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Currently, more than 10% of human cancers are associated with viral infection. Studies on oncoviruses led to the development of clinical intervention strategies and elucidated fundamental cellular events altered upon cell transformation. Cancer cells exhibit several hallmarks including genomic instability, defined as a high frequency of mutations including gain or loss of chromosomes. The centrosome is an organelle that governs mitotic chromosome segregation and that functions as a signaling platform downstream of the DNA damage response. Here, we review the current literature to highlight how oncoviruses induce genomic instability via the deregulation of the centrosome. Viral interference with the centrosome duplication cycle, leading to centrosome amplification, is illustrated, with a special emphasis on mechanisms shared by several viral families. In addition, we discuss how oncoviruses could alter the signaling functions of the centrosome, and we comment on the bibliographic gaps that could be addressed by future research.

Meningeal melanocytic tumors are rare. We report an exceptional case of transformation of a meningeal melanocytoma in a malignant melanoma. The course of the disease extents from 61-years to 85-years and ends with the death of the patient. Besides histopathological and immunohistochemical data, we also report the array CGH study of the melanocytoma and melanoma components suggesting the malignant transformation from whole chromosome gains in the melanocytoma to additional segmental aberrations in the malignant melanoma. Beyond the rarity of this tumor subtype, this case report highlights the potential interest of molecular analyses for diagnostic and prognostic purposes in the field of meningeal melanocytic tumors., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Uveal melanoma is a rare cancer in adults, whose highly stereotyped oncogenic events have been decrypted over the last decade. Its epidemiological, genetic and transcriptional features make it a remarkable model of oncogenesis. Malignant transformation involves almost mutually exclusive alteration of fundamental biologic pathways, including chromatin regulation with inactivation of BAP1, splicing with mutations of SF3B1 or translation with mutations of EIF1AX. Uveal melanoma analyses unraveled the splicing defect due to SF3B1 mutations. Understanding the link between these alterations and malignant transformation will be a key step to define novel therapeutic targets., (© 2018 médecine/sciences – Inserm.)

Maintaining the genetic integrity is a key process in cell viability and is enabled by a wide network of repair pathways. When this system is defective, it generates genomic instability and results in an accumulation of chromosomal aberrations and mutations that may be responsible for various clinical phenotypes, including susceptibility to develop cancer. Indeed, these defects can promote not only the initiation of cancer, but also allow the tumor cells to rapidly acquire mutations during their evolution. Several genes are involved in these damage repair systems and particular polymorphisms are predictive of the onset of cancer, the best described of them being BRCA. In addition to its impact on carcinogenesis, the DNA damage repair system is now considered as a therapeutic target of choice for cancer treatment, as monotherapy or in combination with other cytotoxic therapies, such as chemotherapies or radiotherapy. PARP inhibitors are nowadays the best known, but other agents are emerging in the field of clinical research. The enthusiasm in this area is coupled with promising results and a successful collaboration between clinicians and biologists would allow to optimize treatment plans in order to take full advantage of the DNA repair system modulation., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Theileria are obligate eukaryotic intracellular parasites of cattle. The diseases they cause, Tropical theileriosis and East Coast Fever, cause huge economic loss in East African, Mediterranean and central and South-East Asian countries. These apicomplexan parasites are the only intracellular eukaryotic parasites known to transform their host cell and represent a unique model to study host-parasite interactions and mechanisms of cancer onset.Here, we review how Theileria parasites induce transformation of their leukocyte host cell and discuss similarities with tumorigenesis. We describe how genomic innovation, epigenetic changes and hijacking of signal transductions enable a eukaryotic parasite to transform its host cell.

Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T /NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of histologic subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. The first part published in the October issue was focused on the three more frequent entities, i.e. angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second part presented herein will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma., (© 2015 médecine/sciences – Inserm.)

The p53 gene is essential for tumor suppression, but how it does so remains unclear. Upon genotoxic or oncogenic stresses, increased p53 activity induces transient cell cycle arrest, senescence or apoptosis, the three cornerstones of the so-called triumvirate. Accordingly, it has long been thought that p53 suppresses tumorigenesis by somehow counteracting cell proliferation or survival. However, several recently described genetically modified mice indicate that p53 can suppress tumorigenesis without triggering these three responses. Rather, as an important mechanism for tumor suppression, these mutant mice point to the ability of p53 to prevent the Warburg effect, that is to dampen glycolysis and foster mitochondrial respiration. Interestingly, these metabolic functions of p53 rely, in part, on its "unstressed" (basal) expression, a feature shared by its mechanistically linked anti-oxydant function. Together, these "conservative" activities of p53 may prevent tumor initiation by promoting and maintaining a normal oxidative metabolism and hence underly the "daily" tumor suppression by p53 in most cells. Conversely, destructive activities elicited by high p53 levels and leading to senescence or apoptosis provide a shield against partially or overtly transformed cells. This last situation, although relatively infrequent throughout life, is usual in experimental settings, which could explain the disproportionally high number of data implicating the triumvirate in tumor suppression by p53., (© 2015 médecine/sciences – Inserm.)

In clinical oncology, obtaining sequence data from tumour samples has become practical in terms of logistics, turnover time and costs. The major issue now is the interpretation of this sequence to define actionable targets, i.e. genome changes that are involved in tumorogenesis and that predict the efficacy of existing and available targeted treatments. This is the focus of major efforts from public clinical centres and from companies that see it as a promising commercial activity., (© 2015 médecine/sciences – Inserm.)

Thyroid cancer is an uncommon cancer. Molecular biology plays a vital role in its development. Chemotherapy showed unsatisfactory results in advanced stages where surgery and iodine therapy are not appropriate. These last ten years have been marked by a major advance in understanding the molecular features of this cancer and therapeutic correlations, moreover, clinical trials have focused on the treatment of this disease on metastatic stages and led to a significant therapeutic panel targeting angiogenesis, mutations frequently found in cervical cancer: RET, BRAF, RAS... these are the motesanib, axitinib, sunitinib, pazopanib, vandetanib, cabozotinib and sorafenib. The last three molecules have already the autorisation of FDA and EMA. In this review, we will put the item on oncogenetic characteristics of thyroid carcinoma as well as new targeted therapies in patients refractory to conventional treatment., (Copyright © 2014. Published by Elsevier SAS.)

Post-translational modifications are critical to modulate protein function. A post-translational mechanism, peptidyl prolyl cis-trans isomerisation, plays a key role in protein regulation. Pin1 is a ubiquitous peptidyl prolyl cis-trans isomerase conserved from Archae to Human. This enzyme binds and isomerizes phospho-serine/threonine-proline motifs. This process can induce conformational change in protein targets and modulates their activity, cellular localization, phosphorylation state, stability and/or protein-protein interactions. Pin1 activity regulates proteins involved in cell proliferation, pluripotency or cellular invasion. Pin1 is overexpressed in several human cancers and contributes to tumorigenesis. Its inactivation constitutes a promising therapeutic strategy., (© 2014 médecine/sciences – Inserm.)

In the reductionist perspective, genetic modifications are considered to initiate cancer. Their appearance is a stochastic phenomenon, but there are some biases linked to DNA sequence or exposure to mutagenic agents for instance. Cancer genome sequencing has shown a high inter- and intra-tumoral heterogeneity, sometimes questioning the genetic origin of cancer. Other stochastic processes are also studied in cancer, especially epigenetic modifications. They have a major role in diversifying phenotypes among cancer cells in the progression steps, but might also provide an alternative to genetic theories of cancer initiation. Nevertheless, the reductionist framework remains dominant here. Finally, stochastic cell-to-cell variations in gene expression constitute a third class of stochastic phenomena that can be considered as causal factors in cancer. Highlighting the role of high gene expression variability due to disruption of cellular interactions and communications allows avoiding reductionism by considering the interplay between genetic and tissue levels at every step of the disease. No organization level is privileged in this alternative theory., (© 2014 médecine/sciences – Inserm.)

The debate between reductionism and anti-reductionism, dealing with the ultimate constituents of the world, is one of the fundamental issues in the philosophy of science. However, in biology, reductionism is less of an ontological and more of an epistemological question: it argues that the explanation of biological processes resides in deciphering the genetic code of living entities. This position is still prevalent in cancer biology, which has long been defined as a cellular process where genetic alterations are responsible for aberrant proliferation. While the hypothesis of somatic mutations remains the central theoretical model, a bundle of experimental data reveals how important the disturbances of tissue organisation are in cancer development, leading to a renewal of holistic and organicist approaches. This latter perspective in particular attempts to contextualise and rethink the centrality of the genetic level by proposing a new conception of cancerogenesis as a tissue disease., (© 2014 médecine/sciences – Inserm.)

Progress in genomics with, in particular, high throughput next generation sequencing is revolutionizing oncology. The impact of these techniques is seen on the one hand the identification of germline mutations that predispose to a given type of cancer, allowing for a personalized care of patients or healthy carriers and, on the other hand, the characterization of all acquired somatic mutation of the tumor cell, opening the door to personalized treatment targeting the driver oncogenes. In both cases, next generation sequencing techniques allow a global approach whereby the integrality of the genome mutations is analyzed and correlated with the clinical data. The benefits on the quality of care delivered to our patients are extremely impressive.

Nectin and nectin-like (Necl) are cell adhesion molecules expressed in various tumors. They were alternatively reported as involved in tumor suppressor or oncogenic functions that led to their use as histological or serological cancer markers. Gene inactivation in lung carcinoma but overexpression in leukemia were reported for Necl-2. DNAM-1 and CRTAM are emerging NK receptors of immune cells that were described to interact with nectin and Necl. DNAM-1, constitutively expressed by CD8(+) T cells, NK or γδ T lymphocytes, is a ligand of Necl-5. It participates to tumor immunosurveillance promoting Necl-5 expressing tumor cell lysis. CRTAM, only expressed after lymphocyte activation, is a ligand of Necl-2. Engagement of CRTAM with Necl-2 has opposite effects depending on the type of lymphocyte. For NK or CD8(+) T cells, it promotes cytotoxicity and IFNγ secretion favoring immunosurveillance. By contrast, CRTAM/Necl-2 interaction triggers cell death of activated TVg9Vd2 γδ T cells favoring immune escape. Nectin and Necl-mediated interactions appear to be crucial for the delicate balance between tumor escape and antitumor response., (© 2014 médecine/sciences – Inserm.)

Skin cancer is the most common human malignancy, and sunlight exposure is known to play a role in its genesis. Ultraviolet B (UVB) (300-320 nm) has long been considered responsible for the skin damage underlying these cancers, whereas the toxicity of UVA (320-400 nm) has been largely overlooked The intimate mechanisms of photocarcinogenicity remain poorly understood, but UV-induced DNA damage appears to be a major initiating event. Cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) photoproducts (6-4PPs) are the main dimeric lesions induced by UVB, whereas the genotoxic effects of UVA have long been attributed to oxidative damage, the main lesion being the oxidized base 8-oxo-7,8dihydroguanine (8-oxoGua). However; powerful new techniques for analyzing DNA damage (the Comet assay, and especially HPLC-MSIMS) have demonstrated that UVA irradiation mainly triggers the formation of CPDs, especially CPD-TT both in cell models and in total human skin. A direct photochemical process is currently thought to account for CPD induction by UVA. The multilayer structure of the epidermis protects against UVB-induced dipyrimidine lesions in total skin but offers only weak protection against UVA. In addition, repair efficiency is undermined by UVA. CPDs, the main DNA lesions induced by UVA in total skin (which is more permeable to UVA), are inefficiently repaired CPDs have strong mutagenic potential, and recent studies clearly show that CPDs, rather than 8-Oxo-Gua, are the main mutagenic photoproducts induced by UVA. The UV signature of induced mutations is characterized by transitions from C to T or CC to TT in dipyrimidine sequences. These mutations target the p53, patched 1 and SMO genes in carcinomas, and the PTEN RAC1, PPP6C, STK19 and PPP6C genes in melanomas of exposed skin. UVA also mainly induces CPDs in melanocytes, in amounts similar to those observed in keratinocytes, demonstrating that melanin does not prevent CPD formation. In contrast, UVA induces far more abundant 8-oxo-Gua production in melanocytes than in keratinocytes. Thus, under UVA irradiation, oxidative stress contributes more to DNA damage in melanocytes than in keratinocytes. In addition, baseline oxidative damage (in the absence of UVA) is already higher in melanocytes. The photosensitizer may be melanin itself. This is supported by a recent study based on a murine model, in which melanoma induction was shown to require both UVA and the presence of melanin in melanocytes, and is associated with oxidative damage to DNA. Conversely, UVB was found to initiate melanoma through a direct, pigment-independent pathway. Thus, two wavelength-dependent pathways can induce melanoma, with melanin playing an unexpected role. Constitutive pigmentation is very effective in preventing UV-induced damage, and a clear correlation can thus be found between, on the one hand, the amount of CPD TT produced by both UVB and UVA and, on the other hand, the minimum erythematous dose and the phototype. Melanin is thus a two-facetted molecule, protecting the skin when its synthesis is complete and when melanosomes take on their nucleus-protective geometric configuration in keratinocytes, but having a pro-oxidant action when only partially polymerized and exposed to UV Repeated exposure of volunteer skin shows that a tan induced by UVB provides little protection against DNA damage caused by subsequent exposure, while tanning with UVA provides no protection at all. Yet both UVB and UVA provoke DNA damage. All these recent data highlight the potential role of UVA in skin carcinogenesis, and reinforce epidemiological studies showing an increased risk of melanoma among users of tanning lamps, particularly young women. The decision by the International Agency for Research on Cancer to classify UVA and tanning devices as group 1 carcinogens, and the opinion issued by the French National Academy of Medicine on tanning booths, therefore appear to be fully justified. The use of tanning salons should be permanently banned

We report a rare case of association of two distinct hematologic malignancies: refractory cytopenia with multilineage dysplasia associated with del(5q) and symptomatic multiple myeloma associated with del(17p) and del(13q). After 16 months, the patient presented an acute leukemic transformation of the myelodysplasic syndrome.

From the second part of the 20th century, our knowledge of tumor biology widely benefited of tremendous progress in genetics (oncogenes, tumor suppressor genes, chromosomal abnormalities, etc), then in complex epigenetic process that regulates gene expression. Other players have entered the field of oncology and are now considered for their potential therapeutic interest: energetic metabolism, cancer stem cells as sources of tumor recurrence, microenvironment and above all intratumor heterogeneity. A better understanding of these domains of fundamental oncology should not mask the notion that a tumor is a living entity, which obeys the rules of Darwinian evolution.

Endometriosis is considered as a tumor-like lesion under the World Health Organization (WHO) classification of ovarian tumors. Data from large cohort and case-control studies indicate that patients with a history of endometriosis have an increased risk of ovarian cancer. Recent findings suggest an association between endometriosis and the entire type 1 ovarian tumors group including clear-cell, endometrioid and low-grade serous carcinomas. However, current evidence is lacking to draw definitive conclusion whether this association represents causality or the sharing of common risk factors. Nevertheless, assumption that endometriosis could be a precursor of malignancy raises many issues about serial screening, surgical management and surveillance of endometriosis. Beyond these concerns, endometriosis-associated ovarian cancers seem to be a genuine clinical entity as regards clinicopathological features. In view of the high incidence of endometriosis (10 % of women of childbearing age), the low incidence of endometriosis-associated ovarian cancers and the psychological consequences for those women, systematic screening and surgical exploration seem very questionable in this context., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Chromosome arms 1p and 19q codeletion, corresponding to an unbalanced reciprocal translocation t(1;19)(q10;p10), is seen in oligodendroglial tumours and is associated with better prognosis and better chemosensitivity. BRAF abnormalities are observed in pilocytic astrocytomas (tandem duplication-rearrangement) and in pleomorphic xanthoastrocytomas (BRAF V600E mutation). The vast majority of primary or de novo glioblastomas exhibit genetic abnormalities disrupting the intracellular signaling pathways of: transmembrane tyrosine kinase receptors to growth factors and their downstream signaling pathways (i.e. NF1-RAS-RAF-MAPK and PTEN-PI3K-AKT-TSC-mTOR); RB and; TP53. IDH1 and IDH2 mutations are frequent in diffuse grade II and grade III gliomas and in secondary glioblastomas. They are diagnostic and favorable independent prognostic biomarkers. In contrast, they are rare in primary or de novo glioblastomas and not reported in pilocytic astrocytomas. Germlin mutations in MSH2/MLH1/PMS2/MSH6, CDKN2A, TSC1/TSC2, PTEN, TP53 and NF1/NF2 predispose to glial tumors in the setting of hereditary cancer predisposition syndromes. Single nucleotide polymorphisms in TERT,CCDC26, CDKN2A/CDKN2B, RTEL, EGFR and PHLDB1 confer an inherited susceptibility to glial tumors., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

FGFR3 mutation leads to a constitutive activation of the receptor 3 to Fibroblast Growth Factor. This mutation is early in urothelial carcinogenesis and is strongly associated to low grade papillary tumors. Multiple regional epigenetic silencing (MRES) phenotype corresponds to the transcriptional inactivation of chromosomal regions in muscle invasive bladder cancer, and is strongly associated to the molecular signature of carcinoma in situ. These alterations could be targeted by new specific therapies., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Acute promyelocytic leukaemia (APL) is induced by fusion proteins always implying the retinoic acid receptor RARa. Although PML-RARa and other fusion oncoproteins are able to bind DNA as homodimers, in vivo they are always found in association with the nuclear receptor RXRa (Retinoid X Receptor). Thus, RXRa is an essential cofactor of the fusion protein for the transformation. Actually, RXRa contributes to several aspects of in vivo -transformation: RARa fusion:RXRa hetero-oligomeric complexes bind DNA with a much greater affinity than RARa fusion homodimers. Besides, PML-RARa:RXRa recognizes an enlarged repertoire of DNA binding sites. Thus the association between fusion proteins and RXRa regulates more genes than the homodimer alone. Titration of RXRa by the fusion protein may also play a role in the transformation process, as well as post-translational modifications of RXRa in the complex. Finally, RXRa is required for rexinoid-induced APL differentiation. Thus, RXRa is a key member of the oncogenic complex., (© 2011 médecine/sciences – Inserm / SRMS.)

Nck is an adaptor protein composed of three N-terminal Src Homology (SH) 3 domains followed by a unique C‑terminal SH2 domain. Like other SH2/SH3 domains-containing adaptor proteins, Nck mediates signal transduction from activated cell surface receptors by directing the flow of information to elicit properly orchestrated cell responses. In this way, Nck appears to be unique in its contribution to a wide variety of cellular processes. Moreover, in addition to the typical signal/pY-SH2/SH3-effectors mode of signaling, Nck also transduces signals through an inverse mode of -signaling (signal-SH3/SH2-pY/effectors) and from various cell compartments. Since Nck contributes to important morphogenic and mitogenic processes, deregulated expression of Nck could be detrimental to cellular homeostasis. In agreement, Nck expression has been found upregulated in numerous types of cancer. In this paper we delineate the main molecular -signaling -complexes associated with Nck, focusing on those involved in cancer progression., (© 2011 médecine/sciences - Inserm / SRMS.)

Pancreatic carcinoma is the fifth leading cause of cancer-related mortality. The 5-year overall survival is less than 5 %. This very poor prognosis can be explained both by late diagnosis and by treatment resistance, including resistance to radiation therapy. A better understanding of the pancreatic tumorigenesis and knowledge of the most frequent mutations in pancreatic adenocarcinoma (KRAS, p16, TP53, Smad4) open new perspectives for the development of more effective treatments. This review presents the major genetic and molecular alterations in pancreatic cancer that could be targeted to improve radiosensitization., (Copyright © 2011 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

CYLD deubiquitinase has been originally defined as a tumor suppressor based exclusively on genetic findings. Indeed, inactivation of CYLD in humans results in familial cylindromatosis and multiple trichoepithelioma, two pathologies characterized by the development of tumors originating specifically from the skin appendages. A set of recent publications has revealed that recurrent inactivation of CYLD occurs through diverse mechanisms in several forms of cancer, unequivocally confirming its tumor suppressor function. This property is associated with the critical role played by CYLD in negatively regulating several signaling pathway, among them the NF-κB signaling pathway., (© 2011 médecine/sciences - Inserm / SRMS.)