Genetics of cancer predisposition and progression

Summary The development of human cancer is a multistep process that entails a progressively more malignant phenotype through the evolution of cellular subsets with increasing numbers of genetic alterations. Here we review the molecular genetics of human cancer predisposition and progression and describe paradigmatic cancer types and cancer syndromes. We also briefly consider the future impact of molecular biology on cancer diagnosis and treatment.Abbreviations APC adenomatous polyposis coli - BWS Beckwith-Wiedemann syndrome - DCC deletion in colorectal cancer - EGFR epidermal growth factor receptor - FAP familial adenomatous polyposis - IGF insulin-like growth factor - LOH loss of heterozygosity - MEN multiple endocrine neoplasia - NF neurofibromatosis - NSCLC non-small-cell lung cancer - RCC renal-cell carcinoma - SCLC small-cell lung cancer - VHL von Hippel-Lindau syndrome - WAGR Wilms' tumor, aniridia, genitourinary anomalies, mental retardation syndrome - WT Wilms' tumor - ZF zinc finger     

Array CGH identifies distinct DNA copy number profiles of oncogenes and tumor suppressor genes in chromosomal- and microsatellite-unstable sporadic colorectal carcinomas

DNA copy number changes represent molecular fingerprints of solid tumors and are as such relevant for better understanding of tumor development and progression. In this study, we applied genome-wide array comparative genomic hybridization (aCGH) to identify gene-specific DNA copy number changes in chromosomal (CIN)- and microsatellite (MIN)-unstable sporadic colorectal cancers (sCRC). Genomic DNA was extracted from microdissected, matching normal colorectal epithelium and invasive tumor cells of formalin-fixed and paraffin-embedded tissues of 22 cases with colorectal cancer (CIN = 11, MIN = 11). DNA copy number changes were determined by aCGH for 287 target sequences in tumor cell DNAs, using pooled normal DNAs as reference. aCGH data of tumor cell DNAs was confirmed by fluorescence in situ hybridization (FISH) for three genes on serial tissues as those used for aCGH. aCGH revealed DNA copy number changes previously described by metaphase CGH (gains 7, 8q, 13q, and 20q; losses 8p, 15q, 18q, and 17p). However, chromosomal regions 20q, 13q, 7, and 17p were preferentially altered in CIN-type tumors and included DNA amplifications of eight genes on chromosome 20q (TOP1, AIB1, MYBL2, CAS, PTPN1, STK15, ZNF217, and CYP24), two genes on chromosome 13q (BRCA2 and D13S25), and three genes on chromosome 7 (IL6, CYLN2, and MET) as well as DNA deletions of two genes on chromosome 17p (HIC1 and LLGL1). Finally, additional CIN-tumor-associated DNA amplifications were identified for EXT1 (8q24.11) and MYC (8q24.12) as well as DNA deletions for MAP2K5 (15q23) and LAMA3 (18q11.2). In contrast, distinct MIN-tumor-associated DNA amplifications were detected for E2F5 (8p22-q21.3), GARP (11q13.5-q14), ATM (11q22.3), KAL (Xp22.3), and XIST (Xq13.2) as well as DNA deletions for RAF1 (3p25), DCC (18q21.3), and KEN (21q tel). aCGH revealed distinct DNA copy number changes of oncogenes and tumor suppressor genes in CIN- and MIN-type sporadic colorectal carcinomas. The identified candidate genes are likely to have distinct functional roles in the carcinogenesis and progression of CIN- and MIN-type sporadic CRCs and may be involved in the differential response of CIN- and MIN-type tumor cells to (adjuvant) therapy, such as 5-fluorouracil.     

Developmental noise,ageing and cancer

Development is a very robust but far from perfect process, subjected to random variation due to the combined factors that constitute the so-called developmental noise. The effects of early developmental noise may have long-term consequences resulting from slight differences in the make-up and organisation of the former developing system. Here we present evidence suggesting that cancer is not an acquired but an intrinsic process resulting from random factors acting during early development, thus leading to a mixture of susceptibility types that may develop cancer sooner or later, depending on the combination of the environment acting upon such different susceptibility types. We discuss evidence suggesting that some supposedly tumour-suppressor functions, such as those associated with the p53 protein, actually evolved as buffering functions against the early effects of developmental noise that might compromise the stability of embryonic cells and hence of development. Ageing is a stochastic process characterised by progressive failure of somatic maintenance and repair. We put forth the notion that progressive loss of the morphological coherence of the organism (morphological disorder) is a form of ageing, and that morphological disorder is the common theme of most types of cancer. Thus, we suggest that the exhaustion of both developmental constraints and buffering developmental mechanisms link ageing and cancer. Moreover, we propose that cancer may represent one of the most radical forms of ageing, because it generally satisfies the criteria of senescence: intrinsicality, progressiveness and deleteriousness.     

Multistep carcinogenesis of breast cancer and tumour heterogeneity

 Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens. Received: 24 October 1996 / Accepted: 11 February 1997     

Oncogenes and onco-suppressor genes: their involvement in cancer

We review the involvement of two groups of genes, oncogenes and onco-suppressor genes, in malignant transformation. Approximately 40 oncogenes have been described mainly through studies on retroviruses and by in vitro functional analyses such as transfection of transforming genes into 'normal' cells. Because they are more difficult to identify, only a handful of onco-suppressor genes have been described so far, but potentially they could number as many as oncogenes. Where these genes have been isolated and sequenced, they have been shown to be highly conserved among species, suggesting that these genes play an essential role in the normal cell. Although some of properties of oncogenes have been identified, we do not know in detail the role these genes play in normal cells or how genetic damage contributes to malignancy. The effect of oncogene expression on a cell depends both on the cell type and on the oncogene, and in some circumstances oncogenes act as onco-suppressor genes and vice versa. The elucidation of the mechanism of action of oncogenes and onco-suppressor genes will not only increase our understanding of these important genes but might also provide the framework for a biological approach to the treatment of cancer.     

Mononuclear phagocyte heterogeneity in cancer: different subsets and activation states reaching out at the tumor site

Mononuclear phagocytes are amongst the most versatile cells of the body, contributing to tissue genesis and homeostasis and safeguarding the balance between pro- and anti-inflammatory reactions. Accordingly, these cells are notoriously heterogeneous, functioning in distinct differentiation forms (monocytes, MDSC, macrophages, DC) and adopting different activation states in response to a changing microenvironment. Accumulating evidence exists that mononuclear phagocytes contribute to all phases of the cancer process. These cells orchestrate the inflammatory events during de novo carcinogenesis, participate in tumor immunosurveillance, and contribute to the progression of established tumors. At the tumor site, cells such as tumor-associated macrophages (TAM) are confronted with different tumor microenvironments, leading to TAM subsets with specialized functions. A better refinement of the molecular and functional heterogeneity of tumor-associated mononuclear phagocytes might pave the way for novel cancer therapies that directly target these tumor-supporting cells.     

Natural killer cell-mediated immunosurveillance of human cancer

The contribution of natural killer (NK) cells to immunosurveillance of human cancer remains debatable. Here, we discuss advances in several areas of human NK cell research, many of which support the ability of NK cells to prevent cancer development and avoid relapse following adoptive immunotherapy. We describe the molecular basis for NK cell recognition of human tumor cells and provide evidence for NK cell-mediated killing of human primary tumor cells ex vivo. Subsequently, we highlight studies demonstrating the ability of NK cells to migrate to, and reside in, the human tumor microenvironment where selection of tumor escape variants from NK cells can occur. Indirect evidence for NK cell immunosurveillance against human malignancies is provided by the reduced incidence of cancer in individuals with high levels of NK cell cytotoxicity, and the significant clinical responses observed following infusion of human NK cells into cancer patients. Finally, we describe studies showing enhanced tumor progression, or increased cancer incidence, in patients with inherited and acquired defects in cellular cytotoxicity. All these observations have in common that they, either indirectly or directly, suggest a role for NK cells in mediating immunosurveillance against human cancer. This opens up for exciting possibilities with respect to further exploring NK cells in settings of adoptive immunotherapy in human cancer.     

Loss of heterozygosity of APC and DCC tumor suppressor genes in human sporadic colon cancer

We examined 36 cases of human sporadic colon carcinoma and corresponding normal tissue samples to evaluate loss of heterozygosity at the APC and DCC tumor suppressor genes loci using restriction fragment length polymorphism polymerase chain reaction and variable nucleotide tandem repeat analysis. Observed informativity was 83% for APC and 75% for DCC. DNA from 6 (20%) of 30 informative tumors exhibited loss of heterozygosity at the APC locus. Loss of heterozygosity at the DCC locus was observed in 7 (26%) of 27 informative tumor DNAs. Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression. Received: 7 August 1998 / Accepted: 15 December 1998     

PDSS2基因与肿瘤的研究进展

正癌症作为新世纪人类的第一杀手,已严重危害人类生存和健康,且目前的发病率有逐年上升的趋势。据世界癌症研究机构(International Agency for Research on Cancer,IARC)统计,2012年约有141 000 000例新发癌症,82 000 000例患者死于癌症~([1])。由于肿瘤早期症状不典型,诊断相对困难,多在癌症晚期才被确诊,极大地影响了癌症的治疗时机和预后。因此,     

芹菜素对U251胶质瘤细胞生长及p21、p53蛋白表达的影响

目的 探讨芹菜素对U251胶质瘤细胞生长及p21、p53蛋白表达的影响.方法 常规培养人胶质瘤U251细胞,分别用0、20、40、80 μmol/L芹菜素作用于U251细胞;四甲基偶氮唑盐微量酶反应比色法(MTT法)检测U251细胞增殖抑制率;Western blot检测p53、p21蛋白表达水平.结果 40及80 μmol/L芹菜素抑制人胶质瘤细胞U251的增殖,抑制作用呈剂量和时间依赖性;随着芹菜素浓度的增加,U251中p21和p53表达呈增加趋势.结论 芹菜素可能通过上调p21和p53表达,抑制胶质瘤细胞体外生长.     

Molecular pathology of ovarian carcinomas

 There is evidence that ovarian cancer may be derived from the progressive transformation of benign and/or borderline tumours. Mutations involving different oncogenes and tumour suppressor genes accumulate during the process of malignant transformation, and the alterations of genes involved in the pathogenesis of familial ovarian cancer are probably early events in ovarian tumorigenesis. BRCA-1 and BRCA-2 act as classical tumour suppressor genes in hereditary tumours, but their role in sporadic tumours remains controversial; however, a high frequency of allele losses in BRCA-1 (17q) and BRCA-2 (13q) loci has been observed in both familial and sporadic tumours. The possible role of mismatch repair genes and microsatellite instability is also controversial, but a role for them has been proposed in borderline tumours. Mutations in K-ras are specific for mucinous tumours and may be related to mucinous differentiation. Finally, a role in tumour progression has been proposed for both c-erb B-2 and p53, but their practical value in prognosis remains questionable. Received: 29 May 1997 / Accepted: 2 April 1998     

髓系来源的抑制性细胞一连接炎症与肿瘤的中介

大量实验和数据表明炎症能导致肿瘤的发生。慢性炎症所形成的肿瘤微环境为肿瘤的发生和生长提供了条件,是肿瘤形成过程中必不可少的重要环节。髓系来源的抑制性细胞（MDSC）是一个重要的连接炎症与肿瘤的中介,MDSC通过多种机制抑制机体抗肿瘤免疫应答,从而促进肿瘤的生长。     

Genetics of bladder cancer

Bladder cancer manifests many different forms, ranging from superficial to aggressive muscle invasion, which suggests that various genetic alterations are responsible. Several attempts have been made to establish correlations between specific genetic alterations and various grades of the disease. Numerous types of chromosomal abnormalities have been observed, involving [1p, 1q, 2q, 3p, 4p, 5q, i(5p), +7, +8, 8p, 9p, 9q, 10q23–25, 11p, 11q, +11, 13q, 14q, 17p, 18q, 21q, and Y]. In addition, p53 mutations and loss of heterozygosity on various chromosomes have recently begun to shed light on the molecular pathways of transitional cell carcinomas of the bladder. We have begun to focus on specific genomic sites (especially 9q), although the heterogeneity of the disease and the variable presentation suggests divergent progression pathways. When the genetic basis of bladder cancer is fully understood, new diagnostic and therapeutic strategies will be developed, which in turn may promote better clinical management by pathologists and urologists.Abbreviations CIS Carcinoma in situ - LOH Loss of heterozygosity - p Short arm - q Long arm     

Immunological ignorance of solid tumors

Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, the immune surveillance against clinically manifest carcinomas and sarcomas seems relatively inefficient. Naïve cytotoxic T cells are activated exclusively in secondary lymphoid organs including the spleen and lymph nodes. Tumor antigen might be either cross-presented to naïve cytotoxic T cells by professional antigen-presenting cells (pAPC), or presented directly by tumor cells that migrated to secondary lymphoid organs. Direct priming is quite inefficient during early tumor development because metastasis to lymphoid organs is usually limited to advanced stage diseases. Similarly, the process of cross-priming by pAPC seems to depend on relatively large antigen amounts and on maturation stimuli for dendritic cells, and both requirements may be limiting during initial tumorigenesis. Therefore, the immunosurveillance of solid tumors may fail because they are ignored for too long by the immune system. However, these situations may prove promising for the induction of tumor-specific T cell immunity by vaccination, as the T cell repertoire against these antigens has a naïve phenotype and is not yet affected by tolerance mechanisms.     

Loss of heterozygosity of selected tumor suppressor genes in human testicular germ cell tumors

Human testicular germ cell tumors (TGCTs) are histologically heterogenous neoplasms with a variable malignant potential. Two main groups of germ cell tumors occur in men: seminomas and nonseminomas. In the present study, a set of four tumor suppressor genes was investigated in testicular cancers. CDH1, APC, p53, and nm23-H1 genes were tested for loss of heterozygosity (LOH). Thirty-eight testicular germ cell tumors (17 seminomas and 21 nonseminomas) were analyzed by PCR using restriction fragment length polymorphism or the dinucleotide/tetranucleotide repeat polymorphism method. An allelic loss of p53 at exon 4 was detected in five nonseminomas, whereas LOH of p53 at intron 6 occurred in one of the seminoma and two of the nonseminoma samples. Allelic losses of the APC gene were present in three seminomas and one nonseminoma, whereas one seminoma and three nonseminomas showed LOH of CDH1. The analysis of allelic losses showed no common structural genetic alterations in tumor tissues, although a different pattern of LOH was observed between the two main histological groups of TGCTs.     

Molecular biology of testicular germ cell tumors: current status

Conclusions Changes in proto-oncogenes and tumor-suppressor genes at the molecular level are associated with the development and progression of testicular GCTs (Fig. 3). Investigations at this level, however, are only in their initial stages, and therefore the overall genetic changes which lead to the development of a metastasizing tumor are not known. Investigations show however, that undifferentiated GCTs (seminoma, embryonal carcinoma, chorionepithelioma) display molecular changes that are different from those of differentiated GCTs (teratocarcinoma, mixed tumors). In undifferentiated GCTs the following changes have been demonstrated: an increased expression of the proto-oncogenes c-kit, N-myc, c-myc, and c-mos; mutations in N-ras; missing expression in the RB tumor-suppressor gene; and a general hypomethylation of the DNA. These events possibly lead to a blockade of the differentiation process, and these GCTs may therefore correspond to an earlier stage of embryogenesis. These changes, on the other hand, do not occur in GCTs with differentiated tissue parts. The conspicuous expression of the c-erbB1 and c-erbB2 proto-oncogenes and also that of the RB tumor-suppressor gene is clearly associated in these tumors with differentiation. Important events in the formation or progression of teratocarcinoma and of the partly differentiated nonseminoma are, moreover, a generally lower number of copies of chromosome 15, a possible LOH at the nm23 locus, and hypermethylation, which may result in a switching off of particular genes.How the above molecular changes actually provide a clinically relevant supplement to the traditional classification of GCTs must be demonstrated by further investigations.Abbreviations GCT Germ cell turmor - CIS Carcinoma-in-situ - PCR Polymerase chain reaction - LOH Loss of heterozygosity - SCF Stem cell factor - SSCP Single Strand conformation polymorphism     

High ionic strength: Its significance in immunosurveillance against tumor cells in sharks and rays (elasmobranchs)

It is postulated that the rarity of tumors in elasmobranchs is due to the high ionic strength in their tissues, which is equivalent to a high body temperature. Such conditions should lead to the elimination of variable antigenicity and 100% immune surveillance. The basis for this theory is that the repressor molecule for mitosis, not binding to its operator site cannot bind anywhere.