Dominant inheritance of adenomatous colonic polyps and colorectal cancer

Except in the rare polyposis syndromes, the contribution of heritable factors to the genesis of colorectal cancer and adenomatous polyps is not well understood. We examined the inheritance of susceptibility to colonic polyps and cancer in a large Utah pedigree with multiple cases of common colorectal cancer but no recognizable inheritance pattern among them. Inheritance was clarified, however, by systematic screening for colonic polyps in pedigree members and spouse controls, using flexible proctosigmoidoscopy. One or more adenomatous polyps were found in 21 per cent of family members (41 of 191) but in only 9 per cent of controls (12 of 132) (P less than 0.005). Pedigree analysis was performed with likelihood methods that compared random occurrence of cancer and polyps with autosomal recessive and autosomal dominant patterns of inheritance. The analysis suggested that the observed excess of discrete adenomatous polyps and colorectal cancers was the result of an inherited autosomal dominant gene for susceptibility, rather than an inherited recessive gene for susceptibility or a chance occurrence. This type of inheritance of colorectal polyps and cancer may be more common than previously recognized.     

Prognostic relevance of DNA copy number changes in colorectal cancer

In a study of 109 colorectal cancers, DNA copy number aberrations were identified by comparative genomic hybridization using a DNA microarray covering the entire genome at an average interval of less than 1 Mbase. Four patterns were revealed by unsupervised clustering analysis, one of them associated with significantly better prognosis than the others. This group contained tumours with short, dispersed, and relatively few regions of copy number gain or loss. The good prognosis of this group was not attributable to the presence of tumours showing microsatellite instability (MSI‐H). Supervised methods were employed to determine those genomic regions where copy number alterations correlate significantly with multiple indices of aggressive growth (lymphatic spread, recurrence, and early death). Multivariate analysis identified DNA copy number loss at 18q12.2, harbouring a single gene, BRUNOL4 that encodes the Bruno‐like 4 splicing factor, as an independent prognostic indicator. The data show that the different patterns of DNA copy number alterations in primary tumours reveal prognostic information and can aid identification of novel prognosis‐associated genes. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

趋化因子CXCL14在结直肠癌组织中的表达及其临床相关性研究

 目的:分析趋化因子CXCL14在结直肠癌组织中的表达,并探讨其表达的临床意义。方法:采用实时荧光定量PCR和免疫组化对40例结直肠癌及癌旁正常组织CXCL14的表达进行检测。Kaplan-Meier生存曲线和Cox回归模型评估CXCL14在结直肠癌组织中表达的临床意义。结果:CXCL14 mRNA和蛋白水平在结直肠癌组织中的表达较正常组织明显降低（P＜0.05）。临床相关性分析表明,CXCL14表达的下调与肿瘤淋巴结转移、发生部位以及临床病理分期有关（P＜0.05）。Kaplan-Meier生存分析显示,不同CXCL14蛋白表达水平的患者,生存时间具有显著差异（P＜0.01)。结论:CXCL14可能参与结直肠癌的发生、发展过程。     

Prognostic relevance of tumour-associated macrophages and von Willebrand factor-positive microvessels in colorectal cancer

Tumour-associated macrophages (TAM) are involved in tumour angiogenesis and anti-tumour immune response. In colorectal cancer (CRC), an association of high microvascular density (MVD) and unfavourable prognosis has been reported by some investigators. However, heterogeneous patient groups were studied. We, therefore, analysed the correlation between TAM and MVD and the prognostic relevance of MVD, TAM and T lymphocyte infiltration for long-term survival in a homogeneous group of 70 patients with moderately differentiated cancers of the International Union Against Cancer (UICC) stages II and III, who did not receive chemotherapy. MVD was evaluated using immunohistochemistry with antibodies against CD34 and von Willebrand factor (vWF). TAM and T lymphocytes were visualised with antibodies against CD68 and CD3, respectively. Statistical analysis did not reveal a significant correlation between TAM and T lymphocyte numbers and MVD. Multivariate analysis of immunohistochemical data from all CRC patients and the subgroup of patients with UICC stage-II CRC identified TAM- and vWF-positive microvessel numbers as prognostically relevant markers. Low numbers of TAM- and high numbers of vWF-positive microvessels were associated with an unfavourable prognosis. In conclusion, TAM- and vWF-positive microvessel numbers may serve as independent prognostic markers for patients with UICC stage-II and -III CRC and may help to identify patients with an unfavourable prognosis.     

Comparison of cyclooxygenase-2 and CD44 mRNA expression in colorectal cancer and its relevance for prognosis

This study evaluated CD44 and COX-2 expression in colorectal cancer (CRC) and analyzed its relationship with the clinicopathological characteristics. The prognostic impact on patient survival was compared between the two proteins. CD44 and COX-2 mRNA levels in 42 primary CRCs were analyzed using quantitative real-time PCR, with normalization relative to GAPDH. The cycle threshold (Ct) values were measured, and results are expressed as the Ct ratios of CD44 or COX-2 to GAPDH. The COX-2 Ct ratio was much lower in cases of lymphovascular invasion by the tumor than for no invasion (P = 0.004). During follow-up for a median of 40 months, there was no significant difference in the median CD44 Ct ratio between survivors and non-survivors (P = 0.362), whereas the COX-2 Ct ratio was significantly associated with survival at the time of data analysis (P = 0.042). The survival of colorectal cancer patients with a high COX-2 Ct ratio was significantly longer than that of patients with a low COX-2 Ct ratio (P = 0.048). This study suggests that COX-2 expression has a more significant impact than CD44 expression on the survival of CRC patients. Further studies are needed to resolve these issues with a large sample size.     

Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers

We studied 670 persons in 34 kindreds by flexible proctosigmoidoscopic examination (60 cm) to determine how frequently colorectal adenomas and cancers result from an inherited susceptibility. Kindreds were selected through either a single person with an adenomatous polyp or a cluster of relatives with colonic cancer. The kindreds all had common colorectal cancers, not the rare inherited conditions familial polyposis coli and nonpolyposis inherited colorectal cancer. Likelihood analysis strongly supported the dominant inheritance of a susceptibility to colorectal adenomas and cancers, with a gene frequency of 19 percent. According to the most likely genetic model, adenomatous polyps and colorectal cancers occur only in genetically susceptible persons; however, the 95 percent confidence interval for this proportion was 53 to 100 percent. These results suggest that an inherited susceptibility to colonic adenomatous polyps and colorectal cancer is common and that it is responsible for the majority of colonic neoplasms observed clinically. The results also reinforce suggestions that first-degree relatives of patients with colorectal cancer should be screened for colonic tumors. This evidence of an inherited susceptibility to a cancer with well-recognized environmental risk factors supports the hypothesis that genetic and environmental factors interact in the formation and transformation of polyps.     

癌胚抗原阴性的结、直肠癌检测和结直肠癌预后相关生物标记

目的探讨结直肠癌的发生、发展过程中患者血清质谱多肽蛋白图谱的变化,筛选与结直肠癌预后及癌胚抗原(CEA)阴性检测相关的肿瘤标记分子。方法用蛋白指纹图谱技术检测结直肠癌,结直肠管状腺瘤患者和健康者血清质谱多肽蛋白图谱。结果初步筛选出对结直肠癌有代表性的7个差异蛋白;2个与其淋巴结转移相关的差异蛋白;4个与其远处转移相关的差异蛋白;3个在其根治性切除后表达下降的差异蛋白;而由3398·3u、5477·1u和8453·9u组成的诊断模型对CEA阴性表达结直肠癌的阳性检测率为100%。结论蛋白指纹图谱技术可筛选出有意义的生物标记差异蛋白,这对结直肠癌预后判断、CEA阴性的结直肠癌检测和改变结直肠癌的进程具有重要意义。     

瘦素与结直肠癌的关系

肥胖是结直肠癌发病的危险因素,瘦素是ob基因的表达产物,主要来源于脂肪细胞,是重要的脂肪因子之一,被认为是肥胖和结直肠癌之间联系的重要角色。近年来对瘦素在结直肠癌的形成和进展中的作用及机制的研究对结直肠癌的诊断和治疗具有重要意义。     

Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case–control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson''s χ² test, Cochran–Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30–2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11–1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13–1.98; P=0.007 and OR: 1.49, CI: 1.14–1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10–2.37), 2.09 (CI: 1.43–3.07), 2.87 (CI: 1.76–4.70) and 3.88 (CI: 1.72–8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18–2.46), 2.29 (CI: 1.55–3.38) and 6.21 (CI: 2.67–14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.     

Phacomatoses, the inheritance of cancer, and somatic mutation

There are many hereditary conditions in which benign or malignant tumour formation occurs as a principal feature. Two of these conditions are recessively inherited and in each case the lesions observed may be explained in terms of current knowledge of the action of the genes. The other conditions are all dominantly inherited, affect specific cell types, and have many general similarities. They include at least three of the phacomatoses as originally defined, and this term is extended to cover all such conditions. The theory that neoplastic lesions in these conditions are an effect of heterozygosity is discussed. The heterozygosity is believed to lead to the establishment of clones of cells which will undergo sequential somatic mutations. Selection for increased mitotic rate or cell survival within these clones will lead to benign or malignant tumour formation.     

Reporting colorectal cancer

The management of colorectal cancer is a team process. High-quality reporting of colorectal cancer is very important as the whole team relies upon the skill of the pathologist. Failure to report key features can lead to undertreatment of this disease. The use of a proforma has been demonstrated to be beneficial and we recommend staying with TNM5 due to scientific and reproducibility issues with TNM6. Important features in stage II/Dukes' B cases are extramural vascular invasion, peritoneal involvement, extent of extramural spread, incomplete resection and perforation. All of these may lead to adjuvant therapy being administered. The surgically created circumferential resection margin (CRM) and the mode of its creation are important features and the CRM retains its value after preoperative therapy. Regression grading should be applied only to fully resected tumours and the dissection and sampling must be standardized to allow comparison of results between trials and centres. When reporting local resections of early-stage cancers we need to look for features that predict spread to local lymph nodes to allow a full resection to be considered.     

Microbiome and colorectal cancer: Unraveling host-microbiota interactions in colitis-associated colorectal cancer development

Dysbiosis of gut microbiota occurs in many human chronic immune-mediated diseases, such as inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Reciprocally, uncontrolled immune responses, that may or may not be induced by dysbiosis, are central to the development of IBD and CAC. There has been a surge of interest in investigating the relationship between microbiota, inflammation and CAC. In this review, we discuss recent findings related to gut microbiota and chronic immune-mediated diseases, such as IBD and CAC. Moreover, the molecular mechanisms underlying the roles of chronic inflammation in CAC are examined. Finally, we discuss the development of novel microbiota-based therapeutics for IBD and colorectal cancer.     

Phacomatoses, the inheritance of cancer, and somatic mutation

There are many hereditary conditions in which benign or malignant tumour formation occurs as a principal feature. Two of these conditions are recessively inherited and in each case the lesions observed may be explained in terms of current knowledge of the action of the genes. The other conditions are all dominantly inherited, affect specific cell types, and have many general similarities. They include at least three of the phacomatoses as originally defined, and this term by extended to cover all such conditions. The theory that neoplastic lesions in these conditions are an effect of heterozygosity is discussed. The heterozygosity is believed to lead to the establishment of clones of cells which will undergo sequential somatic mutations. Selection for increased mitotic rate or cell survival within these clones will lead to benign or malignant tumour formation.