Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer

Stephen J. Murphy, Faye R. Harris, Farhad Kosari, Simone Barreto Siqueira Parrilha Terra, Aqsa Nasir, Sarah H. Johnson, Vishnu Serla, James Smadbeck, Geoffrey C. Halling, Giannoula Karagouga, William R. Sukov, Konstantinos Leventakos, Ping Yang, Tobias D Peikert, Aaron Mansfield, Dennis A Wigle, Eunhee S. Yi, Benjamin R. Kipp, George Vasmatzis, Marie Christine Aubry

Research output: Contribution to journalArticle

Abstract

Introduction: Genomic technologies present a promising mechanism of resolving the clinical dilemma of distinguishing independent primary tumors from intrapulmonary metastases in NSCLC. We evaluated the utility of discordant mapping somatic junctions from chromosomal rearrangements in diagnosing metastatic disease compared to the current standard histologic review. Material and Methods: Mate-pair sequencing was performed on DNA extracted from 76 distinct tumors from 37 cases of multiple lung cancers. Discordant mapping junctions and chromosomal copy levels were assessed for each tumor. Blood-derived DNA was available on 22 of these cases for germline assessments. A lung cancer next-generation sequencing panel was additionally performed on tumor pairs from 17 patients. Results: Whereas mate-pair sequencing was able to classify lineage in all tumor pairs, histologic review appeared to misclassify lineage in 9 of 33 (27%) same-histology tumor pair comparisons. Based on disagreement between the reviewing pathologists, histopathologic lineage was classified as indeterminate in seven cases. In two cases where pathologists agreed on a metastatic call, no shared junctions were found suggesting independent primaries. Although germline junctions passing algorithmic filters were common, on average less than three were present and all had predictable structures of small focal rearrangements or transposons. Evaluation of shared chromosomal copy changes and driver mutations through a lung cancer next-generation sequencing panel, while informative, were nondefinitive in calling lineage in all cases. Conclusions: The highly unique nature and prevalence of chromosomal rearrangement in lung cancers provide a useful and definitive technique for calling lineage in multifocal lung cancer.

Original languageEnglish (US)
JournalJournal of Thoracic Oncology
DOIs
StatePublished - Jan 1 2019

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Genomics
Lung Neoplasms
Neoplasms
DNA
Histology
Neoplasm Metastasis
Technology
Mutation

Keywords

  • Copy number changes
  • Gene panel
  • Histologic review
  • Intrapulmonary metastasis
  • Mate-pair sequencing
  • Multifocal lung cancer
  • Rearrangements
  • Synchronous primary

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Murphy, S. J., Harris, F. R., Kosari, F., Barreto Siqueira Parrilha Terra, S., Nasir, A., Johnson, S. H., ... Aubry, M. C. (2019). Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer. Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2019.05.008

Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer. / Murphy, Stephen J.; Harris, Faye R.; Kosari, Farhad; Barreto Siqueira Parrilha Terra, Simone; Nasir, Aqsa; Johnson, Sarah H.; Serla, Vishnu; Smadbeck, James; Halling, Geoffrey C.; Karagouga, Giannoula; Sukov, William R.; Leventakos, Konstantinos; Yang, Ping; Peikert, Tobias D; Mansfield, Aaron; Wigle, Dennis A; Yi, Eunhee S.; Kipp, Benjamin R.; Vasmatzis, George; Aubry, Marie Christine.

In: Journal of Thoracic Oncology, 01.01.2019.

Research output: Contribution to journalArticle

Murphy, SJ, Harris, FR, Kosari, F, Barreto Siqueira Parrilha Terra, S, Nasir, A, Johnson, SH, Serla, V, Smadbeck, J, Halling, GC, Karagouga, G, Sukov, WR, Leventakos, K, Yang, P, Peikert, TD, Mansfield, A, Wigle, DA, Yi, ES, Kipp, BR, Vasmatzis, G & Aubry, MC 2019, 'Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer', Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2019.05.008
Murphy, Stephen J. ; Harris, Faye R. ; Kosari, Farhad ; Barreto Siqueira Parrilha Terra, Simone ; Nasir, Aqsa ; Johnson, Sarah H. ; Serla, Vishnu ; Smadbeck, James ; Halling, Geoffrey C. ; Karagouga, Giannoula ; Sukov, William R. ; Leventakos, Konstantinos ; Yang, Ping ; Peikert, Tobias D ; Mansfield, Aaron ; Wigle, Dennis A ; Yi, Eunhee S. ; Kipp, Benjamin R. ; Vasmatzis, George ; Aubry, Marie Christine. / Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer. In: Journal of Thoracic Oncology. 2019.
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abstract = "Introduction: Genomic technologies present a promising mechanism of resolving the clinical dilemma of distinguishing independent primary tumors from intrapulmonary metastases in NSCLC. We evaluated the utility of discordant mapping somatic junctions from chromosomal rearrangements in diagnosing metastatic disease compared to the current standard histologic review. Material and Methods: Mate-pair sequencing was performed on DNA extracted from 76 distinct tumors from 37 cases of multiple lung cancers. Discordant mapping junctions and chromosomal copy levels were assessed for each tumor. Blood-derived DNA was available on 22 of these cases for germline assessments. A lung cancer next-generation sequencing panel was additionally performed on tumor pairs from 17 patients. Results: Whereas mate-pair sequencing was able to classify lineage in all tumor pairs, histologic review appeared to misclassify lineage in 9 of 33 (27{\%}) same-histology tumor pair comparisons. Based on disagreement between the reviewing pathologists, histopathologic lineage was classified as indeterminate in seven cases. In two cases where pathologists agreed on a metastatic call, no shared junctions were found suggesting independent primaries. Although germline junctions passing algorithmic filters were common, on average less than three were present and all had predictable structures of small focal rearrangements or transposons. Evaluation of shared chromosomal copy changes and driver mutations through a lung cancer next-generation sequencing panel, while informative, were nondefinitive in calling lineage in all cases. Conclusions: The highly unique nature and prevalence of chromosomal rearrangement in lung cancers provide a useful and definitive technique for calling lineage in multifocal lung cancer.",
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AU - Murphy, Stephen J.

AU - Harris, Faye R.

AU - Kosari, Farhad

AU - Barreto Siqueira Parrilha Terra, Simone

AU - Nasir, Aqsa

AU - Johnson, Sarah H.

AU - Serla, Vishnu

AU - Smadbeck, James

AU - Halling, Geoffrey C.

AU - Karagouga, Giannoula

AU - Sukov, William R.

AU - Leventakos, Konstantinos

AU - Yang, Ping

AU - Peikert, Tobias D

AU - Mansfield, Aaron

AU - Wigle, Dennis A

AU - Yi, Eunhee S.

AU - Kipp, Benjamin R.

AU - Vasmatzis, George

AU - Aubry, Marie Christine

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: Genomic technologies present a promising mechanism of resolving the clinical dilemma of distinguishing independent primary tumors from intrapulmonary metastases in NSCLC. We evaluated the utility of discordant mapping somatic junctions from chromosomal rearrangements in diagnosing metastatic disease compared to the current standard histologic review. Material and Methods: Mate-pair sequencing was performed on DNA extracted from 76 distinct tumors from 37 cases of multiple lung cancers. Discordant mapping junctions and chromosomal copy levels were assessed for each tumor. Blood-derived DNA was available on 22 of these cases for germline assessments. A lung cancer next-generation sequencing panel was additionally performed on tumor pairs from 17 patients. Results: Whereas mate-pair sequencing was able to classify lineage in all tumor pairs, histologic review appeared to misclassify lineage in 9 of 33 (27%) same-histology tumor pair comparisons. Based on disagreement between the reviewing pathologists, histopathologic lineage was classified as indeterminate in seven cases. In two cases where pathologists agreed on a metastatic call, no shared junctions were found suggesting independent primaries. Although germline junctions passing algorithmic filters were common, on average less than three were present and all had predictable structures of small focal rearrangements or transposons. Evaluation of shared chromosomal copy changes and driver mutations through a lung cancer next-generation sequencing panel, while informative, were nondefinitive in calling lineage in all cases. Conclusions: The highly unique nature and prevalence of chromosomal rearrangement in lung cancers provide a useful and definitive technique for calling lineage in multifocal lung cancer.

AB - Introduction: Genomic technologies present a promising mechanism of resolving the clinical dilemma of distinguishing independent primary tumors from intrapulmonary metastases in NSCLC. We evaluated the utility of discordant mapping somatic junctions from chromosomal rearrangements in diagnosing metastatic disease compared to the current standard histologic review. Material and Methods: Mate-pair sequencing was performed on DNA extracted from 76 distinct tumors from 37 cases of multiple lung cancers. Discordant mapping junctions and chromosomal copy levels were assessed for each tumor. Blood-derived DNA was available on 22 of these cases for germline assessments. A lung cancer next-generation sequencing panel was additionally performed on tumor pairs from 17 patients. Results: Whereas mate-pair sequencing was able to classify lineage in all tumor pairs, histologic review appeared to misclassify lineage in 9 of 33 (27%) same-histology tumor pair comparisons. Based on disagreement between the reviewing pathologists, histopathologic lineage was classified as indeterminate in seven cases. In two cases where pathologists agreed on a metastatic call, no shared junctions were found suggesting independent primaries. Although germline junctions passing algorithmic filters were common, on average less than three were present and all had predictable structures of small focal rearrangements or transposons. Evaluation of shared chromosomal copy changes and driver mutations through a lung cancer next-generation sequencing panel, while informative, were nondefinitive in calling lineage in all cases. Conclusions: The highly unique nature and prevalence of chromosomal rearrangement in lung cancers provide a useful and definitive technique for calling lineage in multifocal lung cancer.

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KW - Gene panel

KW - Histologic review

KW - Intrapulmonary metastasis

KW - Mate-pair sequencing

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KW - Rearrangements

KW - Synchronous primary

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