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Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.

Zhang X, Zhang S, Yang X, Yang J, Zhou Q, Yin L, An S, Lin J, Chen S, Xie Z, Zhu M, Zhang X, Wu YL - Mol. Cancer (2010)

Bottom Line: Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer.However, expression of EML4 did not differ between the groups.RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK-positive patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Lung Cancer Institute, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.

ABSTRACT

Background: The anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer. Fusion partners of ALK include NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC. Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer.

Results: RACE-coupled PCR sequencing was used to assess ALK fusions in a cohort of 103 non-small cell lung carcinoma (NSCLC) patients. Within this cohort, the EML4-ALK fusion gene was identified in 12 tumors (11.6%). Further analysis revealed that EML4-ALK was present at a frequency of 16.13% (10/62) in patients with adenocarcinomas, 19.23% (10/52) in never-smokers, and 42.80% (9/21) in patients with adenocarcinomas lacking EGFR and KRAS mutations. The EML4-ALK fusion was associated with non-smokers (P = 0.03), younger age of onset (P = 0.03), and adenocarcinomas without EGFR/KRAS mutations (P = 0.04). A trend towards improved survival was observed for patients with the EML4-ALK fusion, although it was not statistically significant (P = 0.20). Concurrent deletion in EGFR exon 19 and fusion of EML4-ALK was identified for the first time in a Chinese female patient with an adenocarcinoma. Analysis of ALK expression revealed that ALK mRNA levels were higher in tumors positive for the EML-ALK fusion than in negative tumors (normalized intensity of 21.99 vs. 0.45, respectively; P = 0.0018). However, expression of EML4 did not differ between the groups.

Conclusions: The EML4-ALK fusion gene was present at a high frequency in Chinese NSCLC patients, particularly in those with adenocarcinomas lacking EGFR/KRAS mutations. The EML4-ALK fusion appears to be tightly associated with ALK mRNA expression levels. RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK-positive patients.

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Kaplan-Meier survival curve, stratified by ALK fusion status. Percent survival of patients with and without ALK fusions was plotted versus the number of months after surgery. Prior to the date of article submission, the ALK fusion-positive patients (n = 12) did not have enough events to determine the median overall survival, while the ALK fusion-negative patients (n = 101) had a median overall survival of 50.5 months. The hazard ratio for death in the ALK fusion-positive group was 0.54 (95% CI, 0.23-1.26). The log-rank (Mantel-Cox) test had a chi-squared value of 2.33 (P = 0.15).
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Figure 4: Kaplan-Meier survival curve, stratified by ALK fusion status. Percent survival of patients with and without ALK fusions was plotted versus the number of months after surgery. Prior to the date of article submission, the ALK fusion-positive patients (n = 12) did not have enough events to determine the median overall survival, while the ALK fusion-negative patients (n = 101) had a median overall survival of 50.5 months. The hazard ratio for death in the ALK fusion-positive group was 0.54 (95% CI, 0.23-1.26). The log-rank (Mantel-Cox) test had a chi-squared value of 2.33 (P = 0.15).

Mentions: To our knowledge, this is the first patient identified with a concurrent EGFR exon 19 deletion and the EML4-ALK fusion translocation. The concurrent mutations occurred in a female, non-smoking Chinese patient with a histological adenocarcinoma. EML4-ALK was significantly associated with non-smoking (P = 0.03). Patients with ALK fusions exhibited a significantly decreased number of smoking pack-years (5.0 vs. 18.5; P < 0.01) and were younger (53 vs. 61; P = 0.03) compared with patients without the fusion gene. No mutation in the kinase domain of ALK was detected by sequencing samples from the first group of 50 NSCLC cases collected consecutively (data not shown). Thus, mutation of ALK in NSCLC likely either does not occur or is rare. A trend towards improved survival was observed in the EML4-ALK cohort, though this was not statistically significant (P = 0.15; Fig. 4). ALK fusion-positive NSCLCs exhibited a hazard ratio of 0.54 (95% CI, 0.23-1.26) for overall survival.


Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.

Zhang X, Zhang S, Yang X, Yang J, Zhou Q, Yin L, An S, Lin J, Chen S, Xie Z, Zhu M, Zhang X, Wu YL - Mol. Cancer (2010)

Kaplan-Meier survival curve, stratified by ALK fusion status. Percent survival of patients with and without ALK fusions was plotted versus the number of months after surgery. Prior to the date of article submission, the ALK fusion-positive patients (n = 12) did not have enough events to determine the median overall survival, while the ALK fusion-negative patients (n = 101) had a median overall survival of 50.5 months. The hazard ratio for death in the ALK fusion-positive group was 0.54 (95% CI, 0.23-1.26). The log-rank (Mantel-Cox) test had a chi-squared value of 2.33 (P = 0.15).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908583&req=5

Figure 4: Kaplan-Meier survival curve, stratified by ALK fusion status. Percent survival of patients with and without ALK fusions was plotted versus the number of months after surgery. Prior to the date of article submission, the ALK fusion-positive patients (n = 12) did not have enough events to determine the median overall survival, while the ALK fusion-negative patients (n = 101) had a median overall survival of 50.5 months. The hazard ratio for death in the ALK fusion-positive group was 0.54 (95% CI, 0.23-1.26). The log-rank (Mantel-Cox) test had a chi-squared value of 2.33 (P = 0.15).
Mentions: To our knowledge, this is the first patient identified with a concurrent EGFR exon 19 deletion and the EML4-ALK fusion translocation. The concurrent mutations occurred in a female, non-smoking Chinese patient with a histological adenocarcinoma. EML4-ALK was significantly associated with non-smoking (P = 0.03). Patients with ALK fusions exhibited a significantly decreased number of smoking pack-years (5.0 vs. 18.5; P < 0.01) and were younger (53 vs. 61; P = 0.03) compared with patients without the fusion gene. No mutation in the kinase domain of ALK was detected by sequencing samples from the first group of 50 NSCLC cases collected consecutively (data not shown). Thus, mutation of ALK in NSCLC likely either does not occur or is rare. A trend towards improved survival was observed in the EML4-ALK cohort, though this was not statistically significant (P = 0.15; Fig. 4). ALK fusion-positive NSCLCs exhibited a hazard ratio of 0.54 (95% CI, 0.23-1.26) for overall survival.

Bottom Line: Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer.However, expression of EML4 did not differ between the groups.RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK-positive patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Lung Cancer Institute, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.

ABSTRACT

Background: The anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer. Fusion partners of ALK include NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC. Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer.

Results: RACE-coupled PCR sequencing was used to assess ALK fusions in a cohort of 103 non-small cell lung carcinoma (NSCLC) patients. Within this cohort, the EML4-ALK fusion gene was identified in 12 tumors (11.6%). Further analysis revealed that EML4-ALK was present at a frequency of 16.13% (10/62) in patients with adenocarcinomas, 19.23% (10/52) in never-smokers, and 42.80% (9/21) in patients with adenocarcinomas lacking EGFR and KRAS mutations. The EML4-ALK fusion was associated with non-smokers (P = 0.03), younger age of onset (P = 0.03), and adenocarcinomas without EGFR/KRAS mutations (P = 0.04). A trend towards improved survival was observed for patients with the EML4-ALK fusion, although it was not statistically significant (P = 0.20). Concurrent deletion in EGFR exon 19 and fusion of EML4-ALK was identified for the first time in a Chinese female patient with an adenocarcinoma. Analysis of ALK expression revealed that ALK mRNA levels were higher in tumors positive for the EML-ALK fusion than in negative tumors (normalized intensity of 21.99 vs. 0.45, respectively; P = 0.0018). However, expression of EML4 did not differ between the groups.

Conclusions: The EML4-ALK fusion gene was present at a high frequency in Chinese NSCLC patients, particularly in those with adenocarcinomas lacking EGFR/KRAS mutations. The EML4-ALK fusion appears to be tightly associated with ALK mRNA expression levels. RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK-positive patients.

Show MeSH
Related in: MedlinePlus