) was significantly associated with a lower risk of colorectal cancer (P = 0.017; OR, 0.496; 95% CI, 0.279–0.883), and colorectal cancer patients carrying this haplotype showed no distant metastasis, different TNM stage, and microsatellite instability at a significantly higher frequency. These results reveal for the first time that polymorphisms in the CHFR gene are associated with colorectal cancer susceptibility.     

抑癌基因ING3在大肠癌中表达及意义

目的：探讨ING3在大肠癌中的表达及意义。方法收集82例大肠癌临床手术标本,通过荧光定量PCR检测癌旁正常黏膜中与癌组织中ING3的表达水平,分析ING3的表达水平与临床病理特征及预后的关系。结果51％的大肠癌患者中,ING3 mRNA在癌组织中的表达水平显著低于癌旁组织, ING3的表达与临床T分期、M 分期及TNM分期密切相关（P＜0．05）。单因素分析显示出T、N、M分期、TNM分期及ING3的表达均与患者术后总无病生存率相关（ P＜0．05）。 ING3低表达组患者长期无病生存率较中高表达组患者显著降低（ P＜0．05）。结论 ING3的表达与大肠癌发生发展相关,有望成为大肠癌早期诊断早期治疗的分子靶点。     

Significance of extranodal tumour deposits in colorectal cancer: A systematic review and meta-analysis

AimsThe presence and significance of extranodal tumour deposits (ENTDs) in colorectal cancer (CRC) continue to cause controversy in terms of origin, classification and prognostic significance. This review aims to assess current evidence on the origin of ENTDs in CRC and their effect on overall and disease-free survival.MethodsA systematic review and meta-analysis were carried out in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. End-points included prevalence of ENTDs, relationship with extramural venous invasion (EMVI), overall survival (OS) and disease-free survival (DFS). Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated using Stata software.ResultsTwenty-six studies comprising 19,980 patients were included. The prevalence of ENTDs ranged from 10.2% to 44.2% (median 21.3%). There was a significantly increased odds of having ENTD if EMVI was present with a pooled OR of 2.51 (95% CI 2.27–2.77) p ≤ 0.001. The pooled HR for adverse OS in patients with ENTD was 1.63 (95% CI 1.44–1.61), p ≤ 0.001. For adverse DFS the pooled HR was 1.77 (95% CI 1.37–2.11), p ≤ 0.001.ConclusionThis meta-analysis confirms the negative impact of ENTDs on OS and DFS despite variations in classification and prevalence. ENTDs are significantly associated with EMVI. The prognostic implications of ENTDs are not sufficiently recognised in current staging systems. TNM 8 has failed to address this and has not made use of the available evidence to determine the correct position of ENTDs according to their prognostic effect. The prognostic hierarchy should be N0, N1, N2 with N1c being the most severe. Additionally the exclusion of lesions of vascular, lymphatic and perineural origin by TNM 8 has no evidence base.     

Frequency of therapy-relevant staging shifts in colorectal cancer through the introduction of pN1c in the 7th TNM edition

BackgroundpN1c is a novel N-category introduced for colorectal cancer (CRC) in current TNM (Tumour, Node, Metastasis) classification. It represents cancers displaying tumour deposits (TDs) in the fat but no involvement of lymph nodes. pN1c is integrated into the UICC (International Union Against Cancer) staging system and shifts previous stage II cancers (6th edition) to stage III. We investigated the frequency of upstaging and TD prognostic significance.Methods414 CRCs, consecutively collected during a population-based epidemiological study, TNM classified and UICC staged according to the 6th TNM edition were reinvestigated for TD presence. The association with survival was investigated after a median follow-up time of 5 years in multivariate analyses among nodal negative and positive cases.ResultsTDs were found in 103 (24.9%) cancers and were strongly associated with T-, N- and M-stages (p < 0.0001, each). Upstaging of previous stage II cancers by the presence of TDs (pN1c) was found in six of 140 cases (4.3% of stage II, 1.4% of all tumours). For stage III CRC, strongly reduced overall, CRC-specific and recurrence-free survival were observed with the presence of TDs (hazard ratios (HR) 2.29, 95% confidence interval 1.27–4.10, HR 2.51, 1.27–4.98, and HR 2.43, 1.32–4.48, respectively).ConclusionsUpstaging of CRCs through the introduction of pN1c occurs in less than 5% of previous stage II and less than 2% of all cancers. Given the biologic relevance of TDs, integration into the UICC staging relevant N-category is justified. The high prognostic impact of TDs, however, is not reflected in nodal positive cancers in both the TNM and UICC staging systems.     

抑癌基因ING1在大肠癌中的表达及预后意义

目的 探讨ING1基因在散发性大肠癌中的表达与预后及多个临床病理变量之间的关系,并分析其在大肠癌预后的危险因素中是否具有显著意义。方法 应用定量RT-PCR方法检测82例大肠癌手术切除标本及相应的癌旁组织中ING1 mRNA的表达水平,分析其表达的差异,研究其表达水平与大肠癌患者临床病理特征及预后的关系。结果 (1)ING1 mRNA在大肠癌及癌旁组织中均可被检出,同一配对组织相比,癌旁组织中ING1表达量明显高于肿瘤原发灶;(2)ING1 mRNA的表达与大肠癌的浸润层次、淋巴结转移、远处转移以及TNM分期密切相关;(3)肿瘤组织与癌旁组织ING1表达量相比,比值越低其DFS也越低(P＜0.0001);(4)经单因素及多因素COX模型分析后显示,ING1作为候选抑癌基因可作为大肠癌预后的独立预测因素(P＜0.0001)。结论 ING1的过度表达是大肠癌发生过程中的分子事件,可能参与大肠癌的发展过程。ING1可作为判断大肠癌预后的重要分子标志。     

SHP-1 is a target of regorafenib in colorectal cancer

Regorafenib is an inhibitor of multiple protein kinases which exerts antitumor and antimetastatic activities in metastatic colorectal cancer (CRC). SH2 domain-containing phosphatase 1 (SHP-1) is reported to have tumor suppressive potential because it acts as a negative regulator of p-STAT3^Tyr705 signaling. However, little is known about the mechanism regarding regorafenib affects SHP-1 tyrosine phosphatase activity and leads to apoptosis and tumor suppression in CRC. Here, we found that regorafenib triggered apoptotic cell death and significantly enhanced SHP-1 activity, which dramatically decreased the phosphorylated form of STAT3 at Tyr705 (p-STAT3^Tyr705). Importantly, regorafenib augmented SHP-1 activity by direct disruption of the association between N-SH2 and catalytic PTP domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 blocked the effect of regorafenib-induced SHP-1 activity, growth inhibition and a decrease of p-STAT3^Tyr705 expression, suggesting that regorafenib triggers a conformational change in SHP-1 by relieving its autoinhibition. In vivo assay showed that regorafenib significantly inhibited xenograft growth and decreased p-STAT3^Tyr705 expression but induced higher SHP-1 activity. Collectively, regorafenib is a novel SHP-1 agonist exerts superior anti-tumor effects by enhancing SHP-1 activity that directly targets p-STAT3^Tyr705. Small molecule-enhancement of SHP-1 activity may be a promising therapeutic approach for CRC treatment.     

Association of polymorphisms in the beta-2 and beta-3 adrenoceptor genes with risk of colorectal cancer in Japanese

Background. The adrenergic receptor system is involved in thermogenesis and in the activation of lipid mobilization in fat cells, and polymorphisms in the beta-2 and beta-3 adrenoceptor genes (BAR2 and BAR3) have been reported to be associated with obesity and insulin resistance. To examine links between polymorphisms in these genes and the risk of colorectal cancer in Japanese, we conducted the present hospital-based case-referent study. Methods. Mutations of the BAR2 gene at codon 27 (Gln27Glu) and of the BAR3 gene at codon 64 (Trp64Arg) were examined in 131 patients with colorectal cancer (cases) and in 239 cancer-free referents. We also collected information on environmental factors, using a questionnaire approach. Odds ratios (ORs) were estimated with an unconditional logistic model, after adjustment for potential confounding factors. Results. The proportional distribution of the mutations in BAR2 and BAR3 did not differ between cases and referents. Analysis of a subgroup with a higher body mass index showed that the Trp64Arg variant increased the OR (2.63; 95% confidence interval, 1.13–6.11) for colon cancer, but not for rectal cancer, compared with the Trp64 geno-type. Altered ORs for colon and rectal cancers with the Gln27Glu variant were not observed in either the subgroup with the lower body mass index or the subgroup with the higher body mass index. Conclusion. These findings suggest that the BAR3 polymorphism may alter the susceptibility to colon cancer risk in obese subjects. To confirm this finding, a further study with a larger number of subjects is now required. Received: December 11, 2000 / Accepted: March 26, 2001