Ignacio Wistuba M.D.

This grant is being fully funded by the Caine Halter Fund for Lung Cancer Research, through the Uniting Against Lung Cancer Grant Program.

Lay Description

Adenocarcinomas of the lung are pathologically heterogeneous tumors, including the non-invasive bronchioloalveolar (BAC) histology pattern. The BAC component of tumors is considered in most cases a precursor of the invasive adenocarcinoma; however, the supporting molecular evidence remains forthcoming. Lung cancer arising from never smokers seems to be a unique disease with defined clinical and pathological characteristics, including a higher frequency of tumors with BAC histology features. Most importantly, lung adenocarcinomas from never smokers have distinct genetic abnormalities compared with adenocarcinomas arising in smokers. We propose to perform 3 types of studies using lung cancer tissue specimens: 1) Compare the genetic characteristics of lung adenocarcinomas with invasive and non-invasive (BAC) components arising from never smokers versus smokers to understand the genetic abnormalities that may be responsible of the progression (invasion) of tumors in these patients. 2) Study the genetic changes present in the normal lung tissues adjacent to the tumors in never smokers and smokers with lung adenocarcinomas to identify the earliest genetic changes that may be responsible of tumor development in these patients. 3) To establish if the study of genetic changes in multiple tumors arising in the same never smoker or smoker patient will help to identify in these cases the presence of multiple independent tumors or whether they are lung metastases. The diagnosis of multiple independent tumors and lung metastases is important to decide treatment in these patients. In summary, we believe that the results of our studies will improve our pathological understanding and diagnosis of lung adenocarcinoma from never smokers and smokers, evaluate the origin of multiple tumors arising in the same patient, and further our understanding of early detection and prevention strategies.

Scientific Abstract

Most lung adenocarcinomas consist of 2 or more histological subtypes, including the non-invasive bronchioloalveolar (BAC) pattern. It is theorized that adenocarcinomas with BAC features may evolve from pure BAC tumors, representing a paradigm for malignant progression in adenocarcinoma of the lung. However, the supporting molecular evidence remains forthcoming. It is known that lung cancer arising in never smokers is a unique disease with distinct clinicopathologic characteristics, including the predominance of adenocarcinoma histology with BAC pattern and a tendency to develop multiple synchronous tumors. Lung adenocarcinomas arising in never smokers and smokers have distinct molecular abnormalities and are therefore likely to have divergent genetic pathways in pathogenesis. Current information suggests that the precursors of lung cancer are frequently extensive and multifocal throughout the respiratory epithelium, suggestive of a field cancerization effect. We hypothesize that comparison of the molecular and genetic characteristics of lung adenocarcinomas with invasive and non-invasive (BAC) components arising from never smokers versus smokers will show distinct molecular pathways and different distributions of the field cancerization phenomenon in the adjacent respiratory epithelium. To test this hypothesis, we will conduct the following aims: Specific Aim 1: Identify the sequence of molecular and genetic events involved in the invasion process of lung adenocarcinoma by comparing the molecular and genetic abnormalities between the invasive and non-invasive (BAC) components of lung adenocarcinomas arising in never smoker and smoker patients. Specific Aim 2: Identify the molecular and genetic events involved in early pathogenesis of lung adenocarcinomas by comparing the molecular/genetic characteristics of the epithelial field cancerization between lung adenocarcinomas from never smoker and smoker patients. Specific Aim 3: Evaluate the early pathogenesis of multiple synchronous lung adenocarcinomas by identifying the molecular and genetic differences between synchronous lung adenocarcinomas with BAC features and their corresponding adjacent epithelial field. In the above aims, we will examine archived tissue specimens from 216 lung adenocarcinomas with BAC features (105 never smokers) and apply a detailed molecular pathology mapping approach of normal and malignant cells. We will focus on specific targets associated with smoking (e.g., KRAS, LKB1, p16, etc) and non-smoking (e.g., EGFR, HER2, estrogen receptors) cancers. The above studies will improve our pathological classification of these tumors, evaluate the origin of multiple tumors arising in the same patient, and further our understanding of early detection and prevention strategies.