Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping

Xiuning Le; Lingzhi Hong; Chuck Hensel; Rongrong Chen; Haley Kemp; Niamh Coleman; Christine A. Ciunci; Stephen V. Liu; Marcelo V. Negrao; Jennifer Yen; Xuefeng Xia; Juergen Scheuenpflug; Christopher Stroh; Dilafruz Juraeva; Anne Tsao; David Hong; Victoria Raymond; Paul Paik; Jianjun Zhang; John V. Heymach

doi:10.1200/PO.21.00135

Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping

Xiuning Le, Lingzhi Hong, Chuck Hensel, Rongrong Chen, Haley Kemp, Niamh Coleman, Christine A. Ciunci, Stephen V. Liu, Marcelo V. Negrao, Jennifer Yen, Xuefeng Xia, Juergen Scheuenpflug, Christopher Stroh, Dilafruz Juraeva, Anne Tsao, David Hong, Victoria Raymond, Paul Paik, Jianjun Zhang, John V. Heymach

Research output: Contribution to journal › Article › peer-review

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Abstract

Purpose: MET exon 14 skipping alterations (METex14) comprise a diverse set of actionable oncogene drivers in non-small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. MATERIALS AND METHODS METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. Results: Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. Conclusion: METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.

Original language	English (US)
Pages (from-to)	1802-1812
Number of pages	11
Journal	JCO Precision Oncology
Volume	5
DOIs	https://doi.org/10.1200/PO.21.00135
State	Published - 2021

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1200/PO.21.00135

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Le, X., Hong, L., Hensel, C., Chen, R., Kemp, H., Coleman, N., Ciunci, C. A., Liu, S. V., Negrao, M. V., Yen, J., Xia, X., Scheuenpflug, J., Stroh, C., Juraeva, D., Tsao, A., Hong, D., Raymond, V., Paik, P., Zhang, J., & Heymach, J. V. (2021). Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping. JCO Precision Oncology, 5, 1802-1812. https://doi.org/10.1200/PO.21.00135

Le, X , Hong, L, Hensel, C, Chen, R, Kemp, H, Coleman, N, Ciunci, CA, Liu, SV, Negrao, MV, Yen, J, Xia, X, Scheuenpflug, J, Stroh, C, Juraeva, D, Tsao, A , Hong, D, Raymond, V, Paik, P, Zhang, J & Heymach, JV 2021, 'Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping', JCO Precision Oncology, vol. 5, pp. 1802-1812. https://doi.org/10.1200/PO.21.00135

@article{70e902e06587457ebbc13de96ac35ce2,

title = "Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping",

abstract = "Purpose: MET exon 14 skipping alterations (METex14) comprise a diverse set of actionable oncogene drivers in non-small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. MATERIALS AND METHODS METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. Results: Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. Conclusion: METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.",

author = "Xiuning Le and Lingzhi Hong and Chuck Hensel and Rongrong Chen and Haley Kemp and Niamh Coleman and Ciunci, {Christine A.} and Liu, {Stephen V.} and Negrao, {Marcelo V.} and Jennifer Yen and Xuefeng Xia and Juergen Scheuenpflug and Christopher Stroh and Dilafruz Juraeva and Anne Tsao and David Hong and Victoria Raymond and Paul Paik and Jianjun Zhang and Heymach, {John V.}",

note = "Publisher Copyright: {\textcopyright} 2021 by American Society of Clinical Oncology.",

year = "2021",

doi = "10.1200/PO.21.00135",

language = "English (US)",

volume = "5",

pages = "1802--1812",

journal = "JCO Precision Oncology",

issn = "2473-4284",

publisher = "American Society of Clinical Oncology",

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TY - JOUR

T1 - Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping

AU - Le, Xiuning

AU - Hong, Lingzhi

AU - Hensel, Chuck

AU - Chen, Rongrong

AU - Kemp, Haley

AU - Coleman, Niamh

AU - Ciunci, Christine A.

AU - Liu, Stephen V.

AU - Negrao, Marcelo V.

AU - Yen, Jennifer

AU - Xia, Xuefeng

AU - Scheuenpflug, Juergen

AU - Stroh, Christopher

AU - Juraeva, Dilafruz

AU - Tsao, Anne

AU - Hong, David

AU - Raymond, Victoria

AU - Paik, Paul

AU - Zhang, Jianjun

AU - Heymach, John V.

PY - 2021

Y1 - 2021

N2 - Purpose: MET exon 14 skipping alterations (METex14) comprise a diverse set of actionable oncogene drivers in non-small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. MATERIALS AND METHODS METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. Results: Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. Conclusion: METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.

AB - Purpose: MET exon 14 skipping alterations (METex14) comprise a diverse set of actionable oncogene drivers in non-small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. MATERIALS AND METHODS METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. Results: Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. Conclusion: METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.

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JF - JCO Precision Oncology

ER -

Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Harboring MET Exon 14 Skipping

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