We report the clinical and immunohistological features of two cases of chronic lymphocytic leukaemia (CLL) with Hodgkin's transformation. These cases occurred in a 70-year-old man with a three-year history of CLL and in a 76-year-old man with a few months history of CLL. Microscopic examination showed the presence of large tumor cells with the morphological and immunophenotypic features of classical Hodgkin and Reed-Sternberg (R-S) cells, in a background of otherwise typical B-CLL. The transformation of CLL into large B cell lymphoma (Richter's syndrome) is a well-documented phenomenon. Only rarely does CLL transform into Hodgkin's lymphoma, but this diagnosis is often easy and offers few differential diagnoses. The major points of interest lie in the pathogenetic relationship between CLL and Hodgkin's disease, and in the potential clinical implications of this peculiar condition. Literature on the subject indicates that identical IgH gene rearrangements in micromanipulated R-S and CLL cells have been identified in 7/12 cases. In these patients, the R-S and CLL cells belong to the same clonal population, suggesting a progression from the underlying CLL cells. This group appears to have a poor prognosis, identical to classical Richter's syndrome. In other cases, the R-S cells were often Epstein-Barr virus (EBV) positive and did not share the clonal rearrangements identified in CLL cells, suggesting that Hodgkin's disease in these patients could represent a second malignancy, EBV-related and favored by immunosuppression, associated with a better prognosis.

Surgical resection of gliomas is a well-established treatment. It allows a histo-genetic diagnosis, a mass effect reduction, an intracranial hypertension treatment, a recovery of an eventual neurological deficit induced by the mass effect, but mostly brings a significant survival. New imaging sequences are optimizing the surgical management of brain tumors by bringing precisions on the tumor morphology, on cortical/subcortical eloquent areas (functional and diffusion MRI), on histology (spectroscopic MR). If the tumor is located in eloquent area, surgery is performed under electrostimulation control to take into account cerebral plasticity and to avoid postoperative functional deficits. Neuronavigation, per-operative echography, and per-operative MRI are recognized tools for optimizing the tumor resection. Ongoing researches concern the adjunction of local treatments within the surgical field (photodynamic therapy, chemotherapy, convection immunotherapy...), but also the development of minimal invasive procedures (radiosurgery, high intensity focalized ultrasounds, laser interstitial thermal therapy).

Gliomas are the most common primary brain tumors. Despite the implementation of therapeutic strategies, these tumors remain fatal. The recent advances in the field of stem cell biology, cell signaling, genomics, bio-informatics and genetic model systems have led to a better understanding of gliomas biology. These advances are facilitating the establishment of a more precise, molecular-based, classification of gliomas and are leading to new therapeutic strategies directed against the key molecular events implicated in gliomas oncogenesis.

In breast cancer, optimal locoregional treatment allows high local control rates and impact long-term survival. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis data showed that radiation therapy (RT) can decrease the risk of breast cancer death at 15 years. In the adjuvant setting, whole breast RT remains the standard of care. Adjuvant systemic therapies, RT indications, techniques and volumes are determined according to the known standard prognosis factors such as age, tumor size and location, nodal involvement, grade, hormone receptors status, proliferative index and lymphovascular invasion. One of the future challenges in breast cancer management is to determine new prognosis and predictive factors that could help to define the subgroups of patients, who will either really benefit from new treatment strategies or particular RT techniques, or for those for whom aggressive local therapeutic option is not needed, as their prognosis is mainly related to an early risk of metastatic diffusion. In the new era of fine biological diagnosis, a better understanding of tumor biology allows a significant development of targeted therapies. Adjuvant strategies including locoregional RT have to be based on the tailored treatment concept. These strategies have to take into account not only the patients profiles regarding the well-established parameters, but also the tumor biology, the new breast cancer subtype classification and gene profiles.

At the time of fertilisation, the parental genomes have a strikingly different organisation. Sperm DNA is packaged globally with protamines, whereas the oocyte's genome is wrapped around nucleosomes. The maternal and paternal genomes are functionally different as well, and are both required for normal uterine and postnatal development. The functional requirement of both parental genomes is a consequence of differential epigenetic marking by DNA methylation during oogenesis and spermatogenesis, on a group of genes called imprinted genes. After fertilisation, these parental marks persist throughout development and convey the allelic expression of imprinted genes. Pathological perturbation of methylation imprints, before fertilisation in the germ cells, or during development, gives rise to growth-related syndromes, and is frequently observed in cancer as well. Alteration of imprints is thought to occur early in carcinogenesis and shows similarities with the acquisition of aberrant DNA methylation at tumour suppressor genes. This suggests that similar underlying mechanisms could be involved.

Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred different genes in cancer development. Today, the model has evolved: it has been demonstrated that malignancies can be initiated not only through genetic alterations but also through epigenetic deregulations. By altering the expression of gene involved in cell regulation, epigenetic alterations, such as histone acetylation, play a key role in the initiation and progression of neoplasm. It has been shown that an imbalance between the acelylated and deacetylated status of chromatin is significantly involved in the acquisition of a malignant phenotype. Thus, the modulation of the histone acetylation level by histone deacetylase (HDAC) inhibitors could lead to a genetic re-programmation in cancer cells that would favor apoptosis and prevent proliferation. The potential therapeutic value of several HDAC inhibitors for cancer patients has been evaluated in clinical assays with very promising outcome. Indeed, the first inhibitors available for patients has been recently approved for cancer patients tracing the way for a new class of promising anti-cancer therapy modalities.

In healthy cells, several epigenetic mechanisms ensure structural and functional differentiation of the genome, and are necessary for the transcriptional silencing of most of the genome while a few genes, specific for each tissue type, are activated. Cell transformation disturbs this organization and induces the aberrant repression or activation of many genes. Whereas the transcriptional silencing of some critical cell regulators clearly contributes to cell malignant transformation, the oncogenic role of the illegitimate activation of tissue-specific genes in cancerous and pre-cancerous cells is still poorly known. This review aims to demonstrate the oncogenic potential of the illegitimate expression, in somatic cells, of genes, whose expression is normally restricted to male germ cells, encoding factors known as cancer testis or C/T, and particularly those involved in re-organizing the epigenome in these cells. The value of these genes, and of the factors they encode, in terms of cancer markers and promissing therapeutic targets will also be stressed.

In eukaryotes, the epigenetic mark DNA methylation is found exclusively at cytosine residues in the CpG islands of genes, transposons and intergenic DNA. Among functional roles, DNA methylation is essential for mammalian embryonic development, and is classically thought to function by stably silencing promoter activity. However, until recently, understanding of the distribution of cytosine methylation in the whole genome - and hence, identification of its targets - was very limited. High-throughput methodologies, including methylated DNA immunoprecipitation, have recently revealed genome-wide mapping of DNA methylation, and provided new and unexpected data. Clearly DNA methylation is selectively associated with some key promoters- and is not a prerequisite for promoter inactivation, since strong CpG island promoters are mostly unmethylated, even when inactive. Most germline-specific genes are methylated and permanently silenced in somatic cells, suggesting a role of this mark in maintaining somatic cellular identity. These large scale studies will also help understanding the deregulation of DNA methylation associated with cancer, among which unmethylation of germinal cells genes, and recent observtion of large hypomethylated regions in tumoral specimens. The next challenge will be to understand if these methylation changes occur randomly, or more likely are specified by oncogenes or linked to environmental pressure.

The processes that affect the activity of the genome in a heritable manner without changing its sequence are called epigenetic. Here we review the modes of epigenetic gene regulation, and describe their alterations in cancer. We show how these mechanisms are interdependent, and how they intersect with genetic mutations. We argue that epigenetic abnormalities can occur both as a cause, and as a consequence of cancer. Indeed, oncogenic transformation can deeply alter the epigenetic information contained in the pattern of DNA methylation or histone tail modification. Conversely, epigenetic dysfunctions can drive cellular transformation. We then touch on some practical consequences of the prominence of epigenetic alterations in cancer : increasing knowledge of this field has allowed the development of a new generation of diagnostic tools and therapeutic avenues. Finally we point out that epigenetic phenomena may act as sensors that link environmental conditions to cancer.

Constitutive heterochromatin, key for the structuration of the centromeres, was long thought as a transcriptionally inert compartment, relatively invariant in composition and structure. Numerous studies have now challenged this view by showing the versatility of these epigenetically defined regions. This review highlights some important aspects of (peri)-centromeric heterochromatin structural and functional plasticity in development and differentiation. The integrity of centromeric regions is crucial for the stability of the genome and the maintenance of ploidy. I outline recent evidence suggesting that epigenetic alterations of heterochromatin can cause defects in chromosome segregation leading to aneuploidy and tumorigenesis.