The genetics of lung cancer : a focus in cell differentation, polarity and immunoescape

Orateur : Montserrat SANCHEZ-CESPEDES (Bellvitge Biomedical Research Institute (IDIBELL))

Lung cancer is the first cause of death due to cancer in most western countries, in part because of the low efficacy of most current therapies. The deciphering of some clues of the lung cancer genetics, such as activating alterations at growth factor receptors e.g. EGFR, ALK, ROS and RET, has successfully impacted the treatment of a subset of lung cancer patients. Other recurrent alterations are also known to be important for the development of this disease. Among many others, there are genetic activation of the KRAS and the MYC oncogenes or inac+va+on of the TP53, RB, CDKN2A, LKB1 tumor suppressor genes (TSGs). More recently, the use of deep sequencing technologies is contributing enormously to describe the profile of genetic aberrations in lung cancers, having iden1fied novel lung cancer genes or pinpointed interes1ng candidates. The genes that are altered in cancer lead to the des-regula’on of key regulatory pathways, including cell growth, apoptosis, cell differentiation, among others. Here, I will report our discoveries of some key TSGs involved in lung cancer development and our efforts toward the understanding of the biological consequences of the inactivation of these genes. Previously, we reported that one third of the lung tumors of the non-small cell lung cancer type (NSCLC) endure inactivation of BRG1, which cons"tutes the fourth most common altered gene in this type of cancer. BRG1 codes for a member of the SWI/SNF chroma’n remodeling complex, and its role in cancer development is still poorly understood, which hinders its potential use in clinical settings. We found that BRG1 inactivation enables the cancer cell to sustain undifferentiated gene expression programs and prevents its response to environmental s’muli. I will also report our discovery of biallelic and tumor-specific inactivation of the MYC-associated factor X gene, MAX, in small cell lung cancer (SCLC). Alterations in MAX were mutually exclusive with alterations at MYC and BRG1 and also prevented the expression of cell differentiation-related programs. In addition to the SWI/SNF and MYC/MAX network, the analysis of other TSGs and networks will also be presented. In particular, I will describe the identification of deleterious and biallelic mutations at PARD3 in lung primary squamous cell carcinomas (SCC) and its effects in suppressing the control for cell polarity in SCC’s carcinogenesis. Finally, I will report our data on the whole exome sequencing and RNA-sequencing of lung cancer pa0ents derived xenografits (PDX).

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