Cancer surveys最新文献

The tumour biology of cervical precancer is unusual. A large variety of individually distinct forms crudely divided into slight, moderate, severe dysplasia and carcinoma in situ exist. Virtually all contain genital human papillomavirus (HPV) either as infectious virions or as episomal or integrated DNA. HPV, which occurs as hundreds of types, subtypes and variants, has a high prevalence in all human populations. Most males are symptomless reservoirs, whereas a proportion of infected women develop condyloma, precancer and subsequently, in a minority, invasive cancer. HPV has unequivocal features of a sexually transmitted infectious agent. Risk of precancer is statistically related to infection with genital HPV, but differences in risk between populations with high and low prevalence of HPV are larger than expected from a direct correlation. Findings fit with HPV as a major risk factor, but other factors must also be operative. These may include shifts in number of target cells, depending on regeneration and infection by various micro-organisms, hormones, smoking and immunity. Final proof of necessity of HPV infection for precancer can probably be delivered only after its elimination by successful vaccination. Genital condyloma, which is not precancerous, is caused by HPV low risk types, typically 6 or 11, in analogy with papilloma formation in skin and mucosa in a large variety of species. This benign lesion is the hallmark of mammalian HPV pathology and a source of interindividual spread of virus. Slight dysplasia is heterogeneous. Many lesions seem to be polyclonal, self limited cell proliferative responses to infection with low grade HPV. A small proportion are associated with either simultaneous presence or subsequent development of higher grades of dysplasia, in situ or invasive cancer. Evidence exists for two mechanisms: clonal selection of cells with increasingly undifferentiated phenotypes, and independent development of different morphological types of precancer. The relative importance of the two is unknown. High risk HPV, typically 16 or 18, is preferentially associated with high grade dysplasia and in situ cancer, either because it increases risk of clonal progression to these forms or induces them de novo. Severe dysplasia, in situ and invasive cancer always present as monoclonal lesions. Genetic links indicate that these pathologies arise by clonal selection from less advanced precursors. The number of potential target cells for precancer confined to a narrow transformation zone is small. Risk of precancer and malignant transformation per target cell is therefore probably far higher than in any other human tissue subject to cancer. Spontaneous mutation rate and physicochemical carcinogens seem insufficient for the creation of a malignant phenotype in cells of the transformation zone. Currently HPV is the only strong candidate for such a feat. Any or all of the following mechanisms may play a role: overexpression of viral E6 and

A large number of potential molecular markers of bladder cancer have been identified, although only a few are truly independent prognostic factors. A number of markers may need to be measured in a single tumour and used as a combination for use in the diagnosis and prognosis of transitional cell carcinoma (TCC). Epidermal growth factor receptor immunoreactivity has been shown to be an independent predictor of survival and stage progression. TP53 may be an independent predictor of recurrence and overall survival in TCC confined to the bladder, and TP53 alterations may predict chemosensitivity in patients who have had TCC treated by radical cystectomy. At present molecular techniques such as fluorescence in situ hybridization and the polymerase chain reaction are restricted to the laboratory, but immunohistochemical methods are available in most hospital pathology departments. There are some discrepancies and conflicting reports of the usefulness of molecular markers in different studies, and these need to be addressed in large, prospective, multi-institutional studies using standardized molecular techniques.

Many malignant lymphomas are characterized by recurrent genetic abnormalities. These include numerical abnormalities, deletions and reciprocal translocations. In this chapter, we have focused on the detection of chromosomal translocations in B cell lymphomas and discussed some trisomies in lymphomas and CLL. FISH is a well developed molecular method by which it is possible to detect numerical and structural chromosomal abnormalities. We addressed various aspects of metaphase, and especially interphase, FISH and also described the recently developed DNA fibre FISH technology. Using this method, it is possible simultaneously to detect and map chromosomal breakpoints. FISH is also compared with more conventional detection methods such as banding analysis, Southern blot analysis and PCR for the translocations t(8;14) and variant translocations in Burkitt's lymphoma, t(14;18) in follicular lymphoma and t(11;14) in MCL. Other breakpoints in B cell lymphoma are also discussed. It might be concluded that the rapid development in interphase and DNA fibre FISH will provide us with quick, easy and cheap tools to identify specific chromosomal translocations and other genomic abnormalities in human tumours.

The polymerase chain reaction (PCR) offers a practical means of studying the molecular genetic features of lymphomas. The method is rapid and, as formalin-fixed, paraffin processed samples can be used, does not require special tissue handling procedures. PCR amplified immunoglobulin and T cell receptor gene rearrangements can be exploited as markers of clonality and lineage and genetic abnormalities such as chromosome translocations and mutations of oncogenes and tumour suppressor genes can be used to identify specific lymphoma types. Polymorphic X linked loci may also be used as markers of clonality in females. Direct sequencing of PCR amplified IGH variable regions has provided insights into the developmental stages, susceptibility to antigen drive and dissemination patterns of lymphomas. The role of oncogenes and tumour suppressor genes such as MYC and TP53 in lymphomas can be studied by PCR amplification of mutation hotspots and direct sequencing of products. Known viral and bacterial DNA can readily be identified using PCR and unknown organisms sought using conserved primers to amplify polymorphic sequences. PCR analysis of the lymphomas and related disorders has accelerated our understanding of their molecular biology and provides a practical tool with diagnostic and prognostic applications. Future development of in situ PCR methods will provide cellular localization of genetic defects and infectious agents.

Lymphomagenesis in HIV positive patients is a complex phenomenon not yet completely understood (Karp and Broder, 1992). The great majority of NHL are of the B cell type. Burkitt lymphoma seems to develop early during the evolution of HIV infection in patients with a CD4 count above 200/microliter. MYC is rearranged in the majority of the cases. EBV latent infection is observed in 30-45%. EBV status is characterized by a negativity for EBNA2 and LMP1 The main sites of the tumour are the lymph node and the bone marrow. Diffuse large cell lymphomas, mostly represented by immunoblastic lymphomas with plasmacytoid differentiation and by centroblastic lymphomas rich in immunoblasts, are a late event in HIV infection, in patients with a low CD4 count (often below 50/microliter). The prognosis is worse than in Burkitt and Burkitt like lymphoma. MYC is rearranged in about 30-40% of the cases, whereas more than 70% are EBV positive. EBV status is characterized by a positivity for both EBNA2 and LMP1. B type ALC lymphomas are more frequently associated with EBV than in the general population and exhibit the same EBV status as diffuse large cell lymphomas. HD occurs at any stage of HIV infection. The majority of patients are in clinical stage III or IV at the time of diagnosis, and HIV associated HD shows a more aggressive course than non-HIV HD. Many cases remain difficult to classify; instead, the immunophenotype of neoplastic cells is similar to that in HD occurring in the general population. Histiocytes and epithelioid cells are even more numerous than T lymphocytes, and the CD4:CD8 ratio is low. Neoplastic cells are EBV positive in most or all cases, although they are consistently HIV negative by in situ hybridization. Lymphomagenesis seems to be very complex, with multiple agents acting together or successively. EBV, other viruses, rearrangement of various genes and production of cytokines all seem to have major roles in addition to immune deficiency.

The entry of a cell into mitosis is regulated by an elaborate network of kinases and phosphatases that control both for the timing of cell division and the complete reorganization of the cellular architecture. The mitotic cyclin/Cdks form part of large multiprotein complexes whose other components are only now beginning to be identified. The continuing identification of proteins that contribute to these complexes and changes in the composition of these complexes are likely to give a more integrated view of how mitotic cyclin/Cdk complexes are regulated and how they function-not only to induce mitosis, but also to aid further mitotic progression. Furthermore, assigning specific G2/M functions to distinct mitotic cyclin/Cdk complexes will require the identification of differences in substrate specificities between the mitotic cyclin/Cdk complexes, perhaps in parallel with specific cyclin knockouts in mice. Such investigations will be complicated by potential functional overlap between mitotic cyclin/Cdk complexes in vitro and in vivo. Although cyclin/Cdk1 is thought to be the major kinase that initiates the onset of mitosis, a more complete understanding of how cells move from G2 to a mitotic state will require further identification of kinases operating upstream, downstream and in parallel with Cdk1, their substrates and their relationship with one another during the G2/M transition.

Checkpoint controls arrest cells with defects in DNA replication or DNA damage. For several reasons, checkpoint controls may be relevant to ontogeny and treatment of cancer. Firstly, mutations in two human genes, TP53 and ATM, give rise to cellular defects in cell cycle checkpoints and are associated with cancer. Secondly, although checkpoint defects potentially render the cell damage sensitive, they may do so only in combination with other defects in the cell's response to damage. Therefore, manipulation of checkpoint defects, requiring a description of normal and mutant pathways, will be required for this type of therapeutic approach. Those pathways are being described in yeast cells. In budding yeast, the study of checkpoint genes has led to the view that these genes have many roles in the cellular responses to DNA damage, including roles in arrest in multiple stages of cell cycle, in transcriptional induction of repair genes, in DNA repair itself and additionally some undefined role in DNA replication. The checkpoint pathways and proteins that carry out these responses may consist of sensor proteins that detect damage, signaller proteins that transduce an inhibitory signal and target proteins that are altered to arrest cell division (or cause other changes in cell behaviour). Yeast genes that may act at each step have been identified, leading to a working model of checkpoint pathways. An initial step in the pathway may involve the processing of damage to an intermediate that signals arrest and acts in DNA repair. Human checkpoint pathways may have defects in processing damage as well.

The cloning of the t(2;5) translocation breakpoints and the identification of the NPM/ALK fusion in Ki-1 ALCL have brought forth from this heterogeneous morphological grouping a subset of cases defined by an aetiological genetic alteration. The analysis of NPM/ALK positive lymphomas as a single clinicopathological entity has already begun to clarify and explain some previous clinical observations in Ki-1 ALCL. It has also confirmed that HD is pathogenetically unrelated to NPM/ALK positive Ki-1 ALCL. This is yet another example of the overall nosological evolution from morphological entities to pathogenetic entities among lymphomas, leukaemias and, more recently, sarcomas. Although much work remains to be done on the mechanism of NPM/ALK lymphomagenesis, rational treatment approaches are now within reach. Such novel approaches could target NPM/ALK at the level of the genomic sequence, transcript, protein or its downstream targets, when the latter are further elucidated. Systems developed to inhibit other fusion transcripts and oncogenic tyrosine kinases can now be applied to NPM/ALK positive lymphomas. Furthermore, the strong and highly selective surface expression of CD30 in Ki-1 ALCL may provide a basis for the targeted delivery of these novel therapeutic agents.

We reviewed 18 cases in which morphology was intermediate between Hodgkin's disease (HD) and anaplastic large cell lymphoma (ALCL). Eight cases exhibited the usual CD30+, CD15+/-, null cell phenotype of classic HD but were rich in neoplastic cells with sinusoidal infiltrating pattern. In this group, there was no expression of antigens (EMA, BNH9, CBF78) associated with ALCL, and only two were positive for Epstein-Barr virus (EBV). Ten EBV negative cases fit the description of HD like ALCL by variable expression of antigens unassociated with HD. EMA was clearly and strongly expressed in all ten, whereas antigens recognized by BNH9 and CBF78 were expressed in four and three cases, respectively. Focal expression of CD45 and CD43 was observed in half of these cases. In only one case was the t(2.5) translocation detected with the new monoclonal antibody, ALK1. Therefore, the expression of EMA, BNH9 and CBF78, often in concert without CD15 and without the specific translocation, appears currently to be the most probable phenotype and genotype of HD like ALCL. There was a tendency for aggressive behaviour of the disease considered HD like ALCL. Whether such patients will benefit from a therapeutic strategy that takes into account both phenotype and genotype remains to be discovered.