Clinical Significance of EML4-ALK Fusion Gene and Association with EGFR and KRAS Gene Mutations in 208 Chinese Patients with Non-Small Cell Lung Cancer

Abstract

The EML4-ALK fusion gene has been recently identified in a small subset of non-small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of the EML4-ALK fusion gene in Chinese patients with NSCLC are poorly understood. Here, we report on the prevalence of EML4-ALK, EGFR status and KRAS mutations in 208 Chinese patients with NSCLC. EGFR mutations were found in 24.5% (51/208) of patients. In concordance with previous reports, these mutations were identified at high frequencies in females (47.5% vs 15.0% in males; P<0.05); never-smokers (42.3% vs 13.9% in smokers; P<0.05), and adenocarcinoma patients (44.2% vs 8.0% in non-adenocarcinoma patients; P<0.05). There were only 2.88% (6/208) patients with KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208), including 4 cases with variant 3 (57.1%), 2 with variant 1, and 1 with variant 2. All positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female, non-smoking adenocarcinoma patients was as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among the EML4-ALK positive patients. Pathological analysis showed no difference between solid signet-ring cell pattern (4/7) and mucinous cribriform pattern (3/7) in ALK-positive patients. Immunostaining showed intratumor heterogeneity of ALK rearrangement in primary carcinomas and 50% (3/6) of metastatic tumors with ALK-negative staining. Meta-analysis demonstrated that EML4-ALK translocation occurred in 4.84% (125/2580) of unselected patients with NSCLC, and was also predominant in non-smoking patients with adenocarcinoma. Taken together, EML4-ALK translocations were infrequent in the entire NSCLC patient population, but were frequent in the NSCLC subgroup of female, non-smoker, adenocarcinoma patients. There was intratumor heterogeneity of ALK rearrangement in primary carcinomas and at metastatic sites.

Lung Adenocarcinoma in Never Smokers: Problems of Primary Prevention from Aspects of Susceptible Genes and Carcinogens

“…Of these cases, six were non-smokers, and five were found among 33 cases of female non-smokers. EML4-ALK translocation was predominant in never smokers with AC (58).…”

“…Driver genes are of interest as genes related to susceptibility to lung AC in Asian women never smokers from the standpoints of signal transduction for cell proliferation, survival migration and angiogenesis, as well as good treatment response to EGFR-TKIs if EGFR mutation was present (57)(58)(59)(60)(61)(62)(63)(64) (Table I). Driver genes include mutations of EGFR, Kirsten rat sarcoma viral oncogene (KRAS), protooncogene B-Raf (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and fusion of echinoderm microtubule-associated protein-like 4 (EML4) and the intracellular signaling portion of the anaplastic lymphoma kinase (ALK) protein (EML4-ALK).…”

“…Among never smokers with AC, the frequency of EGFR mutation was reported to be 42 ~50% in Asia (57,58,60), and 55% in those of European descent (63), while the frequencies of those with fusion of EML4-ALK, PTEN, PIK3CA, c-MET, KRAS, STK11, and BRAF were 9.3%, 9.1%, 5.2%, 4.8%, 4.5%, 2.7%, and 1.9%, respectively (57). Among smoker patients with AC, the frequency of EGFR mutation was reported to be 22.0% (57) or 10% to 20% (60), while the mutation frequency of STK11 was 19.0%, and of KRAS was 12.0% (57).…”

“…It remains unknown why lung AC is seen in Asian women never smokers (4, 16). Association of EGFR mutation and estrogen receptor (ER)-α and -β with lung carcinogenesis has been reported (93,94 (58). Moreover, human papillomavirus (HPV) infection may be involved in Asian non-smoking lung AC, which responds to EGFR-TKIs (95).…”

Implications of Evolving Medical Science for Proof of Lung Cancer Causation

“…A typical tumor contains two to eight driver mutations that can affect as many as 12 key cellular signaling pathways. Reported genetic alterations for lung adenocarcinoma include: EGFR (32,(42)(43)(44)(45)(46)(47), KRAS (42,(48)(49)(50)(51)(52), BRAF (53)(54)(55)(56), and ERBB2 (formerly HER2) (45, 56-60) driver mutations; ROS1 (32,(61)(62)(63), KIF5b-RET (32,64,65), and EML4-ALK rearrangements (20,45,57,61,(66)(67)(68)(69)(70); and other gene amplifications (20). An estimated 50% of lung adenocarcinomas in patients in Western populations have either an EGFR or KRAS driver mutation (42).…”