MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma: Molecular analysis of 25 ALK-positive cases

Jennifer M. Boland, Jin Sung Jang, Jun Li, Adam M. Lee, Jason A. Wampfler, Michele R. Erickson-Johnson, Ibere Soares, Ping Yang, Jin Jen, Andre M. Oliveira, Eunhee S. Yi

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Abstract

INTRODUCTION: Oncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non-small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization. METHODS: Using the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets. RESULTS: Five of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested. CONCLUSIONS: In summary, additional mutations were found in 20% of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed.

Original languageEnglish (US)
Pages (from-to)574-581
Number of pages8
JournalJournal of Thoracic Oncology
Volume8
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

Epidermal Growth Factor Receptor
Mutation
Genes
Fluorescence In Situ Hybridization
Adenocarcinoma of lung
erbB-1 Genes
Neoplasms
Gene Rearrangement
United States Food and Drug Administration
Early Detection of Cancer
Non-Small Cell Lung Carcinoma
Paraffin
Formaldehyde
Lung Neoplasms
Carcinogenesis
Phosphotransferases
Lung
DNA

Keywords

  • Adenocarcinoma
  • ALK
  • EGFR
  • MET

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Boland, J. M., Jang, J. S., Li, J., Lee, A. M., Wampfler, J. A., Erickson-Johnson, M. R., ... Yi, E. S. (2013). MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma: Molecular analysis of 25 ALK-positive cases. Journal of Thoracic Oncology, 8(5), 574-581. https://doi.org/10.1097/JTO.0b013e318287c395

MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma : Molecular analysis of 25 ALK-positive cases. / Boland, Jennifer M.; Jang, Jin Sung; Li, Jun; Lee, Adam M.; Wampfler, Jason A.; Erickson-Johnson, Michele R.; Soares, Ibere; Yang, Ping; Jen, Jin; Oliveira, Andre M.; Yi, Eunhee S.

In: Journal of Thoracic Oncology, Vol. 8, No. 5, 05.2013, p. 574-581.

Research output: Contribution to journalArticle

Boland, JM, Jang, JS, Li, J, Lee, AM, Wampfler, JA, Erickson-Johnson, MR, Soares, I, Yang, P, Jen, J, Oliveira, AM & Yi, ES 2013, 'MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma: Molecular analysis of 25 ALK-positive cases', Journal of Thoracic Oncology, vol. 8, no. 5, pp. 574-581. https://doi.org/10.1097/JTO.0b013e318287c395
Boland, Jennifer M. ; Jang, Jin Sung ; Li, Jun ; Lee, Adam M. ; Wampfler, Jason A. ; Erickson-Johnson, Michele R. ; Soares, Ibere ; Yang, Ping ; Jen, Jin ; Oliveira, Andre M. ; Yi, Eunhee S. / MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma : Molecular analysis of 25 ALK-positive cases. In: Journal of Thoracic Oncology. 2013 ; Vol. 8, No. 5. pp. 574-581.
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abstract = "INTRODUCTION: Oncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non-small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization. METHODS: Using the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets. RESULTS: Five of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested. CONCLUSIONS: In summary, additional mutations were found in 20{\%} of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed.",
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AU - Boland, Jennifer M.

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AU - Li, Jun

AU - Lee, Adam M.

AU - Wampfler, Jason A.

AU - Erickson-Johnson, Michele R.

AU - Soares, Ibere

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AU - Oliveira, Andre M.

AU - Yi, Eunhee S.

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N2 - INTRODUCTION: Oncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non-small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization. METHODS: Using the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets. RESULTS: Five of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested. CONCLUSIONS: In summary, additional mutations were found in 20% of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed.

AB - INTRODUCTION: Oncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non-small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization. METHODS: Using the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets. RESULTS: Five of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested. CONCLUSIONS: In summary, additional mutations were found in 20% of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed.

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