Skip to main content
SpringerLink
Log in

Clonal Origin Evaluated by Trunk and Branching Drivers and Prevalence of Mutations in Multiple Lung Tumor Nodules

  • Original Research Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Introduction

Differentiation between intrapulmonary metastasis (IPM) and multiple primary lung cancers (MPLC) in patients with synchronous or metachronous lung tumor nodules is critical but challenging.

Objective

We proposed an algorithm to evaluate clonal origin based on trunk (initiating) versus branching drivers and the prevalence of mutations in lung adenocarcinomas.

Methods

Driver mutations were examined using next-generation sequencing in five trunk driver genes (BRAF, EGFR, ERBB2, KRAS, and NRAS) and three branching driver genes (ATK1, PIK3CA, and TP53).

Results

Mutational profiling supported same clonality and likely same clonality, respectively, in 39 and 14 of 66 pairs of specimens with known identical clonal origin. Discordance of TP53 mutations (branching drivers) was observed in three pairs. Subsequent analyses of 30 pairs of synchronous or metachronous lung tumor nodules revealed different clonality and likely different clonality in 17 and 2 pairs, respectively, including three pairs with similar histomorphology; same clonality and likely same clonality in three and five pairs, respectively, including two pairs with different histomorphology; and inconclusive or noninformative results in three pairs.

Conclusion

While discordance of trunk drivers indicated MPLC in patients with synchronous or metachronous lung tumor nodules, discordance of branching drivers did not exclude IPM. Concordance of uncommon drivers supported IPM, whereas concordance of common drivers did not exclude MPLC. Additional recommendations from official organizations are needed to guide applications of molecular markers in defining clonality of multiple lung tumor nodules.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Arai J, Tsuchiya T, Oikawa M, Mochinaga K, Hayashi T, Yoshiura K, et al. Clinical and molecular analysis of synchronous double lung cancers. Lung Cancer. 2012;77:281–7.

    PubMed  Google Scholar 

  2. Loukeri AA, Kampolis CF, Ntokou A, Tsoukalas G, Syrigos K. Metachronous and synchronous primary lung cancers: diagnostic aspects, surgical treatment, and prognosis. Clin Lung Cancer. 2015;16:15–23.

    PubMed  Google Scholar 

  3. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70:606–12.

    CAS  PubMed  Google Scholar 

  4. Shen KR, Meyers BF, Larner JM, Jones DR, American College of Chest Physicians.pecial treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. (2007);32(3 Suppl):290S–305S.

  5. Detterbeck FC, Nicholson AG, Franklin WA, Marom EM, Travis WD, Girard N, et al. The IASLC lung cancer staging project: summary of proposals for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11:639–50.

  6. Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC lung cancer staging project: Background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:651–65.

  7. Detterbeck FC, Marom EM, Arenberg DA, Franklin WA, Nicholson AG, Travis WD, et al. The IASLC lung cancer staging project: Background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11:666–80.

  8. Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA, et al. The IASLC lung cancer staging project: Background data and proposals for the classification of lung cancer with separate tumor nodules in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11:681–92.

  9. Rami-Porta R, Ball D, Crowley J, Giroux DJ, Jett J, Travis WD, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2:593–602.

    PubMed  Google Scholar 

  10. Rami-Porta R, Asamura H, Travis WD, Rusch VW. In: Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al., editors. AJCC Cancer Staging Manual. 8th ed. France: Springer International Publishing; 2017. p. 431–56.

    Google Scholar 

  11. Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33:1752–64.

    PubMed  PubMed Central  Google Scholar 

  12. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors. Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243–60.

  13. Lee HJ, Sung P, Yoen H, Kim S, Han S, et al. A novel algorithm to differentiate between multiple primary lung cancers and intrapulmonary metastasis in multiple lung cancers with multiple pulmonary sites of involvement. J Thorac Oncol. 2020;15:203–15.

    PubMed  Google Scholar 

  14. Murphy SJ, Aubry MC, Harris FR, Halling GC, Johnson SH, Terra S, et al. Identification of independent primary tumors and intrapulmonary metastases using DNA rearrangements in non-small-cell lung cancer. J Clin Oncol. 2014;32:4050–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu C, Zhao C, Yang Y, He Y, Hou L, Li X, et al. High discrepancy of driver mutations in patients with NSCLC and synchronous multiple lung ground-glass nodules. J Thorac Oncol. 2015;10:778–83.

    CAS  PubMed  Google Scholar 

  16. Schneider F, Derrick V, Davison JM, Strollo D, Incharoen P, Dacic S. Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging. Mod Pathol. 2016;29:735–42.

    CAS  PubMed  Google Scholar 

  17. Liu Y, Zhang J, Li L, Yin G, Zhang J, Zheng S, et al. Genomic heterogeneity of multiple synchronous lung cancer. Nat Commun. 2016;7:13200.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Schneider F, Dacic S. Histopathologic and molecular approach to staging of multiple lung nodules. Transl Lung Cancer Res. 2017;6:540–9.

    PubMed  PubMed Central  Google Scholar 

  19. Asmar R, Sonett JR, Singh G, Mansukhani MM, Borczuk AC. Use of oncogenic driver mutations in staging of multiple primary lung carcinomas: a single-center experience. J Thorac Oncol. 2017;12:1524–35.

    PubMed  Google Scholar 

  20. Patel SB, Kadi W, Walts AE, Marchevsky AM, Pao A, Aguiluz A, et al. Next-generation sequencing: a novel approach to distinguish multifocal primary lung adenocarcinomas from intrapulmonary metastases. J Mol Diagn. 2017;19:870–80.

    CAS  PubMed  Google Scholar 

  21. Goto T, Hirotsu Y, Mochizuki H, Nakagomi T, Shikata D, Yokoyama Y, et al. Mutational analysis of multiple lung cancers: discrimination between primary and metastatic lung cancers by genomic profile. Oncotarget. 2017;8:31133–43.

    PubMed  PubMed Central  Google Scholar 

  22. Saab J, Zia H, Mathew S, Kluk M, Narula N, Fernandes H. Utility of genomic analysis in differentiating synchronous and metachronous lung adenocarcinomas from primary adenocarcinomas with intrapulmonary metastasis. Transl Oncol. 2017;10:442–9.

    PubMed  PubMed Central  Google Scholar 

  23. Roepman P, Ten Heuvel A, Scheidel KC, Sprong T, Heideman DAM, Seldenrijk KA, et al. Added Value of 50-gene panel sequencing to distinguish multiple primary lung cancers from pulmonary metastases: a systematic investigation. J Mol Diagn. 2018;20:436–45.

    CAS  PubMed  Google Scholar 

  24. Murphy SJ, Harris FR, Kosari F, Barreto Siqueira Parrilha Terra S, Nasir A, Johnson SH, et al. Using genomics to differentiate multiple primaries from metastatic lung cancer. J Thorac Oncol. 2019;14:1567–82.

  25. Chang JC, Alex D, Bott M, Tan KS, Seshan V, Golden A, et al. Comprehensive next-generation sequencing unambiguously distinguishes separate primary lung carcinomas from intra-pulmonary metastases: comparison with standard histopathologic approach. Clin Cancer Res. 2019;25:7113–25.

    PubMed  Google Scholar 

  26. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376:2109–21.

    CAS  PubMed  Google Scholar 

  29. Ahrendt SA, Decker PA, Alawi EA, Zhu Yr YR, Sanchez-Cespedes M, Yang SC, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer. 2001;92:1525–30.

    CAS  PubMed  Google Scholar 

  30. Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7:78985–93.

    PubMed  PubMed Central  Google Scholar 

  31. de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346:251–6.

    PubMed  PubMed Central  Google Scholar 

  32. De Marchi F, Haley L, Fryer H, brahim J, Beierl K, Zheng G, et al. Clinical validation of coexisting activating mutations within EGFR, mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in lung cancers. Arch Pathol Lab Med. 2019;143:174–82.

  33. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31:1023–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Illei PB, Belchis D, Tseng LH, Nguyen D, De Marchi F, Haley L, et al. Clinical mutational profiling of 1006 lung cancers by next generation sequencing. Oncotarget. 2017;8:96684–96.

    PubMed  PubMed Central  Google Scholar 

  35. Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548:234–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lokhandwala PM, Tseng LH, Rodriguez E, Zheng G, Pallavajjalla A, Gocke CD, et al. Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing. BMC Cancer. 2019;19:665.

    PubMed  PubMed Central  Google Scholar 

  37. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67.

    CAS  PubMed  Google Scholar 

  38. Nieto P, Ambrogio C, Esteban-Burgos L, Gómez-López G, Blasco MT, Yao Z, et al. A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature. 2017;548(7666):239–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Tseng LH, De Marchi F, Pallavajjalla A, Rodriguez E, Xian R, Belchis D, et al. Clinical validation of discordant trunk driver mutations in paired primary and metastatic lung cancer specimens. Am J Clin Pathol. 2019;152:570–81.

    CAS  PubMed  Google Scholar 

  40. Zheng G, Lin MT, Lokhandwala PM, Beierl K, Netto GJ, Gocke CD, et al. Clinical mutational profiling of bone metastases of lung and colon carcinoma and malignant melanoma using next-generation sequencing. Cancer Cytopathol. 2016;124:744–53.

    CAS  PubMed  Google Scholar 

  41. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lin MT, Mosier SL, Thiess M, Beierl KF, Debeljak M, Tseng LH, et al. Clinical validation of KRAS, BRAF, and EGFR mutation detection using next-generation sequencing. Am J Clin Pathol. 2014;141:856–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sikkink SK, Liloglou T, Maloney P, Gosney JR, Field JK. In-depth analysis of molecular alterations within normal and tumour tissue from an entire bronchial tree. Int J Oncol. 2003;22:589–95.

    CAS  PubMed  Google Scholar 

  44. Gazdar AF, Minna JD. Multifocal lung cancers-clonality vs field cancerization and does it matter? J Natl Cancer Inst. 2009;101:541–3.

    PubMed  PubMed Central  Google Scholar 

  45. Vignot S, Frampton GM, Soria JC, Commo F, Brambilla C, Palmer G, et al. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol. 2013;31:2167–72.

    CAS  PubMed  Google Scholar 

  46. Yatabe Y, Matsuo K, Mitsudomi T. Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma. J Clin Oncol. 2011;29:2972–7.

    CAS  PubMed  Google Scholar 

  47. Wang S, Wang Z. Meta-analysis of epidermal growth factor receptor and KRAS gene status between primary and corresponding metastatic tumours of non-small cell lung cancer. Clin Oncol (R Coll Radiol). 2015;27:30–9.

    CAS  PubMed  Google Scholar 

  48. Pfeifer JD, Liu J. Rate of occult specimen provenance complications in routine clinical practice. Am J Clin Pathol. 2013;139:93–100.

    PubMed  Google Scholar 

  49. Chang YL, Wu CT, Lin SC, Hsiao CF, Jou YS, Lee YC. Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers. Clin Cancer Res. 2007;13:52–8.

    CAS  PubMed  Google Scholar 

  50. van Rens MT, Eijken EJ, Elbers JR, Lammers JW, Tilanus MG, Slootweg PJ. p53 mutation analysis for definite diagnosis of multiple primary lung carcinoma. Cancer. 2002;94:188–96.

    PubMed  Google Scholar 

  51. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Takahashi Y, Shien K, Tomida S, Oda S, Matsubara T, Sato H, et al. Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis. Cancer Sci. 2018;109:3634–42.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Erika F. Rodriguez and Li-Hui Tseng contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins University School of Medicine, Carnegie 469, Pathology, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    Erika F. Rodriguez, Li-Hui Tseng, Federico De Marchi, Jialing Haung, Deborah Belchis, Rena Xian, Christopher D. Gocke, James R. Eshleman, Peter B. Illei & Ming-Tseh Lin

  2. Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan

    Li-Hui Tseng

  3. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Christopher D. Gocke & James R. Eshleman

Authors
  1. Erika F. Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li-Hui Tseng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Federico De Marchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jialing Haung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Deborah Belchis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rena Xian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christopher D. Gocke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James R. Eshleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter B. Illei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ming-Tseh Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erika F. Rodriguez.

Ethics declarations

Funding

The authors have no funding to disclose.

Conflict of interest

Erika F. Rodriguez (EFR), Li-Hui Tseng (LHT), Federico De Marchi (FM), Jialing Haung (JH), Deborah Belchis (DB), Rena Xian (RX), Christopher D. Gocke (CDG), James R. Eshleman (JRE), Peter B. Illei (PBI), and Ming-Tseh Lin (MTL) have no conflicts of interest that are directly relevant to the content of this article.

Ethical approval and informed consent

This retrospective study for quality improvement was approved by the institutional review board on “Histopathological, immunohistochemical and molecular analysis of pulmonary tumors” (IRB Number 00063529) and conducted according to the principles of the Declaration of Helsinki.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 461 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodriguez, E.F., Tseng, LH., De Marchi, F. et al. Clonal Origin Evaluated by Trunk and Branching Drivers and Prevalence of Mutations in Multiple Lung Tumor Nodules. Mol Diagn Ther 24, 461–472 (2020). https://doi.org/10.1007/s40291-020-00471-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-020-00471-w

Search

Navigation