Clinical and pathological heterogeneity of breast cancer, partly responsible of therapeutic failures, reflects complex and combinatory molecular alterations until now poorly documented by classical investigation tools. Thorough molecular typing is crucial. The advent of DNA microarray-based gene expression profiling allowed consistent progresses in this direction. A novel molecular taxonomy of breast cancer has been defined, signatures that predict clinical outcome or therapeutic response have been identified, some of them being tested in ongoing prospective clinical trials. In this review, we present the main results and their potential clinical applications. We also discuss their current limits and future hopes in the therapeutic management of patients.

Recent developments in molecular biology have provided the clinician with opportunities to investigate a number of new biomarkers. This has led to an abundant literature reporting the biological role, the relation to survival, and the predictive value of treatment responses in adult glioma patients. Consequently, the clinician must assimilate a large amount of information, raising the question of the genuine role of these biomarkers in the daily care of these patients.

Losses of chromosomes 1p and 19q are deemed correlated with diagnosis of oligodendroglioma, higher chemosensitivity and better prognosis. We reviewed the literature to evaluate the usefulness of these correlations in daily clinical practice. The rates of deletions relative to histology (WHO classifications) were extracted from 33 studies, including 2666 patients. The 1p deletions and 1p19q codeletion mean rates were respectively 65.4 and 63.3% in oligodendrogliomas, 28.7 and 21.6% in oligoastrocytomas, 13.2 and 7.5% in astrocytomas, 11.6 and 2.9% in glioblastomas. The presence of 1p deletion and 1p19q codeletion were strongly correlated with the histological diagnosis corresponding to oligodendroglioma. Calculation of specificity, sensitivity, predictive positive values and false negative rates suggests that presence of deletion 1p or codeletion represents a strong argument in favor of the diagnosis of oligodendroglioma. However, considering the high false negative rate, absence of such deletions does not rule out the diagnosis. In grade 3 oligodendroglial tumors, the probability of responding to chemotherapy, and the duration of response, were higher when codeletions were present. This suggests that, in these tumors, the presence of codeletion is a strong argument in favor of adjuvant chemotherapy. However, chemotherapy should not be systematically excluded when codeletions are absent, as the chances of response are about 33% in this situation. Data concerning low-grade gliomas were more controversial. Oligodendroglial tumors with 1p deletion or 1p19q codeletion seemed to have a better prognosis, as five-year survival rates were 50% higher than in tumors without deletion. This might be explained by the correlation between 1p deletion and other identified prognosis factors: (1) higher chemosensitivity, (2) tumor location more frequently in the frontal lobe, leading to better resection and lower risk of neurological deficit, (3) slower growth rate, (4) higher risk of epilepsy, leading to an early detection.

Therapeutic anti-cancer vaccines containing tumor-specific antigens recognized by T lymphocytes are thought to stimulate high numbers of anti-vaccine cytolytic T lymphocytes (CTL) which then can lyse the tumor cells. To understand why these vaccines are followed by tumor regressions in only 10% of the patients, we analysed the tumor-specific immune responses of these patients. Contrary to our expectations, the anti-vaccine CTL responses were of very low level. However, regressing tumors were massively infiltrated by anti-tumor T cells of other specificities, including new anti-tumor CTL clonotypes that emerged following vaccination. We now believe that the role of the anti-vaccine CTL is to activate or restimulate large numbers of other anti-tumor CTL. Their ability to initiate this response is probably more important than their number. These results have important consequences for the improvement of the clinical efficacy of anti-cancer vaccines.

Hereditary non polyposis colorectal cancer or Lynch syndrome is due to germline mutation of one the DNA mismatch repair genes. This mutation is associated with an unstable phenotype in tumor DNA characterized by new microsatellite alleles that are absent in matching normal DNA. Besides the Bethesda reference panel, a new panel of 5 mononucleotide microsatellites (BAT25, BAT26, NR21, NR24, NR27) has been proposed, which is more sensitive and faster to use in a multiplex PCR assay. In tumor cells, immunohistochemistry detects the loss of expression of either MLH1, MSH2, MSH6 or PMS2 protein, corresponding to the mutated gene. Immunohistochemistry guides germline analysis, except for MLH1 extinction which may correspond to either MLH1 germline mutation or methylation of MLH1 promoter resulting in inactivation. The latter is mostly due to aging and is often associated to the V600E BRAF gene mutation in tumor DNA. Combination of these 3 somatic analyses should reduce indications of germline mutation analysis in Lynch syndrome.

The cDNA microarray technology allows the simultaneous analysis of all genes expressed in a tumor. This approach has already permitted to propose a molecular classification of breast cancers. Gene expression profiling is now expected to define prognosis signatures claiming the disease outcome as well as signatures predicting response to therapy. The over-expression of a cluster of genes that are implicated in cell cycle and mitosis control has been shown to discriminate a subgroup of ER+ breast cancers exhibiting a poor prognosis. This "proliferation cluster" is shown to be also present in signatures predicting relapse of ER+ breast cancers treated by the anti-estrogen tamoxifen, including the 36-gene classifier that we have recently identified. Consequently, it seems legitimate to wonder if this part of such predictive signature is really specific to the insensitivity to tamoxifen or rather indicates a poor disease outcome whatever the therapy applied. On the other hand, low expression of ER+ related genes and high expression of genes associated to ER- status or low ERalpha levels have been shown to sign a poor prognosis. Whether the estrogen-related genes that are present in our 36-gene classifier specify the clinical disease outcome or are really specific to the response to tamoxifen, remains to be determined. In any case, the specificity of our 36-gene classifier as those predicting the recurrence of ER+ breast cancer under one treatment or another should be demonstrated. In the same way, future studies should define molecular signatures that will be really predictive of the response to the treatment in order to define which one is the most suitable to decrease the risk of relapse of ER+ breast cancers. These studies should be based on neoadjuvant clinical trials that permit to evaluate the response to treatment in an objective manner.

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic alterations and molecular expression in experimental models as well as in pre-cancerous and cancerous tissues by mean of molecular amplification and large scale transcriptome analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating mutation of the K-ras oncogene on codon 12 seems to occur early in pancreatic carcinogenesis and detecting its mutation in tumor samples could have a clinical relevance in term of positive (improvement of current histological diagnosis) and differential diagnosis (versus chronic pancreatitis) of pancreatic cancer. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, nerve growth factor, gastrin, bombesin), of proangiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, beta integrin, urokinase and tissue plasminogen activator) occur. All these molecular events contribute to the progression and to the metastatic potential of this carcinoma. New markers and targets are currently studied among microRNA and epigenetics events such as methylation and acetylation. Among all these molecular markers, some are now tested for their potential clinical interest in term of diagnosis or therapeutic target.

The authors present six cases of renal carcinoma associated with MiTF/TFE translocation in young adults. This tumour is one of the newly identified entities of the WHO 2004 classification.

Multiple endocrine neoplasia (MEN) 2A is an inherited disease characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma and/or hyperparathyroïdism. It has been shown to be associated with germline mutations in the RET proto-oncogene. Direct DNA testing, therefore allows the identification of subjects with asymptomatic MEN 2A who can be offered prophylactic thyroidectomy and biochemical screening as preventive measures. DNA analysis of RET exon 8, 10, 13, 14, 15 and 16 was performed by direct sequencing of PCR product on automated sequencer and or PCR-digestion. In this report, we describe a MEN2A family witch initially seemed a sporadic case of MTC. We first characterized the C634R RET mutation in the index and then we identified 3 carriers who developed the disease and 3 young carriers who were apparently asymptomatic. A genetic counselling and the management of the carriers were proposed. This study confirmed that genetic testing ; in order to detect gene carriers is technically possible in Morocco. This will contribute to the definition of a national policy of this cancer control.

Five to 10% of breast and ovarian cancer are linked to a BRCA1 or BRCA2 mutation. In our country, the information given to the relatives is inevitably mediated by the persons who have consulted. The report of a gap between the number of presumed persons concerned by the genetic information according to our genealogies and the actual number of consultants brought us to question about the transmission of the information in the family, about the possible motives for the lack of transmission, about the rate of consultation of the concerned relatives and on the presumed motives of non-consultation. This sample includes 31 target consultants (index cases) of mutated families which received the result of the genetic test during the period from January, 2003 till June, 2005. According to the information gathered, most of the relatives (73.1%) are informed about the presence of a deleterious mutation in the family, especially women (80.7%). The motives for non-information are the social and emotional distance, as well as the stressful character of the information. Apparently the information is disclosed through the family by the women who are alive and carry the mutation. On the other hand, a minority of the women (39.7%) who are supposed to be informed and living in the region attended the oncogenetic consultation, which represents 32 % of all concerned women who come of age. The motives for short-term absence of consultation can just be presumed. The characteristics which we studied do not allow us to point out some particularities among women who consulted except the nearness with one mutated relative.

Ewing's tumour is the second most frequent primary tumour of bone. It is associated in 85% of cases with a specific and recurrent chromosome translocation, a t(11; 22)(q24; q12) which generates a fusion gene between the 5' part of EWS and the 3' part of FLI-1, a member of the ETS family. Less frequently, this gene fusion involves EWS and another member of the ETS family which can be: ERG, ETV1, E1AF or FEV depending on the cases. The EWS-ETS fusion is causative in the development of Ewing's tumour. Its mechanism of action mainly relies on the abnormal transcription regulation of key target genes which are involved in the regulation of cell cycle, signal transduction, migration. The cellular context within which EWS-FLI-1 exerts its oncogenic action is a long standing matter of debate. Recent data converge to suggest that the Ewing cell origin is a mesenchymal stem cell.