Colorectal Cancer: A Review of the Genome-wide Association Studies in the Kingdom of Saudi Arabia

Genome-wise association studies (GWAS) identify risk variants and modifiers that can influence the pathophysiological processes involved in colorectal cancer (CRC) and thus are important to detect associations between disease phenotypes. Our literature review, performed as per PRISMA statement indicates a significant lack of GWAS functional studies in Saudi Arabia. Therefore, studies on sequencing and mapping are needed to identify gene variants that play a role in the pathophysiology of CRC in this specific population. Because it is not apt to generalize disease associations found in other racial and/or ethnic groups to the Arabic or Middle Eastern population, it is very important to conduct GWAS taking into account multiple ethnicities in this region. In addition, linkage studies and case–control studies that include the various confounding and epigenetic factors are needed for appropriate diagnosis of CRC. We recommend that studies in this region be conducted to understand the role of gene–environment interactions across the various ethnic groups, stages of cancer, tumor type, clinical variables, and the population risk to CRC.     

Population Screening for Colorectal Cancer Means Getting FIT: The Past,Present, and Future of Colorectal Cancer Screening Using the Fecal Immunochemical Test for Hemoglobin (FIT)

Fecal immunochemical tests for hemoglobin (FIT) are changing the manner in which colorectal cancer (CRC) is screened. Although these tests are being performed worldwide, why is this test different from its predecessors? What evidence supports its adoption? How can this evidence best be used? This review addresses these questions and provides an understanding of FIT theory and practices to expedite international efforts to implement the use of FIT in CRC screening.     

结直肠癌的临床病理特征及其与血清25羟基维生素D相关性的分析

背景:近年结直肠癌(CRC)的发病率和死亡率呈上升趋势,熟悉临床病理特征有助于提高CRC诊断水平。目的:总结CRC的临床病理特征并分析其与血清25羟基维生素D[25(OH)D]的相关性。方法:回顾性分析249例经结肠镜活检或术后病理证实的CRC患者的临床资料,以ELISA法检测血清25(OH)D水平,并分析其与CRC临床病理特征的相关性。结果:CRC好发于60岁的老年人(69.5%),男女之比为1.33∶1;直肠为最常见的发病部位(40.4%),便血为最常见的症状(41.0%),肿瘤大体类型以溃疡浸润型(54.9%)为主,病理类型主要为管状腺癌(75.1%)。与非老年组相比,老年组直肠癌发生率明显降低,右半结肠癌发生率明显上升,浸润型CRC少见,Ⅱ期CRC明显升高,排便习惯和性状改变更常见,细胞中分化率明显升高,差异均有统计学意义(P0.05)。老年、右半结肠和分期较晚的CRC患者血清25(OH)D水平明显降低(P0.05)。结论:老年CRC的发病部位、肿瘤类型、临床分期、临床表现和分化程度与非老年患者均有明显差异。血清25(OH)D水平可能与CRC患者年龄、发病部位、临床分期有关     

Public Awareness of Colorectal Cancer in Saudi Arabia: A Survey of 1070 Participants in Riyadh

Background/Aims:

The aim of this study was to investigate colorectal cancer (CRC) awareness in healthy individuals in Saudi Arabia in order to identify segments of the population that would most benefit from targeted education programs.

Setting and Design:

Survey/questionnaire.

Patients and Methods:

Random, healthy individuals from Riyadh, Saudi Arabia, were approached to participate in a 10-question multiple choice survey about CRC. Data were analyzed by demographic criteria, including age, gender, marital status, and level of education, to determine if members of these groups displayed differential knowledge.

Statistical Analysis:

Differences in responses by demographic data were analyzed using Pearson''s Chi-square test. A P < 0.05 was considered statistically significant.

Results:

In total, 1070 participants completed the survey. Most respondents believe that screening for colon cancer should begin at symptom onset (42.9%). Less than 20% of all respondents believe that polyps are a risk factor for CRC, which varied significantly according to level of education; however, even the most educated answered correctly less than 50% of the time. Similarly, only 34.8% of all respondents knew that a family history of CRC imparted a personal risk for CRC.

Conclusions:

Although older individuals and those with higher education tended to answer questions correctly more often, there were some misconceptions regarding universally accepted screening protocols, symptoms, and general understanding of CRC in Saudi Arabia. A national education/screening program in Saudi Arabia is recommended to improve CRC knowledge.     

miR-483与结直肠癌关系的研究

背景:胰岛素样生长因子2(IGF2)基因在多种恶性肿瘤中呈高表达,在肿瘤发生中起重要作用。miR-483位于IGF2基因第7号内含子中,与宿主基因共表达,但其具体功能尚未明确。目的:检测miR-483-3p、miR-483-5p在结直肠癌中的表达情况,探讨其作为结直肠癌分子标记物的可能性。方法:收集75对结直肠癌组织和相应癌旁非癌组织样本,以real-time PCR检测miR-483-3p、miR-483-5p表达并分析两者间以及两者与肿瘤临床病理特征的关系,以ROC曲线分析两者对结直肠癌的诊断性能。结果:结直肠癌组织中的miR-483-3p、miR-483-5p相对表达量均显著高于相应癌旁非癌组织(P0.000 1),且两者在癌组织中的表达量呈显著正相关(rs=0.554 5,P0.000 1)。miR-483-3p和miR-483-5p诊断结直肠癌的最佳截点分别为9.22和11.61,相应诊断敏感性、特异性分别为78.67%、62.67%和50.67%、85.33%;如两者联合检测(并联试验),诊断敏感性可提高至89.48%。两者表达与结直肠癌患者的性别、年龄以及肿瘤大小、部位、分化程度和TNM分期均无相关性。结论:miR-483-3p、miR-483-5p在结直肠癌中呈高表达,可能与肿瘤发生有关。两者有望成为结直肠癌诊断潜在的分子标记物。     

Trends in Frequency and Management of Obstructing Colorectal Cancers in a Well-Defined Population

Background

Few population-based studies investigate obstructing colorectal cancers. This study was designed to describe trends in their frequency and management.

Methods

Data were obtained for 13,331 colorectal cancers registered by the population-based cancer registry of Burgundy, France, between the years 1976 and 2000.

Results

Obstructing cancers represented 8.3 percent of all colorectal cancers. This proportion was stable throughout the study. Resection for cure increased from 54.9 percent (1976–1980) to 71.4 percent (1996–2000; P?=?0.011). Using multivariate analysis, site of cancer and period of diagnosis were the only factors significantly associated to a curative resection. Postoperative mortality for obstructing colorectal cancers decreased from 32.6 percent (1976–80) to 15.2 percent (1996–2000; P?

Conclusion

The frequency of obstructing colorectal cancers has remained unchanged for 25 years. Operative mortality is still high, although some improvements have occurred. Efforts must be made to diagnose colorectal cancers before obstruction occurs. Mass screening represents a promising approach.

     

TP53 Codon 72 Polymorphism and the Risk of Colorectal Cancer in an Azerbaijani Population

Background:We aimed to evaluate the association between the TP53 Arg72Pro gene polymorphism and risk of colorectal cancer in an Azerbaijani population.Methods: A total of 141 patients with colorectal cancer and 150 gender- and age-matched controls were involved in the study. The genotypes of the TP53 gene Arg72Pro polymorphism were detected by polymerase chain reaction-based restriction fragment length polymorphism analysis.Results: We found that the heterozygous genotypes Arg/Pro (odds ratio, 1.128; 95% CI, 0.657-1.937) and mutant Pro/Pro (odds ratio, 1.274; 95% CI, 0.648-2.504) were more frequent in colorectal cancer patients compared to healthy controls. The frequency of the mutant Pro allele (odds ratio, 1.122; 95% CI, 0.809-1.554) was revealed in 47.5% of colorectal cancer patients and in 44.7% of healthy controls. There was no association observed between TP53 Arg72Pro polymorphism and risk of colorectal cancer in an Azerbaijani population (P > .05).Conclusion: Our findings indicate a lack of relationship between TP53 Arg72Pro polymorphism and risk of colorectal cancer. Furthermore, we have found no statistical differences in the frequency of genotype and allele by sex, age, histological grade, tumor stage, smoking status, and alcohol consumption in this study.     

Interval Cancers in Screening with Fecal Occult Blood Test for Colorectal Cancer

Interval cancers, which are cancers diagnosed in spite of one or more negative screening tests, were studied in a randomized population with Hemoccult-II for colorectal cancer in 61,938 persons between 45 and 74 years old. Three biannual screenings were performed from 1985 to 1991, and 52% of all the cancers detected after doing at least one Hemoccult-II test were interval cancers (81 persons). These were more advanced than cancers diagnosed after a positive Hemoccult-II test, of larger size, less frequently of Dukes stage A, more often invading neighboring organs, and less often resectable for cure. They were located in the rectum more often than cancers diagnosed by screening and cancers in controls. Otherwise, interval cancers did not differ from cancers in controls or cancers in non-responders, and all characteristics suggested that no delay in diagnosis resulted from one or more negative Hemoccult-II tests, compared with controls. However, even if screening with Hemoccult-II demonstrates a reduction in mortality from colorectal cancer, the present high number of interval cancers makes it necessary to look for other methods of screening populations for colorectal cancer.     

微卫星不稳定性与结直肠癌的研究进展

结直肠癌(CRC)在全球范围内的发病率和死亡率均较高。目前研究认为CRC是一种由各种原因造成的遗传不稳定性长期积累、共同作用所致的异质性疾病,微卫星不稳定性(MSI)是其中的主要途径之一。本文就MSI与CRC的研究进展作一综述。     

Screening for Colorectal Cancer in Average-Risk Chinese Population Using a Mixed Strategy with Sigmoidoscopy and Colonoscopy

Purpose The Chinese population has been shown to have more distal colonic neoplasm and a higher sensitivity of sigmoidoscopic screening strategy for detecting advanced neoplasm compared with Western populations. This study was designed to evaluate the efficacy of the mixed screening strategy with sigmoidoscopy and colonoscopy in the average-risk Chinese population. Methods Consecutive average-risk adults aged ≥50 years who underwent colonoscopy as part of a health checkup were enrolled. Data were analyzed in a hypothetical graded screening strategy using colonoscopy on patients older than a certain cutoff age or those with distal sentinel polyps. The sensitivity in detecting advanced colonic neoplasm and advanced proximal neoplasm as well as the number of colonoscopies reduced were assessed. Results Of the 2,106 persons eligible for analysis, 1,193 (56.6 percent) were males and 913 (43.4 percent) were females. If the cutoff ages were 55, 60, and 65 years, and adenoma detected in the distal colon was the indication for subsequent colonoscopy, the detection rate for 1) advanced colonic neoplasm in the entire colon would be 94, 93.1, and 83.6 percent, respectively, and 2) advanced proximal neoplasm would be 84.8, 82.6, and 58.7 percent, respectively. The number of colonoscopic procedures could be reduced by 28, 48, and 65 percent if the cutoff ages were 55, 60, and 65 years, respectively. Conclusions The mixed screening strategy using a cutoff age at 60 years and distal adenoma as the sentinel lesion is an effective screening program in the average-risk Chinese population.     

5-Lipoxygenase is Coexpressed with Cox-2 in Sporadic Colorectal Cancer: A Correlation with Advanced Stage

Purpose It has been extensively documented that the cyclooxygenase inducible form and 15-lipoxygenase are implicated in colorectal carcinogenesis. Nonetheless, the role of other enzymes involved in the arachidonic acid metabolism, such as 5-lipoxygenase, in colorectal neoplasms has not been fully ascertained. This study was designed to evaluate 5-lipoxygenase expression in sporadic colorectal adenocarcinomas by using immunohistochemistry and to analyze its potential correlations with clinicopathologic parameters and with cyclooxygenase-2 expression. Methods Expression of 5-lipoxygenase and cyclooxygenase-2 were evaluated by immunohistochemistry in 50 surgically resected sporadic colorectal adenocarcinomas (28 male and 22 female patients age range, 47–88 (mean age, 69 ± 8) years). The chi-squared and Spearman correlation tests were used to analyze correlations with clinicopathologic characteristics and to evaluate any relationships between expression of the two enzymes. P values <0.05 were considered statistically significant. Results 5-Lipooxygenase and cyclooxygenase-2 immunostaining was found in the cytoplasm of neoplastic cells in 41 (82 percent) and in 43 cases (86 percent), respectively. Spearman correlation test demonstrated a positive correlation in the expression of the two enzymes. A statistically significant correlation also was observed between 5-lipoxygenase expression and tumor stage and lymph node metastasis, whereas no significant correlations emerged regarding cyclooxygenase-2 expression and clinicopathologic parameters. Conclusions Our study demonstrates that 5-lipoxygenase is expressed in colorectal adenocarcinomas in association with cyclooxygenase-2 expression. Moreover, an elevated expression of this enzyme seems to be significantly correlated with tumor aggressiveness. Further studies would clarify the need for target therapies inhibiting both metabolic pathways in such tumors. Supported by the grants from the University of Messina, Messina, Italy. Presented at the meeting of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology (SIAPEC), Venice, Italy, October 4 to 5, 2006.     

Use of Liquid Biopsy in Monitoring Colorectal Cancer Progression Shows Strong Clinical Correlation

Background

Patients with colorectal cancer (CRC) who are sensitive to epidermal growth factor antibodies inevitably acquire drug resistance. This study aimed to determine the usefulness of liquid biopsies for prognosis and clinical correlation.

Vitamin D Receptor Gene Polymorphisms and the Risk of Colorectal Cancer in a Chinese Population

Objective The purpose was to investigate single nucleotide polymorphism of the vitamin D recepter gene and its possible relationship with colorectal cancer (CRC) in a Chinese population. Methods The vitamin D receptor (VDR) genotypes were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) using endonuclease BsmI and FokI, and direct sequencing in 400 Chinese people, comprised of 200 CRC patients and 200 controls from the same area in China. Results The distribution of alleles (F/f) and genotypes (FF/Ff/ff) of the FokI had no significant difference between CRC patients and normal controls (P > 0.05), while that of the B allele and the BB genotype of the BsmI in CRC patients was significantly lower compared with the control group (0.1625 versus 0.740, P < 0.05, OR = 0.068, 95% CI: 0.048–0.096 and 0.060 versus 0.590, P < 0.05, OR = 0.015, 95% CI: 0.007–0.032). Conclusion The BB genotype of the VDR BsmI variant was significantly associated with a decreased risk of CRC in a Chinese population, while the VDR FokI polymorphism was not significantly associated with it.     

Patterns of Surveillance Practices After Curative Surgery for Colorectal Cancer in a French Population

PURPOSE Despite controversies, postoperative surveillance of colorectal cancer is generally recommended. This registry-based study was designed to assess the adherence of surveillance practices to French guidelines and identify three-year surveillance patterns and their demographic and clinical determinants. METHODS All patients (N = 409) diagnosed with first colorectal cancer in 1998 and alive without recurrence at least six months after curative surgery were identified from a population-based registry. Medical charts from multiple sources were reviewed to collect exhaustive information on follow-up procedures used during a three-year period. Multiple correspondence and cluster analyses were used to identify surveillance patterns. RESULTS The proportion of patients with a lower surveillance than that recommended was 35 percent for clinical examination, 65 percent for abdominal ultrasound, 52 percent for chest x-ray, and 20 percent for colonoscopy. Cluster analysis identified three patterns called minimal, moderate, and intensive surveillance patterns, which included 47, 24, and 29 percent of the patients respectively. The main independent predictors of both moderate and intensive surveillance patterns vs. minimal pattern were advanced tumor stage, chemotherapy, and radiation therapy. Younger age also was strongly associated with the intensive surveillance pattern, and the presence of symptoms with the moderate surveillance pattern. CONCLUSIONS Adherence of surveillance practices to French guidelines seems relatively poor. Surveillance patterns are mainly explained by patient age, tumor stage, and treatment modalities. Supported by a 2001 PHRC grant (Programme Hospitalier de Recherche Clinique) from the French Health Ministry. M. Boulin was supported by a grant from the Fondation pour la Recherche Médicale. Presented at the Association des Epidémiologistes de Langue Fran?aise Conference, Bordeaux, France, September 16 to 18, 2004.     

老老年高血压伴慢性心力衰竭患者心功能分级与血红蛋白相关性分析

目的研究老老年原发性高血压伴慢性心力衰竭患者,不同心功能分级之间血红蛋白差异,及两者之间的相关性。方法选取2013年1月—2014年2月广安门医院心内科住院的老老年高血压患者203例,根据纽约心功能分级标准将患者分成心功能Ⅰ级69例,Ⅱ级59例,Ⅲ级52例,Ⅳ级23例,比较各组间血红蛋白的数值。结果各组老老年高血压患者血红蛋白,心功能Ⅳ级组(114.52 g/L±16.18 g/L)心功能Ⅲ级组(122.61 g/L±16.45 g/L)心功能Ⅱ级组(126.33 g/L±14.88 g/L)心功能Ⅰ级组(129.13 g/L±14.40 g/L);将心功能分级与血红蛋白量行Spearman相关性分析显示,两者之间存在显著负相关(r=-0.239,P=0.001)。结论在老老年原发性高血压患者中,不同心功能分级与血红蛋白的关系密切,应注重该指标监测,合理进行临床干预,有利于患者心功能改善,预防心功能进一步恶化,改善老老年高血压患者的生活质量及预后。     

Molecular Features of the Serrated Pathway to Colorectal Cancer: Current Knowledge and Future Directions

Serrated lesions are the precursor lesions of a new model of colorectal carcinogenesis. From a molecular standpoint, the serrated pathway is thought to be responsible for up to 30% of all colorectal cancer cases. The three major processes of this molecular mechanism are alterations in the mitogen-activated protein kinase pathway, production of the CpG island methylation phenotype, and generation of microsatellite instability. Other contributing processes are activation of WNT, alterations in the regulation of tumor suppressor genes, and alterations in microRNAs or in MUC5AC hypomethylation. Although alterations in the serrated pathway also contribute, their precise roles remain obscure because of the various methodologies and definitions used by different research groups. This knowledge gap affects clinical assessment of precursor lesions for their carcinogenic risk. The present review describes the current literature reporting the molecular mechanisms underlying each type of serrated lesion and each phenotype of serrated pathway colorectal cancer, identifying those areas that merit additional research. We also propose a unified serrated carcinogenesis pathway combining molecular alterations and types of serrated lesions, which ends in different serrated pathway colorectal cancer phenotypes depending on the route followed. Finally, we describe some key issues that need to be addressed in order to incorporate the newest technologies in serrated pathway research and to improve overall knowledge for developing specific prevention strategies and new therapeutic targets.     

Significance of Signet-Ring Cells in Patients with Colorectal Cancer

Purpose We performed a retrospective study to determine the pattern of metastases and overall outcome of patients with tumors exhibiting a component of signet-ring cells comprising < 50 percent of the tumor mass. Methods Medical records of 753 patients with primary colorectal cancer were retrospectively studied. Patients who had tumors with < 50 percent signet-ring cells were classified as having a component of signet-ring cells. The outcome of patients with a component of signet-ring cells was compared to all patients with mucinous adenocarcinoma (defined as adenocarcinomas with ≥ 50 percent mucin) to all patients with adenocarcinomas with a component of mucin (defined as adenocarcinomas with < 50 percent mucin) and to 100 randomly selected patients with adenocarcinomas lacking mucin or signet-ring cells. Results Five percent of patients had a component of signet-ring cells, 3 percent had mucinous adenocarcinoma, 9 percent had a component of mucinous adenocarcinoma, and 83 percent had adenocarcinoma lacking mucinous or signet components. Patients with a component of signet-ring cells and mucinous adenocarcinomas metastasized predominantly to the peritoneum/ovaries (75 and 56 percent of metastatic cases, respectively) and rarely to liver/lungs. The pattern of metastases of patients with adenocarcinoma without mucinous or signet components predominantly involved the liver/lungs and rarely the peritoneum/ovaries (12.5 percent). The pattern of metastases for patients with a component of mucinous adenocarcinoma was intermediate between mucinous adenocarcinoma and adenocarcinoma without mucin or signet-ring component. No differences in survival in Stage IV patients were seen among the four subgroups. Conclusions Patients with a component of signet-ring cells cancers, similar to mucinous adenocarcinoma, have a predisposition to metastasize to the peritoneum/ovaries. Supported in part by a grant from the American Cancer Society (to M.G.F.).     

吸烟与结直肠癌诊断年龄关系的研究

吸烟与结直肠癌的发病率和死亡率显著相关。国外研究发现吸烟的结直肠癌患者平均诊断年龄显著低于不吸烟的结直肠癌患者,而国内相关报道尚少。目的：分析不同吸烟变量与结直肠癌诊断年龄之间的关系。方法：以面访问卷调查的方式收集628例连续性结直肠癌患者的资料。先以单因素方差分析筛选出与男性结直肠癌患者诊断年龄相关的吸烟变量．再采用协方差分析均衡混杂因素,比较各吸烟变量不同暴露水平间诊断年龄的差异。结果：男性结肠癌患者中,吸烟者的诊断年龄较不吸烟者提前6．0岁（P=O．031）。吸烟状态、开始吸烟年龄和吸烟年限这三个吸烟变量与诊断年龄相关;均衡混杂因素后,与从未吸烟者相比．开始吸烟年龄≤16岁和吸烟年限15-34年的男性结直肠癌患者诊断年龄分别提前7．89岁（P=O．0420）和5．1l岁（降0．0127）。结论：男性较早开始吸烟和长期吸烟与结直肠癌尤其是结肠癌的发生年龄提前相关。在普通危险人群中．对于开始吸烟年龄≤16岁或吸烟年限15-34年的男性,结直肠癌筛查的起始年龄应提前5-10岁。     

Pleiotrophin Expression in Human Pancreatic Cancer and Its Correlation with Clinicopathological Features, Perineural Invasion, and Prognosis

Pleiotrophin (PTN), a heparin-binding growth factor also known as neurite growth-promoting factor, exhibits several properties related with tumor development. PTN and its receptor, N-syndecan, may play a very important role in tumor growth and neural invasion of pancreatic cancer. We investigated PTN and N-syndecan protein levels in 38 patients with pancreatic cancer by immunohistochemistry, and analyzed for its correlation with clinicopathological features, perineural invasion, and prognosis. The results showed that PTN and N-syndecan proteins were found in 24 (63.2%) and 22 (57.9%) specimens, respectively. PTN and N-syndecan expressions were associated with perineural invasion (P = 0.016 and P = 0.029, respectively). High PTN expression was closely related to an advanced TNM stage (P = 0.007), lymph node metastasis (P = 0.040), and decreased postoperative survival at 3 years (50.0% versus 20.8%, respectively; P = 0.001). We conclude that high expression of PTN combined with N-syndecan may contribute to the increased perineural invasion and poor prognosis of pancreatic cancer.