Almost 10% of mammalian coding mRNAs contain in their 3' untranslated region a sequence rich in adenine and uridine residues known as AU-rich element (ARE). Many of them encode oncogenes (for instance c-Myc and c-Fos), cell cycle regulators (cyclin D1, A1, B1), cytokines (TNFalpha, IL2) and growth factors (GM-CSF) which are overexpressed in cancer or inflammatory diseases due to increased mRNA stability and/or translation. AREs are recognized by a group of proteins, collectively called AUBPs which display various functions. For instance, HuR/ELAV is mainly known to protect ARE-containing mRNAs from degradation, while AUF1, TTP and KSRP act to destabilize their bound target mRNAs and TIA/TIAR to inhibit their translation. Alterations in ARE sequences or AUBP abundance, cellular localization or activity due to post-translational modifications such as phosphorylation can promote or enhance malignancy or perturb immune homeostasis. Here, c-myc and TNFalpha are chosen as examples to illustrate how altered 3' UTR gene regulation impacts on pathologies.

Most cancers have a sporadic physiopathology, but approximately 5 to 10% of breast cancers and 10% of ovarian cancers involve a genetic predisposition. Sometimes, the gene involved in these hereditary cancers can be identified (usually BRCA1 or 2), but most of the time it remains unknown. However, all women considered at high risk, because of their familial history, must be identified so they can be provided with the most adequate care, since the probability is very high that they develop such a cancer in the future. Fortunately, effective strategies have been developed to reduce this risk. Early detection of breast cancer is possible and prophylactic treatments (chemoprevention and prophylactic surgery) exist for both breast and ovarian cancers. Another reason why it is essential that these high risk women are identified is that treatment for hereditary cancers differs in some ways from that of sporadic cancers. It is best that counseling be given in an interdisciplinary cancer genetic clinic, where all practionners are aware of the latest data and guidelines.

EGFR is a tyrosine kinase (TK) receptor overexpressed in lung adenocarcinomas. EGF binding to EGFR leads to K-Ras activation, promoting signaling of division, survival, and cell invasion. Adenocarcinomas addicted to EGFR signaling pathway for proliferation (10%), exhibit mutations of EGFR tyrosine kinase domain. Inhibition of these mutated receptors favors apoptosis signaling, taking account for dramatic tumoral responses. On the other side, 30% of adenocarcinomas have K-Ras mutations making the cells resistant to EGFR TK inhibitors (TKI). Secondary resistances are induced in 50% of initially sensitive tumors by an additional EGFR mutation (T790M), lowering receptor affinity for the inhibitor. The use of high affinity inhibitors ("irreversible") is tested in those patients. In 30% of cases, secondary resistance to TKI is induced by amplification of C-Met gene that encodes for another TK receptor, stimulating cell survival by substitution to EGFR. The use of C-Met inhibitors could overcome this kind of resistance. Angiogenesis is an early event in lung cell cancerization of which main cell signaling uses TK receptors to VEGF. Inhibition of this pathway consists in a major therapeutic advance in solid tumors. Finally, stimulation of anti-tumoral immunological response using anti-tumoral "vaccination", or agonists of innate immunity receptors, has given encouraging therapeutic preliminary results in lung cancer but needs phase 3 validation trials.

Malignant pleural mesothelioma (MPM) is a rare tumour due to occupational asbestos exposure. The incidence of MPM will continue to increase until 2020-2030. The incidence reaches 100 cases/million/year in occupationally exposed populations as opposed to 1 case/million/year in the general population, leading to 800 to 1,000 cases per year in France. The molecular carcinogenesis of MPM is incompletely understood but alterations to genes NF2, c-met, WT1 RASSF and p16 have been described. These genes are involved in cell invasion and motility, cell division and apoptosis control. Histological diagnosis remains difficult and depends on immunohistochemical analysis as described by the French Mesopath group. Clinical diagnosis relies on thoracoscopy and large pleural biopsies, with increasing use of CT-PET for the evaluation of disease extent. Therapeutic strategy includes prophylactic irradiation following drainage or thoracoscopy to prevent tumour nodule development along drainage channels and puncture sites. In selected patients, extensive extra-pleural pneumonectomy can be performed with curative intent. First line chemotherapy is based on a combination of pemetrexed and cisplatin that has demonstrated an improvement in overall survival and quality of life in phase 3 trials. Antiangiogenic agents such as bevacizumab (Avastatin) may be of interest but need to be tested in phase 3 trials. The Mesothelioma Avastatin Pemetrexed Study (MAPS) is ongoing, coordinated by the French Thoracic Cancer Intergroup (IFCT).

Currently, carcinogenesis appears to be a process much more complex than what was believed a decade ago. The study of the genome of human tumour cells has revealed a number of genetic and epigenetic modifications much greater than suspected. Moreover, the delay between the first initiating event (when its timing is precisely known) and the clinical emergence of a cancer can be very long, up to 60 years. This long delay shows that risk factors during infancy and childhood deserve critical analysis. The epidemiological data emphasize the role of promotion. For example, alcohol, asbestos are not mutagenic, but cause irritation and cell proliferation. Even for tobacco, the role of promotion appears to be more important than that of mutations. In human carcinogenesis, initial mutations do not appear to be a limiting or crucial step. Finally, the biological study of carcinogenesis has shown that the initiating cell is not passively affected by the accumulation of damages by the carcinogenic physical or chemical agents. It reacts through at least three mechanisms: (a) by fighting against reactive oxygen species (ROS) generated by any oxidative stress, such as UV or ionizing radiations, (b) by eliminating injured cells (mutated or unstable), through two ways--(i) apoptosis, which can be initiated by doses as low as a few millisieverts, thus eliminating cells with genomes that have been damaged or ill-repaired, (ii) death of cells during mitosis when lesions have not been repaired--, (c) by stimulating or activating DNA repair systems. Furthermore, intercellular communication systems inform a cell about the presence of an insult in neighbouring cells. A system of intercellular induction of apoptosis exists whereby non-transformed cells can selectively remove transformed cells. Modern transcriptional analysis of cellular genes using microarray technology reveals that many genes are activated by doses of carcinogenic agents much lower than those for which mutagenesis is observed. These methods have been a source of considerable progress. Moreover, it was thought that carcinogenesis was initiated by lesions of the genome affecting at random a few specific targets (proto-oncogenes, suppressor genes, etc.). This relatively simple model has been replaced by a more complex one, in which the relationship between the initiated cells and their microenvironment plays an essential role. Thus, the carcinogenic process is counteracted by effective defence mechanisms in the cell, tissue and the organism. With regard to tissue, the mechanisms that govern embryogenesis and direct tissue repair after injury appear to play also an important role in the control of cell proliferation. This is particularly important when a transformed cell is surrounded by normal cells that appear to be able to inhibit its proliferation. Tissue disorganization by inflammation or by the death of a large proportion of cells is often associated with the escape of the initiated cells and the emergence of a clone of pre-neoplastic-neoplastic cells. The effectiveness of immunosurveillance is also shown by the large increase in the incidence of several types of cancers among immunodepressed people.

In spite of the explosion of basic knowledge, breast cancer remains a major problem of public health. Basic endocrinology was at the origin of the first targeted therapy in cancer with the anti-estrogens. Continuous breast cancer cell lines helped to specify the mechanism of the mitogenic activity of estrogens, the basis of their tumour promoter activity. They could not help to explain the deleterious effect of progestins after the menopause and to study the effect of ovarian hormones in the early steps of carcinogenesis. The variations of expression of ovarian hormone receptors in pre-malignant mammary lesions strongly suggest an increased sensitivity to these hormones. Moreover breast carcinogenesis is heterogeneous and the oestrogen receptor negative pathways require other targeted therapies. A better prevention of hormone-dependent cancers will need both increased basic researches translatable to human and good information of women on the avoidable risk factors.

Among the targeted therapies used in the treatment of metastatic colorectal cancer (CRC), cetuximab was registered in France in 2004. This chimeric antibody inhibiting the Epidermal Growth receptor (EGFR) has been demonstrated to be efficient in the treatment of irinotecan-resistant metastatic CRC expressing the EGFR. Panitumumab, a fully humanized anti-EGFR antibody should soon be registered after failure of conventional chemotherapies. However, these costly and potentially toxic treatments are efficient in a little proportion of patients. It is so necessary to identify some factors able to better define whose patients will benefit from these treatments. The major potential predictive factors of response to cetuximab and/or panitumumab that have been evaluated in the literature, which are summarized in this review, are molecular factors involved more or less directly in the EGF signaling pathway. Among them, KRAS mutations, EGFR gene copy number and, more recently, epiregulin and amphiregulin expression are those, along with skin toxicity, which appear to be the most relevant and which will have to be evaluated in future clinical trials to be validated before being incorporated in therapeutic strategy of CRC.

During each cell division, DNA polymerase makes mistakes while copying DNA. These errors, more frequent at the level of repeated sequences called microsatellites are normally repaired by a system called MMR (mismatch repair). Tumors defective in their MMR system accumulate mutations (deletions and insertions of some nucleotides) at the level of microsatellites and are called MSI (microsatellite instability). Microsatellites are numerous and scattered throughout the genome, in coding and non-coding regions. The instability of non-coding microsatellites is not known to have a major role in the process of cell transformation, but is a good indicator of the MSI status. On the other hand, instability by deletion or insertion in a coding region leads to a frameshift within the gene containing the repeat. The consequence is, the more often, the inactivation of this gene that potentially plays a role in initiation and/or MSI tumor progression. The MSI phenotype was first described in about 15 % of colorectal cancers that maybe of sporadic or hereditary (Lynch syndrome, or HNPCC for hereditary non-polyposis colorectal cancer) origin. It is also associated with about 15 % of gastric and endometrial tumors, and to a lesser extent with other human tumors. Besides a fundamental interest because of its original transformation mechanism, the analysis of MSI tumors is also important for clinical reasons. It was indeed shown that MSI tumors were associated with a better prognosis than non-MSI (also called MSS for microsatellite stable) tumors, and responded differently to conventional chemotherapeutic drugs used for the management of colorectal cancers. All these points will be discussed in details in the present review.

Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.

The aim of this review is to draw the attention to the numerous steps of gene expression which operate at the RNA level and which are significant drivers of the transformation process. The analysis of genomic abnormalities was at first limited to gross chromosomal alterations and to DNA point mutations. Then came the era of transciptomes which were originally believed, since they were mRNAs, to be a faithful reflection of the expressed proteins. As a matter of fact, this first-generation transcriptomics gave only a global, quantitative, assessment of gene expression at a given locus but overlooked the qualitative diversity of the messenger population generated by alternative splicing. We will show that beyond their essential role in the regulation of functions specific to metazoan like development, alternative splicing brings about an important vulnerability to mutations which is at the origin of many pathologies including cancer. The second aspect covered by this review is that of a rather novel category of RNAs, the microRNAs which, although non-coding, functionally behave as oncogenes or tumor suppressors through the negative control they exert on conventional oncogenes or suppressors. Beyond their diagnostic and prognostic interest, these two mechanisms offer entirely novel potential therapeutic targets.

The introduction of targeted therapies has largely modified the treatment strategies in oncology. Two targets are currently used for defining the systemic treatment of breast cancer: hormone receptors and HER2 overexpression. Trastuzumab, a monoclonal antibody, is the only registered antiHER2 treatment in Belgium. The association of trastuzumab with chemotherapy is now the recommended adjuvant treatment for early breast cancer overexpressing HER2. Other antiHER2 medications are available and some will probably be registered soon. Angiogenesis is another potential target for improving the treatment results. The CHU Liège, as a reference center for the systemic treatment of solid tumors, participates in many international trials in order to validate these new approaches. The highest quality of care is required to be in compliance with the conduct of these clinical trials. Another benefit for the patient is the easy access to last generation medical treatments, generally not accessible in our health care system in Belgium outside of clinical trials.