How do mutated oncogenes and tumor suppressor genes cause cancer?

In recent decades we have been given insight into the process that transforms a normal cell into a malignant cancer cell. It has been recognised that malignant transformation occurs through successive mutations in specific cellular genes, leading to the activation of oncogenes and inactivation of tumor suppressor genes. The further study of these genes has generated much of its excitement from the convergence of experiments addressing the genetic basis of cancer, together with cellular pathways that normally control important cellular regulatory programmes. In the present review the context in which oncogenes such as proliferation, cell death/apoptosis, differentiation and senescence will be described, as well as how these cellular programmes become deregulated in cancer due to mutations.     

Significance of oncogenes and tumor suppressor genes in AML prognosis

Acute myeloid leukemia (AML) is a heterogeneous disorder among hematologic malignancies. Several genetic alterations occur in this disease, which cause proliferative progression, reducing differentiation and apoptosis in leukemic cells as well as increasing their survival. In the genetic study of AML, genetic translocations, gene overexpression, and mutations effective upon biology and pathogenesis of this disease have been recognized. Proto-oncogenes and tumor suppressor genes, which are important in normal development of myeloid cells, are involved in the regulation of cell cycle and apoptosis, undergo mutation in this type of leukemia, and are effective in prognosis of AML subtypes. This review deals with these genes, the assessment of which can be important in the diagnosis and prognosis of patients as well as therapeutic outcome.     

癌基因与抑癌基因的表达研究进展

肿瘤的发生发展本质上是细胞原癌基因的激活和抑癌基因的失活造成的.癌基因和抑癌基因的研究对探索肿瘤发病机制,寻找预防和治疗肿瘤的新措施具有重要意义.本文较全面地介绍了癌基因和抑癌基因的种类以及它们对细胞的调控作用和致癌、抑癌的分子机制,特别是总结了近年来癌基因及抑癌基因的研究进展.     

Classical oncogenes and tumor suppressor genes: a comparative genomics perspective

We have curated a reference set of cancer- related genes and reanalyzed their sequences in the light of molecular information and resources that have become available since they were first cloned. Homology studies were carried out for human oncogenes and tumor suppressors, compared with the complete proteome of the nematode, Caenorhabditis elegans, and partial proteomes of mouse and rat and the fruit fly, Drosophila melanogaster. Our results demonstrate that simple, semi-automated bioinformatics approaches to identifying putative functionally equivalent gene products in different organisms may often be misleading. An electronic supplement to this article provides an integrated view of our comparative genomics analysis as well as mapping data, physical cDNA resources and links to published literature and reviews, thus creating a "window" into the genomes of humans and other organisms for cancer biology.     

Remarkable difference of somatic mutation patterns between oncogenes and tumor suppressor genes

Cancers arise owing to mutations that confer selective growth advantages on the cells in a subset of tumor suppressor and/or oncogenes. To understand oncogenesis and diagnose cancers, it is crucial to discriminate these two groups of genes by using the difference in their mutation patterns. Here, we investigated>120,000 mutation samples in 66 well-known tumor suppressor genes and oncogenes of the COSMIC database, and found a set of significant differences in mutation patterns (e.g., non-3n-indel, non-sense SNP and mutation hotspot) between them. By screening the best measurement, we developed indices to readily distinguish one from another and predict clearly the unknown oncogenesis genes as tumor suppressors (e.g., ASXL1, HNF1A and KDM6A) or oncogenes (e.g., FOXL2, MYD88 and TSHR). Based on our results, a third gene group can be classified, which has a mutational pattern between tumor suppressors and oncogenes. The concept of the third gene group could help to understand gene function in different cancers or individual patients and to know the exact function of genes in oncogenesis. In conclusion, our study provides further insights into cancer-related genes and identifies several potential therapeutic targets.     

Molecular mechanisms of cancer metastasis: tumor and host properties and the role of oncogenes and suppressor genes

The natural progression of benign tumors to malignancy and metastasis is characterized by their ability to circumvent microenvironmental controls on cellular proliferation, diversity, and positioning, and evolve into heterogeneous phenotypes, a process that probably involves qualitative and quantitative changes in gene expression. The oncogenes and suppressor genes that can effect tumor progression may control important points in the regulation of sets of genes that are ultimately responsible for the cellular alterations seen in highly metastatic cells. Because many cancers metastasize nonrandomly to particular distant sites, their colonization properties cannot be explained by mechanical considerations, such as arrest of tumor cells in the first microcirculatory network encountered. Metastatic cells that show a high propensity to metastasize to certain organs adhere at higher rates to microvessel endothelial cells isolated from their target sites, invade into target tissue at higher rates, and respond better to paracrine growth factors from the target site. These properties depend on multiple tumor cell, host cell, and stromal molecules that are differentially expressed by particular tumor and organ cells and by the organ extracellular matrix. Together these tumor and host factors appear to determine the organ metastatic properties of malignant cells.     

Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer

In attempt to discover novel aberrantly hypermethylated genes with putative tumor suppressor function in epithelial ovarian cancer (EOC), we applied expression profiling following pharmacologic inhibition of DNA methylation in EOC cell lines. Among the genes identified, one of particular interest wаs DOK1, or downstream of tyrosine kinase 1, previously recognized as a candidate tumor suppressor gene (TSG) for leukemia and other human malignancies. Using bisulfite sequencing, we determined that a 5′-non-coding DNA region (located at nt −1158 to −850, upstream of the DOK1 translation start codon) was extensively hypermethylated in primary serous EOC tumors compared with normal ovarian specimens; however, this hypermethylation was not associated with DOK1 suppression. On the contrary, DOK1 was found to be strongly overexpressed in serous EOC tumors as compared to normal tissue and importantly, DOK1 overexpression significantly correlated with improved progression-free survival (PFS) values of serous EOC patients. Ectopic modulation of DOK1 expression in EOC cells and consecutive functional analyses pointed toward association of DOK1 expression with increased EOC cell migration and proliferation, and better sensitivity to cisplatin treatment. Gene expression profiling and consecutive network and pathway analyses were also confirmative for DOK1 association with EOC cell migration and proliferation. These analyses were also indicative for DOK1 protective role in EOC tumorigenesis, linked to DOK1-mediated induction of some tumor suppressor factors and its suppression of pro-metastasis genes. Taken together, our findings are suggestive for a possible tumor suppressor role of DOK1 in EOC; however its implication in enhanced EOC cell migration and proliferation restrain us to conclude that DOK1 represents a true TSG in EOC. Further studies are needed to more completely elucidate the functional implications of DOK1 and other members of the DOK gene family in ovarian tumorigenesis.     

Chromosomal deletions and tumor suppressor genes in prostate cancer

Chromosomal deletion appears to be the earliest as well as the most frequent somatic genetic alteration during carcinogenesis. It inactivates a tumor suppressor gene in three ways, that is, revealing a gene mutation through loss of heterozygosity as proposed in the two-hit theory, inducing haploinsufficiency through quantitative hemizygous deletion and associated loss of expression, and truncating a genome by homozygous deletion. Whereas the two-hit theory has guided the isolation of many tumor suppressor genes, the haploinsufficiency hypothesis seems to be also useful in identifying target genes of chromosomal deletions, especially for the deletions detected by comparative genomic hybridization (CGH). At present, a number of chromosomal regions have been identified for their frequent deletions in prostate cancer, including 2q13–q33, 5q14–q23, 6q16–q22, 7q22–q32, 8p21–p22, 9p21–p22, 10q23–q24, 12p12–13, 13q14–q21, 16q22–24, and 18q21–q24. Strong candidate genes have been identified for some of these regions, including NKX3.1 from 8p21, PTEN from 10q23, p27/Kip1 from 12p13, and KLF5 from 13q21. In addition to their location in a region with frequent deletion, there are functional and/or genetic evidence supporting the candidacy of these genes. Thus far PTEN is the most frequently mutated gene in prostate cancer, and KLF5 showed the most frequent hemizygous deletion and loss of expression. A tumor suppressor role has been demonstrated for NKX3.1, PTEN, and p27/Kip1 in knockout mice models. Such genes are important targets of investigation for the development of biomarkers and therapeutic regimens.     

2000 Standards,Options and Recommendations for prognostic value of oncogenes and tumor suppressor genes in non small cell lung cancer

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French cancer centers (FNCLCC), the 20 French cancer centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines for non small cell lung cancer patients according to the definitions of the Standards, Options and Recommendations project. METHODS: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers. RESULTS: This article presents the chapter "Prognosis significance of oncogenes and tumor suppressor genes" from the full report "Standards, Options and Recommendation for non small cell lung cancer" validated in August 2000. The main recommendations are: 1) No clear clinical prognostic value of oncogenes and tumor suppressor genes (p53, bcl-2, Ki-ras, c-erbB-2, Rb, p16) in non small cell lung cancer, can be established from the available evidences (standard, level of evidence C). 2) Prospective multicenter studies should be performed to assess prognostic significance of oncogenes and tumor suppressor genes in non small cell lung cancer.     

Coffee intake, variants in genes involved in caffeine metabolism, and the risk of epithelial ovarian cancer

We evaluated whether genetic variability, as well as menopausal status, modify the association between coffee intake and risk of ovarian cancer. Risk factor information and biologic specimens from three large epidemiological studies, the Nurses’ Health Study (NHS), NHSII, and the New England based Case-Control Study of ovarian cancer (NECC) were pooled resulting in 1,354 ovarian cancer cases and 1,851 controls for analysis. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using conditional (NHS/NHSII) and unconditional (NECC) logistic regression. Coffee consumption was not associated with overall risk (OR = 0.99; 95% CI 0.77–1.28); however, there was a suggested increased risk of ovarian cancer among premenopausal women in the NECC only and an inverse association among postmenopausal women. Carrying one or both of the variant CYP19013 A or CYP19027 G alleles was associated with an 18% increased (P for trend = 0.02) and 15% decreased (P for trend = 0.05) risk of ovarian cancer, respectively. Variation in CYP1A1, CYP1A2, or CYP2A6 did not explain the inconsistent reports of coffee intake and risk. Furthermore, we did not observe any clear gene–environment interactions between caffeine metabolizing genes and ovarian cancer. Future studies evaluating mechanisms by which coffee mediates this relationship are warranted.

抑癌基因p16和转移抑制基因nm 23在卵巢上皮性肿瘤中的表达

目的:探讨抑癌基因p16及转移抑制基因nm23与卵巢上皮性肿瘤病理特点及生物学行为的关系。方法:免疫组化SP法检测30例正常卵巢,50例卵巢上皮性良性肿瘤及50例卵巢癌组织中P16蛋白和nm23蛋白,并分析其阳性表达与肿瘤的关系。结果:nm23蛋白在卵巢癌组织中的阳性率(70.0%)明显高于正常卵巢(43.3%)及良性肿瘤组(44.0%)(P<0.05);在浆液性癌(87.5%)和粘液性癌(47.8%)中的阳性差率也有显著差异(P<0.05);特别是在有淋巴结转移(39.1%)和无淋巴结转移(92.6%)的中检出率相非常显著(P<0.01),而与卵巢癌的临床分期及病理分级无明显相关性。p16蛋白在卵巢癌中的检出率(26.0%)明显低于正常卵巢(80.0%)和良性上皮性肿瘤(52.0%)(P<0.01),在晚期肿瘤中的表达率(20.5%)也远低于早期肿瘤(63.6%),而且在高度恶性组织中表达水平(11.1%)与中低度恶性组织的表达水平(43.5%)也有显著差异(P<0.05)。结论:nm23基因的表达与卵巢癌的淋巴结转移等生物学行为有关,p16基因可作为临床判断预后的重要指标之一。nm23、p16基因与卵巢上皮性肿瘤的发生、发展密切相关。     

Aberrant expression of tumor suppressor genes and their association with chimeric oncogenes in pediatric acute lymphoblastic leukemia

Aberrant expression of tumor suppressor genes WT 1, RB 1, p53, homozygous deletion of p16 gene and their relationship with expression of oncogenes BCR-ABL, TEL-AML 1, MLL-AF 4, E2A-PBX 1, SIL-TAL 1 were determined in bone marrow samples of children with de novo B-lineage (n=170) and T-lineage (n=25) acute lymphoblastic leukemia (ALL). In contrast to expression of chimeric oncogenes alterations in p16, WT 1, RB 1 and p53 expression were T/B-lineage-unrestricted. Significant association between expression of MLL-AF 4 and WT 1, E2A-PBX 1 and p53; SIL-TAL 1 and homozygous deletion of p16 has been demonstrated.