Clinicopathologic Implications of ALK Gene Copy Number Gain in Non-small Cell Lung Cancer

Seol-Bong Yoo; Hyojin Kim; Xianhua Xu; Ping-Li Sun; Yan Jin; Jin Ho Paik; Sanghoon Jheon; Choon-Taek Lee; Jin-Haeng Chung

doi:10.6058/jlc.2011.10.2.87

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Yoo, Kim, Xu, Sun, Jin, Paik, Jheon, Lee, and Chung: Clinicopathologic Implications of ALK Gene Copy Number Gain in Non-small Cell Lung Cancer

Original Article

J Lung Cancer 2011;10(2):87-93.

Published online: 11 January 2011

DOI: https://doi.org/10.6058/jlc.2011.10.2.87

Clinicopathologic Implications of ALK Gene Copy Number Gain in Non-small Cell Lung Cancer

Seol-Bong Yoo, M.D.^1,², Hyojin Kim, M.D.¹, Xianhua Xu, M.D., Ph.D.^1,², Ping-Li Sun, M.D.^2,³, Yan Jin, M.D.², Jin Ho Paik, M.D., Ph.D.², Sanghoon Jheon, M.D., Ph.D.³, Choon-Taek Lee, M.D., Ph.D.⁴, Jin-Haeng Chung, M.D., Ph.D.^1,²

¹Department of Pathology, Seoul National University College of Medicine Seoul, Korea

²Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea

³Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Korea

⁴Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

Address for correspondence Jin-Haeng Chung, M.D., Ph.D. Department of Pathology, Seoul National University Bundang Hospital, 300, Gumi-dong, Bundang-gu, Seongnam 463-707, Korea Tel: 82-31-787-7713 Fax: 82-31-787-4012 E-mail: chungjh@snu.ac.kr

This work was supported by the Korea Healthcare Technology R&D project, Ministry of Health & Welfare, Republic of Korea (A111405) and the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Edu-cation, Science and Technology (2010- 0022451).

Revised 10 November 201121 November 2011 Accepted 29 November 2011

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose:

The anaplastic lymphoma kinase ( ALK) gene is a potential molecular target in non-small cell lung carcinoma (NSCLC). The clinicopathologic implication of a change in the ALK gene copy number (GCN) is unclear. Materials and Methods: A total of 434 primary NSCLC samples were analyzed by fluorescence in situ hybridization (FISH) for ALK GCN.

Results:

Ninety-six cases (22.1%) showed ALK GCN gain with amplification in 16 (3.7%) cases. The cases with ALK GCN gain consisted of 47 adenocarcinomas (49.0%), 41 squamous cell carcinomas (42.7%), 5 adenosquamous carcinomas (5.2%) and 3 other NSCLCs (3.1%). ALK gene amplification was identified in 7 adenocarcinomas (43.7%) and 9 squamous cell carcinomas (56.3%). There was no significant difference between ALK GCN gain/amplification and histologic subtypes. Uni-variate survival analysis revealed that patients with ALK GCN gain/amplification showed shorter progression-free survival durations and decreased overall survival rates (p＜0.001). However, multivariate analysis proved that ALK GCN gain/amplification is not an independent prognostic factor for progression-free survival or overall survival.

Conclusion:

ALK GCN gain is frequently identified in NSCLCs and the incidence is similar among histologic subtypes. Although ALK GCN gain/amplification is not an independent prognostic marker, it is associated with tumor progression in NSCLC.

Keywords: ALK, Copy number gain, Gene amplification, Non-small cell lung carcinoma

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Fig. 1.

ALK gene status by fluorescence in situ hybridization (FISH) (×1,000). (A) ALK gene rearrangement (break-apart pattern). (B) ALK gene copy number gain. (C) ALK gene amplification. (D) ALK wild type.

Fig. 2.

ALK gene copy number gain/amplification showed significantly shorter progression-free survival (A) and overall-survival (B).

Table 1.

Clinicopathologic Characteristics in ALK Gene Status

Number (%)			ALK gene
Number (%)			Wild type	Copy number gain	Amplification	p-value∗
	Total	434 (100)	322 (74.2)	96 (22.1)	16 (3.7)
Sex	Male	299 (68.9)	221 (73.9)	66 (22.1)	12 (4.0)	0.865
	Female	135 (31.1)	101 (74.8)	30 (22.2)	4 (3.0)
Age, yr	＜64	309 (71.2)	243 (78.6)	61 (19.7)	5 (1.6)	＜0.001
	≥64	125 (28.8)	79 (63.2)	35 (28.0)	11 (8.8)
Tumor size, mm	＜34	254 (58.5)	220 (86.6)	32 (12.6)	2 (0.8)	＜0.001
	≥34	180 (41.5)	102 (56.7)	64 (35.6)	14 (7.8)
Histology	ADC	236 (54.4)	182 (77.1)	47 (19.9)	7 (3.0)	0.251
	SCC	166 (38.2)	116 (69.9)	41 (24.7)	9 (5.4)
	ASC	12 (2.8)	7 (58.3)	5 (41.7)	0 (0.0)
	Others	20 (4.6)	17 (85.0)	3 (15.0)	0 (0.0)
Smoking status	Non-smoker	159 (36.6)	124 (78.0)	32 (20.1)	3 (1.9)	0.208
	Smoker	275 (63.4)	198 (72.0)	64 (23.3)	13 (4.7)
T stage	T1, T2	311 (71.7)	230 (74.0)	80 (25.7)	1 (0.3)	＜0.001
	T3, T4	122 (28.1)	92 (75.4)	16 (13.1)	14 (11.5)
	NA	1 (0.2)	0 (0.0)	0 (0.0)	1 (100.0)
N stage	N0	238 (54.8)	235 (98.7)	1 (0.4)	2 (0.8)	＜0.001
	N1-3	192 (44.2)	83 (43.2)	95 (49.5)	14 (7.3)
	NA	4 (1.0)	4 (100.0)	0 (0.0)	0 (0.0)
pStage	I, II	274 (63.1)	269 (98.2)	3 (1.1)	2 (0.7)	＜0.001
	III, IV	155 (35.7)	48 (31.0)	93 (60.0)	14 (9.0)
	NA	5 (1.2)	5 (100.0)	0 (0.0)	0 (0.0)

^∗ Pearson Chi-Square values.

ADC: adenocarcinoma, SCC: squamous cell carcinoma, ASC: adenosquamous carcinoma, NA: not applicable.

Table 2.

Clinicopathologic Characteristics in ALK Gene Status

Number (%)			ALK gene
Number (%)			Wild type	Copy number gain/amplification	p-value∗
	Total	434 (100)	322 (74.2)	112 (25.8)
Sex	Male	299 (68.9)	221 (73.9)	78 (26.1)	0.842
	Female	135 (31.1)	101 (74.8)	34 (25.2)
Age, yr	＜64	309 (71.2)	243 (78.6)	66 (21.4)	0.001
	≥64	125 (28.8)	79 (63.2)	46 (36.8)
Tumor size, mm	＜34	254 (58.5)	220 (86.6)	34 (13.4)	＜0.001
	≥34	180 (41.5)	102 (56.7)	78 (43.3)
Histology	ADC	236 (54.4)	182 (77.1)	54 (22.9)	0.141
	SCC	166 (38.2)	116 (69.9)	50 (30.1)
	ASC	12 (2.8)	7 (58.3)	5 (41.7)
	Others	20 (4.6)	17 (85.0)	3 (15.0)
Smoking status	Non-smoker	159 (36.6)	124 (78.0)	35 (22.0)	0.17
	Smoker	275 (63.4)	198 (72.0)	77 (28.0)
T stage	T1, T2	311 (71.7)	230 (74.0)	81 (26.0)	0.226
	T3, T4	122 (28.1)	92 (75.4)	30 (24.6)
	NA	1 (0.2)	0 (0.0)	1 (100.0)
N stage	N0	238 (54.8)	235 (98.7)	3 (1.3)	＜0.001
	N1-3	192 (44.2)	83 (43.2)	109 (56.8)
	NA	4 (1.0)	4 (100.0)	0 (0.0)
pStage	I, II	274 (63.1)	269 (98.2)	5 (1.8)	＜0.001
	III, IV	155 (35.7)	48 (31.0)	107 (69.0)
	NA	5 (1.2)	5 (100.0)	0 (0.0)

^∗ Pearson Chi-Square values.

ADC: adenocarcinoma, SCC: squamous cell carcinoma, ASC: adenosquamous carcinoma, NA: not applicable.

Table 3.

Multivariate Analysis of Progression-free Survival

		p-value	HR	95% CI
T stage	1∼2 vs. 3∼4	0.005	2.242	1.283∼3.916
pstage	I∼ II vs. III∼ IV	0.018	0.528	0.311∼0.898
Tumor size, mm	＜34 vs. ≥34	0.791	0.954	0.672∼1.353
ALK gene	Wild type vs. copy number gain/amplification	0.067	0.598	0.345∼1.037

HR: hazard ratio, CI: confidence interval.

Table 4.

Multivariate Analysis of Overall Survival

		p-value	HR	95% CI
T stage	1∼2 vs. 3∼4	0.005	3.624	1.470∼8.936
pstage	I∼ II vs. III∼ IV	＜0.001	0.275	0.134∼0.563
Tumor size (mm)	＜34 vs. ≥34	0.781	0.94	0.605∼1.459
ALK gene	Wild type vs. copy number gain/amplification	0.379	0.726	0.355∼1.482

HR: hazard ratio, CI: confidence interval.

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