Cancer de la peau

Résumé

Les cancers de la peau sont des tumeurs malignes d'histologie variée, développées aux dépens des cellules de la peau. On distingue principalement : les épithéliomes, dérivant du tissu épithélial, eux-mêmes composés de deux grands groupes de carcinomes : le carcinome basocellulaire et le carcinome spinocellulaire ; les mélanomes, développés à partir des cellules næviques, qui peuvent résulter de la transformation d'un nævus ou se développer de novo ; et les sarcomes, développés à partir du tissu conjonctif. Certaines lésions sont précancéreuses ou sont des cancers superficiels comme la maladie de Paget, ou la maladie de Bowen. Enfin, les hémopathies malignes peuvent proliférer dans le tissu cutané, comme la maladie de Kaposi ou les leucémies aiguës. En France, le syndicat national des dermatologues-vénérologues a mis sur pied en 2015 chaque 28 mai une Journée nationale de prévention et de dépistage gratuit des cancers de la peau. En 2015, cette seule journée a permis de dépister 2650 cancers. Depuis 2017, cette journée s'est muée en une "semaine de prévention et de dépistage des cancers de la peau" Le mélanome cutané a vu son incidence et son niveau de la mortalité augmentés sur la période 1980-2012. L'augmentation du nombre de cas est de 2,9 % par an en moyenne chez l’homme et de 1,7 % chez la femme. 15 404 personnes diagnostiquées et 1 783 décès ont été relevés en 2017. L’adoption d'habitudes de prévention telles que le dépistage et la protection contre les UV permettent de réduire les risques. Il y a une association significative entre un apport alimentaire élevé en folate, la consommation d'alcool et un risque accru de carcinome basocellulaire, tandis que la consommation de caféine est associée à un risque plus faible. Les caroténoïdes se sont également avérés bénéfiques pour réduire le risque de carcinome spinocellulaire. Aucune association n'a été trouvée entre l'apport de graisses, de rétinol, de vitamine E, de vitamine D et de sélénium et le risque de cancer de la peau autre que le mélanome, l'acide folique, la caféine, l'alcool et le risque de carcinome spinocellulaire, et l'apport de caroténoïdes et le risque de carcinome basocellulaire.

Source officielle

https://fr.wikipedia.org/wiki/Cancer_de_la_peau

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Publications associées (10)

Personnes associées (1)

Concepts associés (67)

Cours associés (6)

Séances de cours associées (77)

Cancer is the second leading cause of death worldwide. Cancer develops through multiple hallmark functions including apoptosis evasion, unlimited replicative potential, metastasis, and immune avoidance. Over the past few decades, researchers have reported a substantial amount of information about the role of gene expression dysregulation in cancer, whereas transposable elements (TEs) have been overlooked despite the fact they constitute nearly half of the human genome. TEs are DNA repetitive sequences that spread across the genome of living organisms throughout the evolution of species, contributing to genomic diversity and shaping the epigenomic landscape. The vast majority of TEs appear to be transcriptionally silent in adult tissues, thus avoiding deleterious mutational insertions and recombination events in somatic tissues. Due to the global epigenetic dysregulation that occurs during tumorigenesis, some TEs lose repressive marks and become transcriptionally active in cancer cells. Consequently, TE insertions into oncogenes and tumor suppressor genes may occur, thereby contributing to cancer development and disease progression. It is also widely accepted that some TEs harbor transcription factor recognition sites and have regulatory functions on gene expression. Some transcriptionally active TEs can give rise to alternative TE-derived chimeric gene products. Given these facts, integrative transcriptome analysis of TEs and genes may contribute to a better understanding of complex traits of cancer and help to better classify cancer subtypes with clinical implications for patients.To gain insights into the underlying mechanisms of cancer pathogenesis, we constructed a co-expression network based on the similarity in expression levels of TEs and genes. We focused on colorectal cancer (CRC), a heterogeneous disease with different genetic and molecular backgrounds, contributing to patient outcomes and response to therapy. We investigated the coordinated activity of TEs and genes in view of recurrent CRC chromosomal aberrations, genome organization, and functional significance. We further examined co-expression changes in network structure under the contrasting conditions of cancerous versus matched healthy colic mucosal tissues. We found that the cancer network was associated with a dramatic decrease in the number of gene interactions as opposed to an increase in TE interactions. Physical chromosomal distance affects the degree of co-expression, where the proximal distance effect of TE is contrasted with the distant effect of the gene. Our study sheds light on the complex interplay between TEs and genes and how they coordinately shape cancer and normal co-expression networks. Furthermore, we integrated gene and TE expression to develop a new consensus molecular subtype (CMS) classifier derived from multiple layers of TE and gene signatures. We demonstrated that our new approach led to better identification of CRC patients of the former CMS3 subtype, the most heterogeneous subtype with mixed biological characteristics, and a global reduction of the expected misclassification of other CMS subtypes. We further optimized our classifier for potential clinical use and obtained a set of 50 genes and 20 TE integrants with the best ability to identify CMS subtypes. Our integrative model could be a major add on for the development of future clinical trials by improving patient stratification over current gene-restricted molecular classifications.

EPFL2022

Role of Activin-A signaling in melanoma

Olivier Andreas Dubey

Cutaneous melanomas arise from transformed skin melanocytes. While accounting for only 1% of skin malignancies, melanoma is responsible for the majority of skin cancer-related deaths. Owing to lifestyle changes and increased exposure to sunlight, melanoma occurrence is on the rise in developed countries. Identification of the molecular mechanisms driving melanoma formation led to the development of new classes of therapeutics which revolutionized the standard of care. Among these, small molecule inhibitors targeting the MAPK pathway and immune checkpoint inhibitors resulted in unprecedented clinical success. Nevertheless, many patients still do not benefit from these therapies. Activin-A, a secreted ligand of the TGF-Î² superfamily, was recently found to be overexpressed in melanoma. However, whether Activin-A signaling promotes melanoma progression or therapy resistance is unknown. In this thesis, the contributions of autocrine and paracrine Activin-A signaling to melanoma growth are analyzed using lentiviral expression in melanoma cells of a constitutively active mutant type I Activin receptor (caALK4), of secreted Activin-A (gain-of-function), or of a ligand trap (loss-of-function). Paradoxically, while forced ALK4 signaling in melanoma grafts restored tumor suppression by inhibiting tumor cell survival and proliferation, transgenic Activin-A accelerated tumor growth. Conversely, expression of a ligand trap comprising the extracellular domain of Activin receptor IIB fused to human Fc (AIIB-Fc) slowed melanoma growth. Importantly, in immunodeficient Rag1-/- mice, effects of paracrine Activin-A gain and loss-of-function were abrogated, suggesting that Activin-A promotes melanoma progression by inhibiting the adaptive anti-tumor response. Flow cytometry analysis of tumor immune infiltrates combined with antibody-mediated cell depletion experiments confirmed that Activin-A promotes melanoma progression by inhibiting CD8+ tumor-infiltrating lymphocytes (TILs). Furthermore, inhibition of endogenous Activin-A sensitized a treatment-resistant melanoma model to immune checkpoint inhibition by anti-PD1 and anti-CTLA4 antibodies. Activin-A therefore emerges as a promising target to improve immunotherapy outcome in melanoma.

EPFL2019

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Breast cancer is a highly heterogeneous disease. The efficacy of tailored therapeutic strategies relies on the precise detection of diagnostic biomarkers by immunohistochemistry (IHC). Therefore, considering the increasing incidence of breast cancer cases, a concomitantly time-efficient and accurate diagnosis is clinically highly relevant. Microfluidics is a promising innovative technology in the field of tissue diagnostic, enabling for rapid, reliable, and automated immunostaining. We previously reported the microfluidic-based HER2 (human epidermal growth factor receptor 2) detection in breast carcinomas to greatly correlate with the HER2 gene amplification level. Here, we aimed to develop a panel of microfluidic-based IHC protocols for prognostic and therapeutic markers routinely assessed for breast cancer diagnosis, namely HER2, estrogen/progesterone receptor (ER/PR), and Ki67 proliferation factor. The microfluidic IHC protocol for each marker was optimized to reach high staining quality comparable to the standard procedure, while concomitantly shortening the staining time to 16 min-excluding deparaffinization and antigen retrieval step-with a turnaround time reduction up to 7 folds. Comparison of the diagnostic score on 50 formaldehyde-fixed paraffin-embedded breast tumor resections by microfluidic versus standard staining showed high concordance (overall agreement: HER2 94%, ER 95.9%, PR 93.6%, Ki67 93.7%) and strong correlation (rho coefficient: ER 0.89, PR 0.88, Ki67 0.87; p < 0.0001) for all the analyzed markers. Importantly, HER2 genetic reflex test for all discordant cases confirmed the scores obtained by the microfluidic technique. Overall, the microfluidic-based IHC represents a clinically validated equivalent approach to the standard chromogenic staining for rapid, accurate, and automated breast cancer diagnosis.

2019

EPFL2022

Role of Activin-A signaling in melanoma

Olivier Andreas Dubey

EPFL2019