GAB2 Amplification in Squamous Cell Lung Cancer of Non-Smokers

Abstract

Lung squamous cell cancer (SCC) is typically found in smokers and has a very low incidence in non-smokers, indicating differences in the tumor biology of lung SCC in smokers and non-smokers. However, the specific mutations that drive tumor growth in non-smokers have not been identified. To identify mutations in lung SCC of non-smokers, we performed a genetic analysis using arrays comparative genomic hybridization (ArrayCGH). We analyzed 19 patients with lung SCC who underwent surgical treatment between April 2005 and April 2015. Clinical characteristics were reviewed, and DNA was extracted from fresh frozen lung cancer specimens. All of copy number alterations from ArrayCGH were validated using The Cancer Genome Atlas (TCGA) copy number variation (CNV) data of lung SCC. We examined the frequency of copy number changes according to the smoking status (non-smoker [n = 8] or smoker [n = 11]). We identified 16 significantly altered regions from ArrayCGH data, three gain and four loss regions overlapped with the TCGA lung squamous cell carcinoma (LUSC) patients. Within these overlapped significant regions, we detected 15 genes that have been reported in the Cancer Gene census. We also found that the proto-oncogene GAB2 (11q14.1) was significantly amplified in non-smokers patients and vice versa in both ArrayCGH and TCGA data. Immunohistochemical analyses showed that GAB2 protein was relatively upregulated in non-smoker than smoker tissues (37.5% vs. 9.0%, P = 0.007). GAB2 amplification may have an important role in the development of lung SCC in non-smokers. GAB2 may represent a potential biomarker for lung SCC in non-smokers.

Non-Smoking-Associated Lung Cancer: A distinct Entity in Terms of Tumor Biology, Patient Characteristics and Impact of Hereditary Cancer Predisposition

“…More than 85% of lung cancer cases are related to a positive history of smoking (i.e., smoking-related or smoking-associated lung cancer). Smoking leads to an accumulation of genetic alterations in oncogenes and tumor suppressor genes ultimately causing cancer [4]. Previous reports and literature reviews have addressed the topic of lung cancer in non- and never-smokers [5,6,7,8,9,10,11,12], and here we aim at providing a more updated review by going into detail also with molecular, immunological and genetic aspects.…”

“…The main reason for the favorable outcome in non-smokers is the occurrence of certain molecular subtypes (oncogene-addicted lung cancer), enabling the specific treatment with Previous epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) or other agents [19,20]. Such genetic alterations and patterns of mutation that are specific for lung cancer have primarily been outlined for AC, whereas no genetic mutations have been linked to squamous cell carcinoma (SCC) specifically, especially not for non-smokers [4].…”

Inherited lung cancer: a review

“…The study identified significant familial clustering among tobacco-related cancers, such as cancers of the lung, larynx, lip and cervix, which was attributable to shared environmental factors potentially associated with genetic susceptibility. The authors also reported a greater RR for female relatives of female probands than for male relatives of male probands [11,19]. The Swedish study showed that the risk of lung cancer in first-degree relatives of 88,589 lung cancer cases was increased by 1.9 times (95% CI 1.6-2.4), similar to that of other common cancers with well-known genetic components, including breast (λ = 1.5) and colon (λ = 1.9) cancers.…”

“…Squamous cell carcinoma, which is usually more prevalent among smokers, also may have a genetic trigger in non-smokers. In 2017, to better understand tumour growth, Park and colleagues [19] analysed the genetic profile of squamous cell carcinoma in non-smokers using comparative genomic hybridisation arrays. They found that the proto-oncogene GAB2 (11q14.1) was frequently amplified in these patients and was likely to contribute to disease development [19].…”

Integrated analysis of genomic and transcriptomic profiles identified a prognostic immunohistochemistry panel for esophageal squamous cell cancer

“…Protein is the ultimate performer of multiple biological functions, and the relationships between abnormal expressed proteins and cancer have been widely studied . Previous studies have reported the vital effect of multiple somatic genetic alterations in the development of cancers, in which copy number variations (CNVs) of DNA are closely related to abnormal expression of protein and can be used for the selection of prognostic biomarkers in malignant tumors . In addition, other studies have aimed to identify potential prognostic proteins based on altered transcriptomic levels .…”