AS266 - Serum Levels of EGFR-Signaling-Network Activators/Inhibitor and Lung Cancer Risk

[This page is intended to provide a study summary, the sections of which are below.  Please complete these sections, as applicable.  The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]

Investigator Names and Contact Information

Gloria Ho, Ph.D.  []


Although smoking is the major cause of lung cancer, there remains many gaps in our knowledge of its etiology, which is thought to be heterogeneous by smoking status, gender, and histological subtype.  The purpose of this study is to elucidate the risk factors of lung cancer in these individual subgroups.  We will focus on the serum levels of 6 physiological factors that activate (IGF-I, HGF, NGF, insulin, and IL-6) or inhibit (IGFBP-3) the epidermal growth factor receptor (EGFR) signaling network, which encompasses multiple pathways regulating cell proliferation, survival, and migration.  It will be a nested case-control study with 973 lung cancer cases and 1,126 controls in the WHI Observational Study cohort.  We will examine if serum/plasma levels of the 6 activators/inhibitor are associated with risk of lung cancer, and whether the associations vary depending on smoking status and histological subtype.  The large WHI cohort provides a rare opportunity to study the heterogeneous etiology of lung cancers in subgroups of women.  Identifying susceptibility factors in smokers and risk factors in never-smokers will provide insights into the development of lung cancer screening and prevention programs for women.


Specific Aims

Smoking is the major cause of lung cancer,2 but there remains many gaps in our knowledge of the etiology of lung cancer.  For example, only a minority of smokers develops lung cancer, and the host factors for susceptibility to tobacco carcinogens, in addition to genetic predisposition, remain to be identified.  Moreover, the differences in tumor biology between lung cancers by smoking status, sex, and histological subtype suggest heterogeneity in the etiology by these factors,3-5 and yet few epidemiological studies have focused on these individual subgroups.  This proposed nested case-control study, with a focus on the epidermal growth factor receptor (EGFR) signaling network, aims to address some of these etiological issues.
            Lung cancers are broadly divided histologically into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).  NSCLCs account for about 85% of lung cancers and are further categorized into three major subtypes – adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.  Adenocarcinoma is the most common histological subtype, accounting for about 50% of lung cancers in women.6,7  The vast majority of lung cancers have somatic mutations, and the most frequent ones are mutations in the p53, epidermal growth factor receptor (EGFR), and KRAS genes.8  While mutations in p53 are found in 50-70% of lung cancers regardless of smoking status, EGFR mutations are common in never-smokers,9,10 and KRAS mutations arise almost exclusively in smokers.11  Interestingly, both KRAS and EGFR genes are involved in the EGFR signaling network, suggesting a significant role of this signaling network in lung tumorigenesis in both smokers and never-smokers. 
EGFR is a receptor tyrosine kinase that activates four signaling pathways – Ras/MAPK, STAT, PI3K, and PLCγ which we designate as the EGFR signaling network.  We focus on this signaling network in this proposed study for several reasons.  (1) As mentioned above, two of the most common somatic mutations in lung cancers occur in this signaling network.  (2) These four pathways play an important role in regulating cell proliferation, survival, migration, and differentiation.12  (3) Other than the ligands for EGFR, these four pathways can also be activated by growth factors, proinflammatory cytokines, and hormones through their own receptors (Table 1).13-15  Many of these activators are associated with increased cancer risk in epidemiological studies.16-18  
Table 1: Activators/inhibitor of EGFR signaling pathways examined in this proposed Study


Growth Factors
    Insulin-like growth factor I (IGF-I)
    Hepatocyte growth factor (HGF)
    Nerve growth factor (NGF)
Proinflammatory Cytokine
    Interleukin 6 (IL-6)
Insulin-like growth factor binding protein 3 (IGFBP-3)
            In this proposed study, we will examine lung cancer risk in relation to plasma/serum levels of 5 activators and one inhibitor of the EGFR signaling network (Table 1) and whether these associations vary by smoking status and histological subtype.   It will be a case-control study nested within the Observational Study of the Women’s Health Initiative (WHI-OS).  The 973 cases and 1,126 controls will be matched on smoking status, age, ethnicity, and year when baseline blood sample was collected.  The specific aims are:
(1)    To delineate the associations between risk of lung cancer and plasma/serum levels of signaling-pathway activators and inhibitor (Table 1) by smoking status.  Specifically
(1a)    Among never-smokers, to examine whether increased levels of the signal-transduction activators and decreased levels of the inhibitor are associated with increased risk of lung cancer.  There will be about 153 cases who were never-smokers and 306 controls (1:2 ratio).
        (1b)    Among smokers, to examine if levels of the activators/inhibitor are susceptibility factors for lung cancer given that these women were/had been exposed to tobacco smoke.  Analyses will first be performed in former and current smokers separately.  There will be about 560 cases and 560 controls (1:1 ratio) who were former smokers and 260 cases and 260 controls (1:1 ratio) who were active smokers.
        (1c)    To test for multiplicative interactions between smoking and the signal-transduction activators/inhibitor – i.e., to examine whether the associations between lung cancer and the signaling activators/inhibitor are heterogeneous depending on smoking status (never, past, current) and number of pack-years smoked.
(2)    To study if plasma/serum levels of the signal-transduction activators/inhibitor are associated with different histological subtypes of lung cancer.  Particularly, we will examine SCLCs and NSCLCs as well as various types of NSCLCs (adenocarcinoma, squamous cell carcinoma, and other NSCLCs).

We are aware that a lung cancer study entitled “Interaction Effects of Genes in the Inflammatory Pathway and Dietary, Supplement, and Medication Exposures on General Cancer Risk (BAA06),”  is being conducted by Dr. Jianfeng Xu.  In BAA06, 500 lung cancer cases and 500 controls were genotyped for about 9,000 SNPs in 1,000 genes involved in immunity and inflammation.  Genes in three of the four EGFR signaling pathways (Ras/MAPK, PI3K, and STAT) were genotyped in BAA06, but only 3 genes that are relevant to this proposed study were significantly associated with lung cancer (Dr. Xu, personal communication).  We do not plan to genotype these 3 genes in the additional cases and controls, who were not already included in BAA06, to examine for interaction between these genes and the activators/inhibitor proposed here. 

Plasma levels of C reactive protein (CRP) and TNF-α were also assayed in BAA06.  The results of these 2 inflammation markers are not available at this time, but they are irrelevant to this proposed study.  TNF-a does not signal through any of the 4 EGFR pathways.  Although CRP is induced by IL-6, they have distinct bioactivities.  Therefore, one can not make any inference about our study hypothesis regarding IL-6 based on the associations of CRP and TNFa with lung cancer. 




1.       Singh AB and Harris RC, Autocrine, paracrine and juxtacrine signaling by EGFR ligands. Cellular Signalling  17:1183-93,2005.
2.       Khuder SA, Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer  31:139-48,2001.
3.       Muscat JE and Wynder EL, Lung cancer pathology in smokers, ex-smokers and never smokers. Cancer Letters  88:1-5,1995.
4.       Patel JD, Bach PB, and Kris MG, Lung cancer in US women: a contemporary epidemic. Jama  291(14):1763-8,2004.
5.       Belani CP, Marts S, Schiller J, et al., Women and lung cancer: epidemiology, tumor biology, and emerging trends in clinical research. Lung Cancer  55(1):15-23,2007.
6.       Brambilla E, Travis WD, Colby TV, et al., The new World Health Organization classification of lung tumours. Eur Respir J  18(6):1059-68,2001.
7.       Sun S, Schiller JH, and Gazdar AF, Lung cancer in never smokers--a different disease. Nat Rev Cancer  7(10):778-90,2007.
8.       Fong KM, Sekido Y, Gazdar AF, et al., Lung cancer. 9: Molecular biology of lung cancer: clinical implications. Thorax  58(10):892-900,2003.
9.       Sun L and Carpenter G, Epidermal growth factor activation of NF-kB is mediated through IkBa degradation and intracellular free calcium. Oncogene  16:2095-102,1998.
10.      Shigematsu H and Gazdar AF, Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer  118(2):257-62,2006.
11.      Nelson HH, Christiani DC, Mark EJ, et al., Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst  91(23):2032-8,1999.
12.      Jorissen RN, Walker F, Pouliot N, et al., Epidermal growth factor receptor: mechanisms of activation and signalling. Experimental Cell Research  284:31-53,2003.
13.      Heinrich PC, Behrmann I, Haan S, et al., Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemistry Journal  374:1-20,2003.
14.      Siddle K, Ursø B, Niesler CA, et al., Insulin action. Biochemical Society Transactions  29:513-25,2001.
15.      Karamouzis MV and Papavassiliou AG, The IGF-1 network in lung carcinoma therapeutics. Trends in Molecular Medicine  12:595-602,2006.
16.      Renehan AG, Zwahlen M, Minder C, et al., Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis. Lancet  363:1346-53,2004.
17.      Gunter MJ, Hoover DR, Yu H, et al., A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev  17:921-9,2008.
18.      Gunter MJ, Hoover DR, Yu H, et al., Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res  68(1):329-37,2008.