Elsevier

Lung Cancer

Volume 102, December 2016, Pages 122-134
Lung Cancer

Review
Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers

https://doi.org/10.1016/j.lungcan.2016.10.010Get rights and content

Highlights

  • Increased odds of EGFR in adenocarcinomas compared to non-small cell lung cancer.

  • Increased odds of ALK-EML4 in adenocarcinomas compared to other lung cancers.

  • Increased odds of EGFR and ALK-EML4 in never smokers compared to ever smokers.

  • EGFR mutations was higher in Asian women compared to other ethnicities.

  • Never smokers had a decreased odds of KRAS mutations among ethnicities.

Abstract

Lung cancer is the leading cause of cancer-related mortality. While the majority of lung cancers are associated with tobacco smoke, approximately 10–15% of U.S. lung cancers occur in never smokers. Evidence suggests that lung cancer in never smokers appears to be a distinct disease caused by driver mutations which are different than the genetic pathways observed with lung cancer in smokers. A meta-analysis of human epidemiologic data was conducted to evaluate the profile of common or therapy-targetable mutations in lung cancers of never and ever smokers. Epidemiologic studies (N = 167) representing over 63,000 lung cancer cases were identified and used to calculate summary odds ratios for lung cancer in never and ever smokers containing gene mutations: EGFR, chromosomal rearrangements and fusion of EML4 and ALK, and KRAS. This analysis also considered the effect of histopathology, smoking status, sex, and ethnicity. There were significantly increased odds of presenting the EGFR and ALK-EML4 mutations in 1) adenocarcinomas compared to non-small cell lung cancer and 2) never smokers compared to ever smokers. The prevalence of EGFR mutations was higher in Asian women as compared to women of Caucasian/Mixed ethnicity. As the smoking history increased, there was a decreased odds for exhibiting the EGFR mutation, particularly for cases >30 pack-years. Compared to ever smokers, never smokers had a decreased odds of KRAS mutations among those of Caucasian/Mixed ethnicity (OR = 0.22, 95% CI: 0.17–0.29) and those of Asian ethnicity (OR = 0.39, 95% CI: 0.30–0.50). Our findings show that key driver mutations and several patient features are highly prevalent in lung cancers of never smokers. These associations may be helpful as patient demographic models are developed to predict successful outcomes of targeted therapeutic interventions NSCLC.

Introduction

Lung cancer is the leading cause of cancer-related mortality, with approximately 1.38 million deaths occurring annually worldwide [1]. Although the majority of lung cancers are believed to be associated with exposure to tobacco smoke, available data suggest that approximately 25 percent of worldwide lung cancers and 10 to 15 percent of U.S. lung cancers have occurred in lifelong non-smokers [1], [2], [3], [4], [5]. A number of factors have been associated with increased risk of lung cancer in never-smokers, including environmental and occupational exposures, genetic alterations, and medical history [6], [7], [8].

Lung cancer is comprised of two morphological groups, small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is further grouped into sub-types including large cell carcinoma (LCC), squamous cell lung cancer (SC), and adenocarcinoma (AC) [8], [20]. Over 65 percent of never smoking lung cancer patients are diagnosed with adenocarcinoma [8], [9]. Lung cancer in never smokers appear to be a distinct disease with separate genetic pathways that are caused by discrete mutations in tumor promoting genes (i.e. driver mutations), unlike the genetic changes observed in the lung cancer in smokers [1], [5], [10], [11], [12]. Certain somatic mutations, or acquired mutations in (oncogenic) or tumor promoting genes, are found more frequently in the tumors of lung cancers from never smokers compared with ever smokers [4]. For example, mutations in the epidermal growth factor receptor genes (EGFR) are found in approximately 40 percent of never smokers; this frequency is as low as 28 percent in American never smokers and as high as 68 percent in Asian never smokers [1], [2], [4], [13]. EGFR, a receptor tyrosine kinase, plays a critical role in development, cell differentiation, proliferation and maintenance in both physiologically normal and cancerous conditions [14]. EGFR is a common target for mutations and abnormal activation in the first four exons (18–21) encoding the tyrosine kinase (TK) domain in NSCLCs. Deletion mutations in exon 19 and point mutations at codon 858 in exon 21 are most prevalent and have been utilized as predictors of therapeutic intervention and sensitivity [14], [15], [16].

Mutations in oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) occur in 15–30% of NSCLCs and approximately 97% of NSCLCs involve point mutations in codons 12 or 13 in exon [14]. KRAS encodes GTPase activity in proteins that regulate cell growth, differentiation, and apoptosis and serves as a downstream mediator of EGFR-induced cell signaling and chromosomal translocations and rearrangements in anaplastic lymphoma receptor tyrosine kinase (ALK) genes. Mutations in KRAS and ALK have been observed at differing rates in never- and ever-smokers [1], [2], [4], [14], [17]. Some solid tumors, such as NSCLCs, initiate ALK signaling by creating distinctive oncogenic fusion of the ALK gene at chromosomal locus 2p23 through chromosomal translocations that result in oncogenic fusion genes leading to constitutive activation of the ALK kinase domain [18]. Recent studies suggest that therapeutic targeting of one or more of these driver mutations can be useful to halt cancer progression and improve survival in NSCLCs patients [19], [20], [21].

Previous studies investigated the prevalence of EGFR mutations and ALK rearrangements among lung cancer patients and observed that both types of genetic events are more frequent in women, adenocarcinomas, and patients of East Asian ethnicity [4], [10], [22], [23]. Though these trends are consistent, some investigators have questioned whether or not the association of EGFR with the female gender may be more related to other factors; for example, women generally smoke fewer cigarettes than men and are more frequently diagnosed with adenocarcinomas [24]. To quantify the relationships between smoking histories, pathological characteristics of the lung cancer, and the prevalence of key mutations, we conducted a meta-analysis of human epidemiologic data to evaluate the profile of common or therapy-targetable mutations.

Section snippets

Literature search, study selection, and data extraction

The meta-analysis described herein adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [25]. We performed a comprehensive literature search of the PubMed database for English-language articles published through July 10, 2015, with no lower date truncation, that evaluated EGFR, KRAS, and/or ALK status in lung tumors of never smokers and/or ever smokers. Both clinical and observational human studies were considered. Using AND operators, keywords

Results

Our analysis comprised a robust assessment of the influence of patient characteristics and smoking status on the mutational profile of EGFR, ALK, and KRAS in never and ever smokers. Over 200 epidemiological studies were reviewed and 167 were included in our meta-analysis, which represented over 63,000 lung cancer cases. The mutation patterns of EGFR, ALK, and/or KRAS were significantly different across certain patient features (e.g., sex, ethnicity, histologic lung cancer type) and smoking

Discussion

We investigated the importance of key driver mutations and the association of several patient features, such as ethnicity, gender, sex, smoking history, and histological tumor type, with the prevalence of lung cancers in never smokers compared to ever smokers. This meta-analysis demonstrates that the mutation pattern of lung cancer in never smokers is distinct and separate from that observed in lung cancer patients of smokers. EGFR mutations were more prevalent in female Asian never smokers

Conflict of interest statement

The authors report no conflicts of interest. Funding for this manuscript was provided entirely by Cardno ChemRisk, LLC, a consulting firm that provides scientific advice to the government, corporations, law firms, and various scientific/professional organizations. This paper was prepared and written exclusively by the authors without review or input by any outside sources.

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