Author of

• 17153

  +

  MTE10 - Unique Biologic Aspects of Tobacco-Induced Lung Cancer (Ticketed Session) (ID 304)

  • Event: WCLC 2016
  • Type: Meet the Expert Session (Ticketed Session)
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 07:30 - 08:30, Schubert 1

  • 17154

    +

    MTE10.01 - Unique Biologic Aspects of Tobacco-Induced Lung Cancer (ID 6557)

    07:30 - 08:30  |  Author(s): M.G. Papotti
    • Abstract
    • Presentation
    • Slides

    Abstract:
    Lung cancer is the leading cause of cancer death worldwide and cigarette smoking is a major causative environmental factor. Some unique biologic profiles are associated to tobacco-induced lung cancer, including clinical, pathological and genetic features. Lung cancer in never smokers (up to 20% of cases worldwide) has been suggested to represent a distinct disease, compared to tobacco-induced lung cancer. Cigarette smoke is a mixture of more than 5000 chemical compounds, among which more than 60 are recognized to have a specific carcinogenic potential. Carcinogens and their metabolites (i.e., N-nitrosamines and polycyclic aromatic hydrocarbons, among others) can activate multiple pathways, contributing to pulmonary cell transformation in different ways. Nicotine, originally thought to be responsible for tobacco addiction, only, is also involved in tumor promotion and progression with anti-apoptotic and indirect mitogenic properties (Tonini et al. Future Oncol 2013;9:649-55). Preclinical models were employed to define epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. In a study, smoke condensate significantly repressed miR-487b, that directly targets several genes, including SUZ12, BMI1, WNT5A, MYC, and KRAS. Such repression correlated with overexpression of the above targets in lung cancer and coincided with DNA methylation within the miR-487b genomic locus, indicating this molecule as a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis. These findings may potentially pave the way for DNA demethylating agent treatment, in order to re-activate miR-487b in lung cancer therapy (Xi et al. JCI 2013; 123:1241-61). Among other effects of cigarette smoking, a synergy was described with the aryl hydrocarbon receptor (AHR), which is partially responsible for tobacco-induced carcinogenesis through incompletely understood mechanisms. It was reported that smoking induces AHR activating ligands, which in turn induced adrenomedullin both in vitro and in vivo, thus significantly contributing to the carcinogenicity of tobacco-activated AHR. These effects were not reproduced in fibroblasts and mice lacking the aryl hydrocarbon receptor (Portal-Nuñez et al. Cancer Res 2012; 72:5790-800). Genetic factors involved in tobacco-induced lung cancers have been widely investigated to determine the genetic susceptibility to lung cancer, including epigenomic alterations (Fujimoto et al. PlosOne 2010;5:e11847. Liu et al. Oncogene 2010;29:3650-64). In addition, tobacco-induced lung cancer is characterized by a deregulated inflammatory microenvironment (Spitz et al. Cancer Epidemiol Biomark Prev 2012; 21:1213-21). Therefore variants in inflammation pathway associated genes, as well as a number of genetic polymorphisms have been identified as putative candidates predisposing to lung cancer development. The effects of single polymorphisms on lung cancer development risk have been investigated, with inconsistent results. Most currently identified polymorphisms involve genes encoding proteins associated with the metabolic processing of tobacco smoke carcinogens and the repair of mutations induced by those carcinogens. Polymorphisms on chromosomes 5p15.33, 6p21, and 15q24-25.1 were identified, being the former specifically associated to a higher risk for adenocarcinoma (Yokota et al. Adv Cancer Res 2010;109:51-72). Regarding inflammation genes, analyzing a comprehensive panel of over 11,000 inflammation pathway single-nucleotide polymorphisms (SNP), six SNPs were significantly (p < 0.05) associated to a higher risk of lung cancer development, including two SNP variants in former smokers (BCL2L14) and in current smokers (IL2RB) (Spitz et al. Cancer Epidemiol Biomark Prev 2012; 21:1213-21). The above genetic alterations are observed in all histological subtypes of lung cancer with several differences, especially between small cell lung carcinoma (and the other neuroendocrine tumors) and non-small cell lung cancers. Though all lung cancers are generally tobacco related, changes of incidence of different histological types (with an increase of adenocarcinoma in both sexes) are well known, reflecting modifications of smoking habits, cigarette types, filter types and content of tar, among others. Wide sequencing of single cancer histotypes has provided a relatively complete map of most common alterations in each tumor. In adenocarcinoma, a mean exonic somatic mutation rate of 12.0 events/megabase was identified, which included most previously reported genes in adenocarcinoma as significantly mutated, as well as recurrent mutations in U2AF1, RBM10 and ARID1A genes, and structural rearrangements within EGFR and SIK2 kinases (Imielinski et al. Cell 2012; 150, 1107–1120). Regarding squamous cell carcinoma, the Cancer Genome Atlas Network profiled 178 tumors and found complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor. Recurrent mutations were found in 11 genes, with TP53 mutations occurring in nearly all specimens and novel alterations affecting a proportion of cases, including HLA-A class I major histocompatibility gene, NFE2L2, KEAP1, phosphatidylinositol-3-OH-kinase pathway genes, CDKN2A, RB1 and specific squamous differentiation genes (Cancer Genome Atlas Res Network. Nature 2012;489:519-525). As far as small cell lung cancer is concerned, high mutation rates (up to 8.6 non-synonymous mutations per million base pairs) were identified. Of these, up to 28% were found to be C:G>A:T transversions, a type of alteration associated to heavy smoking, although the smoking history was not correlated with the type and number of mutations. Other genes exhibiting mutations and inactivating translocations included the histone acetyltransferase genes CREBBP and EP300, genes with functional roles in the centrosome (ASPM, ALMS1 and PDE4DIP), in the RNA-regulating gene XRN1 and the tetraspanin gene PTGFRN. Damaged genes were commonly found, including the known TP53, RB1, but also TP73, CREBBP and COL22A1, as well as FMN2 and NOTCH family genes (mostly inactivation in the latter) (George et al. Nature 2015; 524: 47–53). Whether the identified genetic signatures and peculiar biological features will produce a corresponding reproducible therapeutic “signature” is still not the case, but the way is paved for stratifying patient groups based on their unique pathological and genetic tumor characteristics, among different histotypes and also within individual neoplastic variants. The future challenge will be to define the biological profile of immunocheckpoint molecule expression in tobacco related lung cancers, in order to identify a reliable predictive marker of response to treatments targeting PD1 or PDL1, in relationship with the different mutational burden and immunological status of individual cases.
    
    

    Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

    Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.