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Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas.
Br J Cancer. 2014 May 27; 110(11):2688-99.BJ

Abstract

BACKGROUND

c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas.

METHODS

In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ⩾3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ⩾2.

RESULTS

We observed c-MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08-2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06-3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24-17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15-18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11-4.10 for DFS).

CONCLUSIONS

c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death.

Authors+Show Affiliations

1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Kyungpook National University College of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 700-842, Korea.Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea.1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.1] Department of Thoracic Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Thoracic Surgery, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.1] Department of Thoracic Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Thoracic Surgery, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.1] Department of Internal medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Internal medicine, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24809777

Citation

Seo, A N., et al. "Clinicopathologic and Prognostic Significance of c-MYC Copy Number Gain in Lung Adenocarcinomas." British Journal of Cancer, vol. 110, no. 11, 2014, pp. 2688-99.
Seo AN, Yang JM, Kim H, et al. Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas. Br J Cancer. 2014;110(11):2688-99.
Seo, A. N., Yang, J. M., Kim, H., Jheon, S., Kim, K., Lee, C. T., Jin, Y., Yun, S., Chung, J. H., & Paik, J. H. (2014). Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas. British Journal of Cancer, 110(11), 2688-99. https://doi.org/10.1038/bjc.2014.218
Seo AN, et al. Clinicopathologic and Prognostic Significance of c-MYC Copy Number Gain in Lung Adenocarcinomas. Br J Cancer. 2014 May 27;110(11):2688-99. PubMed PMID: 24809777.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas. AU - Seo,A N, AU - Yang,J M, AU - Kim,H, AU - Jheon,S, AU - Kim,K, AU - Lee,C T, AU - Jin,Y, AU - Yun,S, AU - Chung,J-H, AU - Paik,J H, Y1 - 2014/05/08/ PY - 2013/10/27/received PY - 2014/03/26/revised PY - 2014/04/01/accepted PY - 2014/5/10/entrez PY - 2014/5/9/pubmed PY - 2014/7/16/medline SP - 2688 EP - 99 JF - British journal of cancer JO - Br. J. Cancer VL - 110 IS - 11 N2 - BACKGROUND: c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas. METHODS: In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ⩾3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ⩾2. RESULTS: We observed c-MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08-2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06-3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24-17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15-18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11-4.10 for DFS). CONCLUSIONS: c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death. SN - 1532-1827 UR - https://www.unboundmedicine.com/medline/citation/24809777/Clinicopathologic_and_prognostic_significance_of_c_MYC_copy_number_gain_in_lung_adenocarcinomas_ L2 - http://dx.doi.org/10.1038/bjc.2014.218 DB - PRIME DP - Unbound Medicine ER -