Genetic polymorphisms of matrix metalloproteinases in lung, breast and colorectal cancer

The matrix metalloproteinases (MMPs) can degrade various components of the extracellular matrix and are implicated in the development and progression of cancer. There is evidence suggesting an association of MMP gene polymorphisms with cancer susceptibility and/or metastasis. This paper reviews the findings on several single nucleotide polymorphisms in the collagenase, stromelysin and gelatinase genes in lung cancer, breast cancer and colorectal cancer.     

Nuclear magnetic resonance spectroscopy reveals dysregulation of monounsaturated fatty acid metabolism upon SPINK1 attenuation in colorectal cancer

Metabolic reprogramming, a key hallmark of cancer, plays a pivotal role in fulfilling the accelerated biological demands of tumor cells. Such metabolic changes trigger the production of several proinflammatory factors, thereby inciting cancer development and its progression. Serine protease inhibitor Kazal Type 1 (SPINK1), well known for its oncogenic role and its upregulation via acute-phase reactions, is highly expressed in multiple cancers including colorectal cancer (CRC). Here, we show accumulation of lipid droplets in CRC cells stained with Oil Red O upon SPINK1 silencing. Furthermore, NMR spectroscopy analysis revealed an accretion of monounsaturated fatty acids (MUFAs) and phosphatidylcholine in these CRC cells, while the levels of polyunsaturated fatty acids remained unaltered. This alteration indicates the presence of MUFAs with the triglycerides in the lipid droplets as observed in SPINK1-silenced CRC cells. Considering the role of MUFAs in the anti-inflammatory response, our data hint that suppression of SPINK1 in CRC leads to activation of an anti-inflammatory signaling milieu. Conclusively, our study uncovers a connection between lipid metabolism and SPINK1-mediated CRC progression, hence paving the way for further exploration and better prognosis of SPINK1-positive CRC patients.     

Single-nucleotide polymorphisms of mismatch repair genes in healthy Chinese individuals and sporadic colorectal cancer patients

Mismatch repair (MMR) genes are among of the most important genes associated with colorectal cancer (CRC). Single-nucleotide polymorphisms (SNPs) are generally thought to provide important information across a wide spectrum of life sciences; however, no study of association between SNPs of MMR genes and Chinese sporadic colorectal cancer (SCRC) is available. We chose 29 reported single-nucleotide variants that have rarely been verified in a population-based study. We identified SNPs and the genotype-phenotype association in Chinese populations of 150 healthy individuals and 160 SCRC patients. We extracted the genomic DNA from the blood of these individuals and used sequencing to determine these SNPs. Three SNPs (MLH1 394G-->C, 655A-->G, 1151T-->A) occurred with a frequency of 8.8-11.2% in the Chinese population. These SNPs formed a series with combined effects. The haplotype of concurrent MLH1 655 and 1151 SNPs and the haplotype combinations of MLH1 1151, MLH1 394 occurred exclusively in SCRC. None of the other 26 variants were detected in the Chinese population.     

类风湿关节炎脂肪酸代谢相关基因的生物信息学鉴定与验证

背景:研究表明,脂肪酸代谢基因与类风湿关节炎发展紧密相关,因此基于脂肪酸代谢基因探索类风湿关节炎发病进展具有重要的临床意义。目的:探究脂肪酸代谢基因是否可以作为预测类风湿关节炎进展的可靠生物标志物。方法:从基因表达综合数据库(GEO)下载与滑膜组织相关的基因数据,应用STRING构建蛋白质-蛋白质相互作用网络分析,对其使用Cytoscape进行生物学注释(GO基因本体论)和信号通路富集分析(KEGG京都基因与基因组百科全书)。从分子特征数据库(MSigDB)筛选脂肪酸代谢相关基因,使用套索算法和支持向量机的递归特征消除算法筛选潜在生物标志物。通过CIBERSORT算法评估正常人和类风湿关节炎患者的免疫细胞浸润水平。最后,在GSE77298使用受试者工作特征曲线验证脂肪酸代谢相关基因的表达水平。结果与结论:①确定了361个类风湿关节炎差异表达基因,其中13个与报告的脂肪酸代谢相关基因重叠;②基于机器学习算法筛选出5个基因,受试者工作特征曲线显示有5个基因(PCK1、PDK1、PTGS2、PLA2G2D、DPEP2)可以预测类风湿关节炎的发展;③CIBERSORT算法结果表明上述5个基因和活化肥大细胞、中性粒细胞、静息肥大细胞、记忆性静息CD4^(+)T细胞浸润水平密切相关;④受试者工作特征曲线显示,PLA2G2D和PCK1具有较高的诊断价值;⑤提示脂肪酸代谢相关基因表达特征可作为预测类风湿关节炎临床结果的潜在生物标志物,可进一步提高类风湿关节炎预测的准确性。     

Genetic pathways in colorectal cancer

The model of colorectal tumorigenesis put forward by Fearon and Vogelstein has had great influence on molecular oncology. They proposed that a series of mutations occur in the progression from normal cells to colorectal cancer and that these mutations are associated with the histological features of such tumours. Several postulates of the model appear to be correct, particularly its emphasis on the stepwise accumulation of genetic changes and the inclusion of mutations at the adenomatous polyposis coli ( APC ) and TP53 loci. Since the publication of the original model, however, mutations at other loci have been identified which may be alternatives or additions. There is also evidence to suggest that some colorectal cancers develop along a different genetic pathway. In this review, we discuss how tumour development can occur as Darwinian evolution through selection of advantageous somatic mutations. The non-random nature of mutation selection gives rise to genetic pathways of tumorigenesis. In addition, we consider the Fearon and Vogelstein model, its shortcomings and possible additions to it. The evidence suggests that not all colorectal cancers follow the same genetic pathway during carcinogenesis.     

Genetic polymorphisms of genes involved in DNA repair and metabolism influence micronucleus frequencies in human peripheral blood lymphocytes

The cytokinesis-block micronucleus cytome (CBMNCyt) assay is a widely used technique for measuring DNA damage in human populations. The formation of micronuclei (MN) in dividing cells can result from chromosome breakage due to unrepaired or mis-repaired DNA lesions or chromosome malsegregation due to mitotic malfunction. The sensitivity of the MN assay to polymorphisms in various genes involved in DNA repair, activation/deactivation of carcinogens/chemicals/drugs/alcohol, folate metabolism pathway and micronutrient transport has been extensively reported in the literature. MN frequency is also an important index for determining DNA repair efficiency phenotype (including mis-repair), response to environmental exposure and identifying various dietary factors required for optimal genome stability. The aim of the present study is to review the reported in vivo associations between genotype and MN frequency in humans taking into considerations the presence of interactions with nutrients levels and/or exposure to genotoxins. One hundred and eleven publications linking MN frequency in peripheral blood lymphocytes to gene polymorphism were retrieved from PubMed. After applying exclusion criteria, only 37 studies were evaluated in the present review. Polymorphisms in XRCC1 (Arg280His), ERCC2 (Lys751Gln), CYP2E1 (c1/c2) and MTR (A2756G) were consistently associated with the MN formation. These results contribute substantial evidence to the hypothesis that genotype may influence MN frequency in human cells.     

Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia.

Expression of the primary enzyme catalyzing the synthesis of fatty acids, ie, fatty acid synthase (FAS), and ex vivo fatty acid synthetic activity were examined in colorectal epithelium and neoplasms, including the relationship to tumor progression and prognosis. Immunohistochemistry for FAS showed only faint staining of native colorectal mucosa, but increased expression was found in all sporadic adenomas (n = 18), adenomas associated with familial adenomatous polyposis (n = 7), hyperplastic polyps (n = 3), dysplasias arising in ulcerative colitis (n = 17), and colorectal carcinomas (n = 130) including 11 with contiguous adenomas. The intensity of staining was strong in 53% of carcinomas, intermediate in 38%, and weak in 9%. Activity of the fatty acid synthetic pathway measured by labeling of six surgical specimens with [U-14C]acetate was 2- to 7-fold higher in colorectal carcinomas than adjacent native mucosa (P = 0.006) and 6- to 16-fold higher than serosal fat (P = 0.01). Activity correlated with immunohistochemical expression (Spearman's rank correlation coefficient = 0.85; P < 0.001). There was no statistically significant association between patient survival and FAS staining intensity of carcinomas. Our study shows that FAS is expressed in all colorectal neoplasms and there is a concomitant increase in fatty acid synthesis. FAS may therefore represent a potential therapeutic target.     

Genetic prognostic markers in colorectal cancer.

The contribution of molecular genetics to colorectal cancer has been restricted largely to relatively rare inherited tumours and to the detection of germline mutations predisposing to these cancers. However, much is now also known about somatic events leading to colorectal cancer. A number of studies has been undertaken examining possible relations between genetic features and prognostic indices. While many of these studies are small and inconclusive, it is clear that a number of different pathways exist for the development of this cancer and some molecular characteristics correlate with clinicopathological features. With the advent of methods for the rapid genotyping of large numbers of colorectal cancers, it should be possible to evaluate fully the clinical usefulness of colorectal cancer genotypes through multivariate analyses.     

基质金属蛋白酶-2和-9基因多态性与结直肠癌的相关性

目的探讨基质金属蛋白酶（matrix metalloproteinase，MMP）-2和-9基因启动子区多态性与结直肠癌的关系。方法应用变性高效液相色谱法和限制性片段长度多态性分析方法分别检测126例结直肠癌患者和126名正常对照者的MMP-2—1306C/T和MMP-9—1562C／T多态性，分析其基因型与结直肠癌发病风险及临床病理参数的相关性。结果MMP-2—1306C／C基因型频率在结直肠癌组中显著高于对照组（P〈0．05），与CT＋TT基因型携带者比较，CC基因型携带者患结直肠癌的风险约增加2倍（OR：1．959；95％CI：1．055～3．637）。而且在结直肠癌中，MMP-2—1306C／T多态性与肿瘤的浸润深度之间差异有统计学意义（P〈0．05），CC基因型的肿瘤更容易浸润到外膜。MMP-9—1562C／T多态性的基因型及等位基因频率在结直肠癌组和对照组间的分布差异无统计学意义（P〉0．05）。结论MMP-2—1306C／T多态性可能与中国人群结直肠癌的遗传易感性相关，且CC基因型的肿瘤更易浸润到外膜。     

Altered cholesterol and fatty acid metabolism in Huntington disease

Huntington disease is an autosomal-dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins that result in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state, resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.     

Genetic susceptibility to non-polyposis colorectal cancer

Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APC gene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for approximately 5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1, MSH2, MSH6, PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still molecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example.Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (1) tumours that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor beta type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such as K-ras, APC, and p53, and behave aggressively, of which FAP is an example. This review focuses most heavily on the clinical features, pathology, molecular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a detailed differential diagnosis of the several hereditary CRC variants is provided. The extant genetic and phenotypic heterogeneity in CRC leads to the conclusion that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Therefore, it is important to ascertain cancer of all anatomical sites, as well as non-cancer phenotypic stigmata (such as the perioral and mucosal pigmentations in Peutz-Jeghers syndrome), when taking a family cancer history.     

Genetic polymorphisms in mouse genes regulating age-sensitive and age-stable T cell subsets

To see whether genetic polymorphisms regulate inter-individual differences in T cell subset levels, we have conducted a genome scan in two populations of mice, bred as the progeny of a cross between CB6F1 females and C3D2F1 males. The data document quantitative trait loci (QTL) with statistically significant effects on CD4, CD8, and CD8 memory T cells, and on subsets of CD4 and CD8 T cells that express P-glycoprotein. Some of the loci detected were robust, in the sense that they produced effects of similar size both in mated female mice, and in a population that included male and female virgin animals. Some of the effects were stable, in that they were apparent at both 8 and 18 months of age, but others were age-specific, showing effects either at 8 or at 18 months but not at both ages. Genes that had an effect on the same T cell subset were in almost all cases additive rather than epistatic, and their combined effects could produce large overall effects, leading in the most dramatic case to a two-fold difference in CD8 memory cells. The analysis also documented two QTL, on chromosomes 4 and 13, that regulate an age-sensitive composite index of T cell subset pattern which has been shown previously to be a predictor of life expectancy in these mice. The analysis thus reveals both subset-specific genes and others which modulate the overall pattern of age-sensitive changes in T cell subset distributions.     

Genetic and expressional alterations of CHD genes in gastric and colorectal cancers

Kim M S, Chung N G, Kang M R, Yoo N J & Lee S H
(2011) Histopathology 58 , 660–668
Genetic and expressional alterations of CHD genes in gastric and colorectal cancers Aims: Chromodomain helicase DNA‐binding protein (CHD) is a regulator of the chromatin remodelling process. The aim was to determine the CHD1, CHD2, CHD3, CHD4, CHD7, CHD8 and CHD9mutational status of mononucleotide repeats in gastric and colorectal cancers with microsatellite instability (MSI). Methods and Results: The repeats were determined in 28 gastric cancers (GCs) with high MSI (MSI‐H), 45 GCs with low MSI (MSI‐L)/stable MSI (MSS), 35 colorectal cancers (CRCs) with MSI‐H and 45 CRCs with MSI‐L/MSS by single‐strand conformation polymorphism analysis. CHD4 and CHD8 expressionwas also examined in GCs and CRCs by immunohistochemistry. CHD1, CHD2, CHD3, CHD4, CHD7, CHD8 and CHD9 mutations were found in five, 19, three, five, seven, 10 and seven cancers, respectively. They were detected in MSI‐H cancers, but not in MSI‐L/MSS cancers. Loss of CHD4 expression was observed in 56.4% of the GCs and 55.7% of the CRCs, and loss of CHD8 was observed in 35.7% of the GCs and 28.6% of the CRCs. The cancers with CHD4 and CHD8 mutations showed loss of CHD4 and CHD8 expression, respectively. Conclusions: Frameshift mutation and loss of expression of CHD genes are common in GCs and CRCs with MSI‐H.These alterations might contribute to cancer pathogenesis by deregulating CHD‐mediated chromatin remodelling.