IP: Dra. Maria Teresa Landi

Resumen del proyecto: Lung cancer in never smokers includes approximately 10-25% of all lung cancers worldwide, ranks among the most common causes of cancer mortality, and has a distinct natural history, restricted histological subtype (almost exclusively adenocarcinoma), likely different profile of oncogenic mutations, and response to targeted therapy compared to lung cancer in smokers. Although few risk factors are known to contribute to the etiology of lung cancer in never smokers, a large fraction of cancer cases cannot be explained by established environmental and genetic risk factors, highlighting the need for research in this area. One promising approach to identify the etiological factors involved in lung tumorigenesis in never smokers is based on the study of the “mutational signatures” that the exogeneous and endogenous processes leave on the tumor tissue and surrounding areas. This approach has identified over 50 different mutational signatures in other cancer types to date, corresponding to several oncogenic processes. We plan to conduct an integrative genomic analysis of mutational signatures in tumors and surrounding non-tumor (“normal”) lung tissue from 2,000 never smokers. The study subjects will include a subset of “special exposure cases” exposed to high levels of known risk factors for lung cancer (n=~500) and cases from the “general population” without known risk factors (n=~1,500). Never smoker subjects will be drawn from studies with lung tissue samples and high-quality epidemiological and clinical data. We will strive to include subjects from many geographical areas and ethnic groups to study the contribution of different germline and environmental factors. The tumor/normal genomics analysis will include whole genome sequencing, RNA sequencing, and genome-wide methylation arrays. The integrated molecular landscape will be ordered along the evolutionary trajectory of the tumors to infer the cascade of events leading to tumor formation and progression. Data on the molecular and evolutionary landscape will be combined with data from the histological examination of H&E slides from multiple tissue blocks per tumor and related to CT-scan imaging to provide a more refined classification of lung cancers among never smokers. We plan to conduct a stratified analysis of tumors based on mutations in EGFR or other mutually exclusive genes in the RTK-RAS pathway (e.g., ALK and MET) to possibly identify distinct etiological processes between tumors with and without RTK-RAS mutations or fusions. Additional studies will include lineage phylogenetic analysis to infer the clonal evolution of lung tumors using multi-region tumor sampling; deep target sequencing of cancer driver genes and ultra-low pass whole genome sequencing of cell-free circulating tumor DNA; tumor microenvironment analyses based on immunohistochemistry or fluorescence-based imaging and RNA sequencing; and analyses of large-scale electronic medical records.

Entidad financiadora: National Cancer Institute (NCI); EEUU.