General morphological and biological features of neoplasms: integration of molecular findings.

Department of Histopathology, King's College Hospital and King's College London School of Medicine, London, UK.
Histopathology (Impact Factor: 2.86). 08/2008; 53(1):1-19. DOI:10.1111/j.1365-2559.2007.02937.x
Source: PubMed

ABSTRACT This review highlights the importance of morphology-molecular correlations for a proper implementation of new markers. It covers both general aspects of tumorigenesis (which are normally omitted in papers analysing molecular pathways) and the general mechanisms for the acquired capabilities of neoplasms. The mechanisms are also supported by appropriate diagrams for each acquired capability that include overlooked features such as mobilization of cellular resources and changes in chromatin, transcription and epigenetics; fully accepted oncogenes and tumour suppressor genes are highlighted, while the pathways are also presented as activating or inactivating with appropriate colour coding. Finally, the concepts and mechanisms presented enable us to understand the basic requirements for the appropriate implementation of molecular tests in clinical practice. In summary, the basic findings are presented to serve as a bridge to clinical applications. The current definition of neoplasm is descriptive and difficult to apply routinely. Biologically, neoplasms develop through acquisition of capabilities that involve tumour cell aspects and modified microenvironment interactions, resulting in unrestricted growth due to a stepwise accumulation of cooperative genetic alterations that affect key molecular pathways. The correlation of these molecular aspects with morphological changes is essential for better understanding of essential concepts as early neoplasms/precancerous lesions, progression/dedifferentiation, and intratumour heterogeneity. The acquired capabilities include self-maintained replication (cell cycle dysregulation), extended cell survival (cell cycle arrest, apoptosis dysregulation, and replicative lifespan), genetic instability (chromosomal and microsatellite), changes of chromatin, transcription and epigenetics, mobilization of cellular resources, and modified microenvironment interactions (tumour cells, stromal cells, extracellular, endothelium). The acquired capabilities defining neoplasms are the hallmarks of cancer, but they also comprise useful tools to improve diagnosis and prognosis, as well as potential therapeutic targets. The application of these concepts in oncological pathology leads to consideration of the molecular test requirements (Molecular Test Score System) for reliable implementation; these requirements should cover biological effects, molecular pathway, biological validation, and technical validation. Sensible application of molecular markers in tumour pathology always needs solid morphological support.

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    ABSTRACT: OBJECTIVE: To understand developmental characteristics of urinary bladder carcinomas (UBC) by evaluating genomic alterations and p53 protein expression in primary tumors, their recurrences, and in the morphologically normal urothelium of UBC patients. METHODS: Tumors and their respective recurrences, six low-grade and five high-grade cases, provided 19 samples that were submitted to laser microdissection capture followed by high resolution comparative genomic hybridization (HR-CGH). HR-CGH profiles went through two different analyses-all tumors combined or classified according to their respective histologic grades. In a supplementary analysis, 124 primary urothelial tumors, their recurrences, and normal urothelium biopsied during the period between tumor surgical resection and recurrence, were submitted to immunohistochemical analyses of the p53 protein. During the follow-up of at least 21 patients, urinary bladder washes citologically negative for neoplastic cells were submitted to fluorescence in situ hybridization (FISH) to detect copy number alterations in centromeres 7, 17, and 9p21 region. RESULTS AND CONCLUSIONS: HR-CGH indicated high frequencies (80%) of gains in 11p12 and losses in 16p12, in line with suggestions that these chromosome regions contain genes critical for urinary bladder carcinogenesis. Within a same patient, tumors and their respective recurrences showed common genomic losses and gains, which implies that the genomic profile acquired by primary tumors was relatively stable. There were exclusive genomic alterations in low and in high grade tumors. Genes mapped in these regions should be investigated on their involvement in the urinary bladder carcinogenesis. Successive tumors from same patient did not present similar levels of protein p53 expression; however, when cases were grouped according to tumor histologic grades, p53 expression was directly proportional to tumor grades. Biopsies taken during the follow-up of patients with history of previously resected UBC revealed that 5/15 patients with no histologic alterations had more than 25% of urothelial cells expressing the p53 protein, suggesting that the apparently normal urothelium was genomically unstable. No numerical alterations of the chromosomes 7, 17, and 9p21 region were found by FISH during the periods "free-of-neoplasia." Our data are informative for further studies to better understand urinary bladder urothelial carcinogenesis.
    Urologic Oncology 07/2011; · 3.65 Impact Factor
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    ABSTRACT: Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning.
    International Journal of Molecular Sciences 01/2012; 13(2):1951-2011. · 2.46 Impact Factor
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    ABSTRACT: Molecular Genetics and its integration in Pathology have represented a complete change in our understanding of disease and how to diagnose it. From the days of Mendel to the Human Genome Project, the power gained from this knowledge has set the stage for subsequent developments of diagnostic and therapeutic targets. In tumor pathology,(1-3) the molecular tests for neoplasm screening must consider: I) Careful knowledge of the natural history of neoplasms,(4) including: molecular definition of the irreversible stage, identification of the clonal marker for a given neoplasm, and connection of molecular genetic markers with tumor cell kinetics, promotion and progression.(5,6) These concepts become even more relevant considering the heterogeneous genetic background and heterotypic environment of neoplasms.(4,7-9) II) Automated molecular cytogenetics (painting of the entire chromosome, comparative genome hybridization, spectral karyotyping, multicolor FISH or fiber FISH). Karyotyping of all 24 chromosomes in different colors with one hybridization experiment, has proven to be extremely useful for the precise definition of chromosomal complex aberrations in both constitutional and cancer cytogenetics and is expected to permit the detection of new chromosomal aberrations in cancers leading to the definition of more disease-associated chromosomal rearrangements and genes and ultimately in better adapted therapies. III) Specific diseases, such as breast cancer (BRCA1 -BRCA 2 genes), the HNPCC-associated stomach cancer, the MEN-2 associated medullary thyroid cancer as well as the 5q preleukemic syndrome. These conditions highlight the importance of familial cancer syndromes for the identification of molecular pathways relevant in tumorigenesis of both inherited and sporadic cancers. Breast cancer is the most common disease and leading cause of lethality in women. Among the various factors responsible for the development of this neoplasia, a family history of the disease seems to play a major role. The identification and cloning of the BRCA1 and BRCA2 genes have demonstrated that mutations in these two genes account for almost all of the families with multiple cases of breast and ovarian cancer. The BRCA1 and BRCA2 regions of human chromosomes are frequently involved in loss of heterozygosity in familial breast and ovarian tumors. To understand the biological function of these genes, mutations that result in loss of function have been generated in mice. Human and murine Brca1 and Brca2 proteins interact with Rad51, a protein involved in the DNA recombination repair pathway. This interaction suggests that Brcal and Brca2 are involved in detecting and repairing double-strand breaks thereby controlling cell cycle progression. HNPCC is the most common form of colorectal cancer and accounts for approximately 5-10% of the colorectal cancers annually. 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The outcome and impact of the implemention of genetic screening programmes is variable, depending on the target and the type of neoplasm (prevalence, aggressiveness). The evaluation of the Ashkenazy Jewish population pre-symptomatical, premarital or prenatal screening for 8 severe genetic diseases and for breast and colon susceptibility genes are examples of this variability. It has mentioned that during the past 15 years over 95,000 singles have voluntarily participated in a system for compatibility testing prior to match and more than 230 potential matches have been avoided, demonstrating that an effective genetic screening programme can be designed to special culture needs. The subject of gene therapy, which is considered by the majority of the scientific community as the big promise to 'cure' genetic disorders, is one of the main consideration at the time of establishing any screening programme. At the present time more than 200 gene therapy clinical trials are underway worldwide with a large number of patients enrolled. The efficacy of gene therapy cannot be yet evaluated, but it seems likely that problems will be solved in the next decade and gene therapy will become a routine part of the clinical practice. Sentiments of fear can be expressed from failing connections between research and practice. The lack of sufficient cross-talk between academic researchers, who serve as designers or discoverers of new drugs and new techniques, and clinicians, industrialists and/or governments, who have the task to apply such discoveries within the society have resulted in the practical, moral and economic issues that the human society is facing today. Ethical aspects of molecular genetic screening of tumors include:(10) Medical confidentiality, the " right not to know" versus the " right to know", to test or not to test (provision of genetic counseling), psychological, emotional, cultural and socio-economic burden, religious influence, and the role of the mass media. In conclusion, molecular screening will become routine practice in certain areas provided that the tests are affordable, target prevalent tumor conditions, the molecular target is at or beyond the irreversible point of the tumor natural history, and the molecular pathway evaluated provided a kinetic advantage. A proper implementation must also consider relevant ethical elements and has to be based and adequate informed consent.
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