Numerous parameters influenced tumour radiosensitivity. The number of clonogenic cells, growth fraction, hypoxia and intrinsic radiosensitivity are among the most important determinants of radiocurability. Detection of DNA damage and repair pathways are important components of intrinsic radiosensitivity. ATM plays a major role in the cellular response to ionizing radiation: it induced DNA repair, cell cycle arrest, and apoptosis via induction of p53. Analysis of single nucleotide polymorphisms could help us to predict normal tissue sensitivity on an individual basis. Mutations of ATM is probably involved in some cases of severe radiation-induced late effects. Measure of residual double-strand breaks by immunochemistry of H2AX, but also ATM or MRE11, is another way to evaluate tumour radiosensitivity. Integration of genomics and functional approach are needed to better predict what the best candidates for a curative radiotherapy are.

ADN ploidy was shown to play a role in genomic instability of cancer cells and prognosis. The implication of the centrosome in the cell cycle was also described. Therefore, new prognostic factors could be suggested for a better-tailored therapy. The purpose of this study is to search for correlation between centrosomal abnormality and ADN ploidy in breast cancer. Cell prints were prepared from cell culture of mesothelial ascitis, fibroblast cell line MRC5 and breast cancer cell lines MCF7 and T47D. Fresh cell prints were also obtained from cases with invasive carcinoma. The centrosome was labelled by an indirect immunofluorescence assay using anti-γ-tubulin antibody and F(ab')(2) FITC before quantification with fluorescence microscopy. ADN ploidy was scored with DNA index obtained by means of flux cytometry. The normal mesothelial cells (94% of cells with only one centrosome) and the diploid cell line MRC5 (68% of cells with two centrosomes) were used as controls. DNA ploidy was found to be correlated with centrosomal abnormality in MCF7 cell line (64% of cells had more than three centrosomes) but not in the 10 cases of invasive ductal carcinoma analysed in this study. The absence of correlation between DNA ploidy and centrosomal abnormality in breast cancer samples may be due to the small numbers of cases, the cell prints or tumorigenesis. Correlation analysis of a larger number of cases and types of breast lesions to numerical and morphological abnormalities of the centrosome are ongoing.

Hereditary non-polyposis colorectal cancer (HNPCC) is associated in more than 95% to a germline mutation in the genes of the mismatch repair (MMR) of DNA. The aim of this study was to assess the utility of immunohistochemistry, a simple and fast technique, in the triage of families where HNPCC is suspected. Tumor samples included in this study were from patients with resection for colorectal cancer, examined in our laboratory between 2004 and 2007. For each case, a formalin-fixed paraffin-embedded tissue block containing tumor tissue and normal adjacent mucosa was selected. Tumor specimens were examined with immunohistochemistry for the presence of hMLH1, hMSH2, and hMSH6 proteins. Scoring of the tumor staining was performed without any knowledge of patients' family history. The loss of protein expression was noted in four patients among 48 cases tested: two cases with isolated loss of hMSH2, a case with isolated loss of hMSH6 and one case with combined loss of MSH2/MSH6. No case has shown a suppression of hMLH1 protein. Comparing the immunohistochemical results for clinical has revealed a clear correlation between loss of protein expression demonstrated by immunohistochemistry and clinical data. Indeed, three cases among the four who showed no expression of MMR proteins showed at least one clinical criterion predictive of HNPCC. In conclusion, our study support the potential utility of immunohistochemistry to identify a significant portion of colorectal tumors derived from germline mutation of MMR genes and can be used as an adjunct measure in the identification of HNPCC.

The HNPCC syndrome (hereditary non polyposis colon cancer) or Lynch syndrome stands for an autosomic dominant condition leading to the most prevalent hereditary colo-rectal cancers (CCR). MMR (mismatch repair)'s genes are involved in carcinogenesis as they play a role in ADNA mismatch repair. Microsatellite instability (MSI+ phenotype) induced by germline mutations is characteristic of such tumors and is necessary to assert the diagnosis. The HNPCC syndrome is associated with a significant increased risk of CCR altogether with endometrium, upper urinary tract and small bowel carcinomas as well as ovarian, biliary system and gastric cancers although of lesser extent. It is of importance to diagnose HNPCC syndrome prior to the treatment starts because it may influence patient's (as well as her/his relatives) disease management (type of surgery, surveillance and screening exams). New French recommendations, developed in 2009, about prophylactic colo-rectal and gynecologic surgeries and monitoring update latest ones published on 2004.

Poly(ADP-ribosyl)ation is a post-translational modification of proteins catalyzed by poly(ADP-ribose) polymerases (PARPs). In response to genotoxic stress, PARP-1 senses DNA breaks and through the synthesis of poly(ADP-ribose) restores genome integrity by stimulating a base excision and single-strand break repair process. These properties highlight the innovative potency of PARP inhibitors to target cancer cells in their repair capacity. They open the way to promising therapeutic strategies aimed to combine PARP inhibitors with DNA-damaging chimio- or radiotherapy and as single agents for the treatment of BRCA mutation-associated tumors. The benefits to potential risks ratio of these approaches will be discussed.

The role of DNA repair pathways is to maintain cellular integrity. However, genetic instability is a driving force in the development of tumor cells and many tumors are characterized by the loss of functionality in one or several DNA repair pathways. However, if genetic instability trespasses a certain point, it will induce cell death. Therefore, the dysfunctionality of several DNA repair pathways could represent an Achille's heel for the tumor, if such pathways could be pharmacologically targeted. For instance, the inhibition of PARP1, a protein in the base excision repair pathway (BER) is sufficient to induce cell death in cancer cells bearing BRCA1 or BRCA2 mutations, which are essential proteins in the homologous recombination repair pathway (HR). This phenomenon called "synthetic letality" constitutes recent knowledge and we discuss here the possibility that this strategy might be applied to innovative treatment options in lung cancer. Further, several DNA repair proteins could be used in lung cancer as prognostic and/or predictive biomarkers of response to chemotherapy or radiation. Indeed, specific biomarkers of each DNA repair pathway do exist and could guide oncologists in therapeutic decisions (e.g. ERCC1 and cisplatin). Finally, pharmacologic modulation of DNA repair proteins might also be interesting as it might increase therapeutic efficacy of anticancer strategies (DNA-interacting chemotherapy and radiotherapy). Here, we will present the principal DNA repair pathways and associated biomarkers (ERCC1, MSH2, PARP1 and BRCA1/2), and discuss their status in non-small call lung cancer (NSCLC).

To study the biological mechanisms of the repair of the radiation-induced DNA damage leads to two major medical applications: (1) the identification of the radiosensitive patients by using appropriate predictive assays in order to avoid toxicity due to radiation therapy and sometimes to chemotherapy; (2) the decrease of the radioresistance of tumour cells to obtain a better local control. To transpose fundamental biological knowledge from experimental in vitro clinic is delicate and sometimes too hasty, though necessary. In mechanistic terms, clinical features are once again a very rich and under-exploited approach to identify the molecular mechanisms of the DNA repair function. An exhaustive survey of the clinical cases of radiosensitivity with biological samples and with long course surveillance is an inverse approach, probably promising but still difficult to apply. Unlike classical reviews, this article attempts to identify the major genetic syndromes associated with radiosensitivity and cancer predisposition in order to deduce the different stages of major mechanisms of DNA double-strand breaks repair. Emphasis is placed on the importance of studying this repair at the functional level. Surprisingly, among the genetic syndromes associated to radiosensitivity there are some anomalies, not linked to DNA repair itself but to the intracellular trafficking. The repair function but therefore also the signalling are then logically therapeutic targets applicable in radiotherapy but with a very accurate ballistic sparing of the healthy tissues.

Genome study and expression profiling of the tumor seem to be the most significant biologic prognostic factor in uveal melanoma. Many cytogenetic and molecular tests are reported; our aim was to assess their ability to detect high metastatic risk patients through a literature review. Standard karyotyping, fluorescence in situ hybridization and microsatellite analysis are not adequate. DNA-based genome techniques must analyse the entire genome (comparative genomic hybridization [CGH]) and, optimally, detect chromosome 3 isodisomy ("single-nucleotid polymorphism" SNP-array). Multiplex ligation-dependent probe amplification (MLPA) is less expensive than array-CGH, but its interpretation may be delicate. Gene expression profiling is the most accurate molecular test for predicting metastatic death in patient with uveal melanoma even if it remains a costly technique. These prognostic tests could be useful to identify high-risk patients in future adjuvant therapy protocols.

Ovarian carcinogenesis and the early stages of malignant transformation are limited because of the lack of a candidate precursor. There have been several proposed hypotheses: first, ovary and the ovarian surface epithelium and more recently observations have increasingly focused attention of the Fallopian tube. Moreover, molecular genetic analysis has designed two main pathways of tumorogenesis. In this review, we discuss the different and perhaps complementary hypotheses about ovarian carcinogenesis.

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.

The incidence of acute myeloblastic leukemia increases with age. The unfavorable biology of the disease, comorbidities, and significant side effects of the intensive treatment make treatment decisions difficult. New and less toxic targeted approaches are under investigations in this setting and the main problem remains to determine which strategy for patients over 65 years of age. Some of them will be treated successfully using intensive chemotherapy, while a majority of them will fail. Older patients are heterogeneous and enrolling them in investigational therapy is justified, according to proven methods to stratify them.

Smoking status is essential to know when taking care of a lung cancer patient. Never-smoking patients account for 15% of lung cancer patients, more often women and adenocarcinoma. Environmental tobacco smoke and occupational exposure could be important risk factors. Lung cancer in never-smoker appears to be a distinct entity from lung cancer in smoker, with specific molecular characteristics such as frequent EGFR mutations. New molecular targets are on investigation, such as EML4-ALK translocation. Treatment of lung cancer in never-smoker is getting different from that of smoker with more efficacy of molecular targeted therapies.

Bronchioloalveolar carcinoma (BAC) is a primary pulmonary adenocarcinoma (ADC) developped from the terminal respiratory unit. Its restrictive definition adopted by the 1999 WHO pathological classification needs a complete tumor resection to exclude any signs of histological invasion. Although IIIB-IV tumors were excluded from the strict WHO definition of BAC, the first international workshop on BAC in 2004 had focussed on the need to include in the same spectrum of disease pure BAC and ADC with BAC feature (ADC-WBF). BAC and ADC-WBF affect more frequently women, non-smokers and Asian people than other non-small cell carcinoma. Their predominant lepidic and aerogenous tumor progression results in a frequent pneumonic, multifocal or diffuse presentation and explains why death is more frequently related to bilateral pulmonary involvement than extrathoracic metastasis. Natural history is slower and prognosis better than for other ADC. Within this entity, there are different cytological subtypes: mucinous, non-mucinous and mixed and according to them different clinical and biological phenotypes, with different sensitivity to therapeutic agents. At present, the diagnosis, the staging and the therapeutic strategy does not differ from that of non-small lung carcinoma cells. In localized forms, surgical resection remains the best therapeutic option for localized tumors. In diffuse forms, high frequency of epidermal growth factor receptor (EGFR) expression on tumor cells and its gene amplification and/or mutation as well as a particular sensitivity of this entity to EGFR tyrosine kinase inhibitors offer new strategy of therapeutical management in patients with non-resectable tumor. However, the place of chemotherapy has recently been revisited in this entity known until now as chemoresistant tumors. The results are being evaluated. It is necessary to continue therapeutic trials to determine criteria for choosing a first-line TKI or conventional chemotherapy in that entity. Cytological subtype will probably have an important role to play in this choice.

DNA repair is implemented through a large variety of mechanisms, each of them being adapted to a specific type of lesion: direct repair, mismatch repair for the errors occurring during the replication process, base-excision repair, nucleotide-excision repair, double-strand breaks DNA repair by homologous or non-homologous recombination. Each of these mechanisms involves numerous proteins associated as supramolecular functional complexes. Some anticancer drugs are able to generate DNA lesions which may overflow the repair mechanisms. The impossibility to repair DNA damage usually leads to cell death, but alterations of repair mechanisms may favour genetic instability and hence contribute to oncogenesis.

MiRNAs are small noncoding RNA ensuring post-transcriptional regulation of gene expression. Their expression is tissue-specific and some miRNAs have diagnostic and/or prognostic interest for tumor classes. MiRNAs are involved in tumoral process in quantitative (amplification, deletion of chromosomal regions) or qualitative terms (mutation in the miRNA or in the corresponding site of interaction in the mRNA). Overexpression of three miRNAs (miR-146b, miR-221 and miR-222) correlates with the development of papillary thyroid tumors. Polymorphisms in the c-kit gene or in that encoding miR-146a are susceptibility factors for the development of papillary thyroid tumors.

Recent advances in oncogenetics have enabled the development of tests for predisposition to breast and ovarian cancers. Where no mutation has been identified in the BRCA1 or 2 genes, the proband (first person tested in a family with a genetic risk) can receive an uncertain outcome: negative inconclusive or identification of a variant of unknown clinical significance. From the demonstration of such outcomes, their psychological impact has been studied among women concerned.

Expressed in thyroid, lung and diencephalon, the Thyroid transcription factor-1 (TTF-1) regulates, in these organs, the transcription of specific genes. This review focuses on the use of TTF-1 as a diagnostic tool in thyroid and lung carcinomas. According to the literature, TTF-1 seems to be involved in aggressive relapses. In some cases it could be also involved in the remission. The use of TTF-1 as a prognostic tool for some neoplasms is discussed.