BA17 - Proteomics-based Discovery of Blood-based Biomarkers and Risk Factors for Lung Cancer among Women Smokers and Never-smokers

This page provides study documentation for AS191.  For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Samir Hanash, MD, PhD


Lung cancer is the leading cause of cancer death in the world1. While most cases are attributable to smoking, a significant percentage of female cases, that in some countries is as high as 80%, are not attributable to smoking1-3. Based on 2006 estimates, in the U.S. 10% of lung cancer diagnosed among men (9,270 cases) and 15% (12,265 cases) to 25% (20,442 cases) of those diagnosed among women occur among never smokers4-9. The incidence of lung cancer among never smokers ranges from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men9. Lung cancer among never smokers also accounts for a significant proportion of lung cancer deaths. Approximately 15% to 20% (17,000 to 26,000 cases per year) of all lung cancer deaths occur in never smokers10.

Despite these statistics, very few lung cancer studies have focused on never smokers. It is particularly unfortunate that despite having never smoked, patients with lung cancer who are never smokers often are viewed as if their cancer is somehow related to personal habits and their particular cancer type is not well investigated. Very few studies have systematically searched for differences and similarities, at the biological and molecular levels, between lung cancers among never smokers and smokers. There are several reasons for considering lung cancer among never smokers as a complex disease that likely has different etiology and biology in comparison to lung cancer occurring among smokers11. First as stated, lung cancer among never smokers occurs more frequently among women. Data from six large cohort studies that evaluated over 1.5 million people indicate that lung cancer incidence among never smoker women may be twice as high as among never smoker men9. Second, unlike lung cancer among smokers in most of the world, adenocarcinoma is the predominant cell type of lung cancer occurring among never smokers (60% to 70%)12. Third, lung cancer among never smokers may be unique at the molecular genetics level13,14. Given the considerable public health importance of lung cancer as the second most commonly diagnosed cancer and the most common cause of cancer death among U.S. women, we believe there is ample justification for a study that takes advantage of the WHI resources to discover both lung cancer early detection and risk prediction biomarkers using preclinical samples, and to compare these biomarkers among lung cancer cases who were either smokers or never smokers.
The principal objectives of this project are:
1)    To discover and compare lung cancer early detection candidate biomarkers among smokers and never smokers using WHI blood specimens collected before a diagnosis of lung cancer. This analysis will involve lung cancer cases diagnosed within two years following a study blood draw. Controls will be matched to cases on age, smoking status, race/ethnicity, and timing of blood draw. Candidate biomarkers will be identified using in-depth quantitative proteomics analysis of plasma.
2)    To discover and compare biomarkers of lung cancer risk among smokers and never smokers. This analysis will involve lung cancer cases whose blood was collected >2 and <6 years prior to their lung cancer diagnosis. Controls will be matched to cases on age, smoking status, race/ethnicity, clinical center, and timing of blood draw. Candidate proteins identified will be compared with the list of candidate biomarker identified in objective (i) and will be analyzed with respect to their role and involvement in functional pathways.
Important secondary objectives include:
3)    Testing the hypothesis that changes in plasma proteins reflective of inflammation and sub-clinical lung disease are detectable prior to diagnosis, the severity and type of which may be indicative of an increased risk for lung cancer; and that alterations in processes related to angiogenesis, growth factors, cytokines and other signaling molecules are detectable among both smokers and never smokers that developed lung cancer.
4)    Testing the hypothesis that hormonal effects in particular effects related to estrogen may account for the development of lung cancer among women smokers and/or women who never smoked.
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13.   Sonobe, M., Manabe, T., Wada, H. & Tanaka, F. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 93, 355-363 (2005).
14.   Shigematsu, H., et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97, 339-346 (2005).