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Clinical and Translational Oncology

, Volume 20, Issue 8, pp 1080–1086 | Cite as

Deep sequencing reveals the molecular pathology characteristics between primary uterine leiomyoma and pulmonary benign metastasizing leiomyoma

Research Article

Abstract

Purpose

Pulmonary benign metastasizing leiomyoma (PBML), a rare condition of smooth muscle tumor, originates from women with a history of uterine leiomyoma (LM). Numerous genetic studies of uterine LM have been reported; however, there are few cytogenetic and molecular descriptions of PBML. Therefore, molecular subtyping is necessary to understand the pathogenesis of metastasizing sites.

Methods

Driver gene exon-capture sequencing was performed on one patient’s peripheral blood, paraffin samples from primary uterine LM, and lung metastasizing leiomyoma 8 years later.

Results

The results showed that the same missense mutations of BLMH, LRP2, MED12, SMAD2, and UGT1A8 were concurrently mutated in the primary uterine LM and the PBML. Moreover, a splice mutation of PTEN (c.492+1G>A) was uniquely identified in the lung metastasis of the patient.

Conclusion

This study indicates that the metastatic lung lesions were derived from the same malignant cell clone of uterine LMs and later acquired the novel driver mutations in the evolution of the tumor. In addition, driver gene sequencing can discriminate somatic driver mutations as biological indicators of potential malignant leiomyoma and can identify pathogenic variation driver mutations, which could be used for individualized therapy.

Keywords

Benign metastasizing leiomyoma Uterine leiomyoma Driver gene Targeted deep sequencing 

Abbreviations

PBML

Pulmonary benign metastasizing leiomyoma

LM

Leiomyoma

CT

Chest computed tomography

ER

Estrogen receptor

PR

Progesterone receptor

SNV

Somatic single nucleotide variations

InDel

Insertions or deletion

BML

Benign metastasizing leiomyoma

MED12

Mediator subcomplex 12

Notes

Acknowledgements

We would like to thank Dr. Lianpeng Chang for his contribution in data analysis. The present study was supported by the Science Technology Department of Zhejiang Province (Grant number 2016C33116), the National Natural Science Fundation of China (Grant numbers 81772575, 81502463), the CSCO Merck Serono Oncology Research Fund, SCORE (Grant number Y-MX2015-038), the Natural Science Foundation of Zhejiang Province (Grant numbers LY15H160053, LQ15H070004) and the Key Research Project of Science Technology Department of Zhejiang Province (Grant number 2015C03030).

Compliance with ethical standards

Conflict of interest

No potential conflicts of interest were disclosed.

Ethical approval

The project was approved by the Ethics Committees of Zhejiang Provincial People’s Hospital.

Informed consent

Written informed consent was obtained from the patient and her respective family.

Supplementary material

12094_2018_1847_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 19 kb)

References

  1. 1.
    Steiner PE. Metastasizing fibroleiomyoma of the uterus: report of a case and review of the literature. Am J Pathol. 1939;15(1):89–110.7.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Chen S, Liu RM, Li T. Pulmonary benign metastasizing leiomyoma: a case report and literature review. J Thorac Dis. 2014;6(6):E92–8.  https://doi.org/10.3978/j.issn.2072-1439.2014.04.37.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Ras R, Ksiazek M, Barnas E, Skret-Magierlo J, Kaziolka W, Fudali L, et al. Benign metastasizing leiomyoma in triple location: lungs, parametria and appendix. Przeglad Menopauzalny Menopause Rev. 2016;15(2):117–21.  https://doi.org/10.5114/pm.2016.61195.CrossRefGoogle Scholar
  4. 4.
    Patton KT, Cheng L, Papavero V, Blum MG, Yeldandi AV, Adley BP, et al. Benign metastasizing leiomyoma: clonality, telomere length and clinicopathologic analysis. Mod Pathol Off J US Can Acad Pathol Inc. 2006;19(1):130–40.  https://doi.org/10.1038/modpathol.3800504.Google Scholar
  5. 5.
    Bowen JM, Cates JM, Kash S, Itani D, Gonzalez A, Huang D, et al. Genomic imbalances in benign metastasizing leiomyoma: characterization by conventional karyotypic, fluorescence in situ hybridization, and whole genome SNP array analysis. Cancer Genet. 2012;205(5):249–54.  https://doi.org/10.1016/j.cancergen.2012.04.005.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cho KR, Woodruff JD, Epstein JI. Leiomyoma of the uterus with multiple extrauterine smooth muscle tumors: a case report suggesting multifocal origin. Hum Pathol. 1989;20(1):80–3.CrossRefPubMedGoogle Scholar
  7. 7.
    Sprio RH, McPeak CJ. On the so-called metastasizing leiomyoma. Cancer. 1966;19(4):544–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Awonuga AO, Shavell VI, Imudia AN, Rotas M, Diamond MP, Puscheck EE. Pathogenesis of benign metastasizing leiomyoma: a review. Obstet Gynecol Surv. 2010;65(3):189–95.  https://doi.org/10.1097/OGX.0b013e3181d60f93.CrossRefPubMedGoogle Scholar
  9. 9.
    Abell MR, Littler ER. Benign metastasizing uterine leiomyoma. Multiple lymph nodal metastases. Cancer. 1975;36(6):2206–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Yang L, Wang G, Zhao X, Ye S, Shen P, Wang W, et al. A novel WRN frameshift mutation identified by multiplex genetic testing in a family with multiple cases of cancer. PLoS One. 2015;10(8):e0133020.  https://doi.org/10.1371/journal.pone.0133020.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213–9.  https://doi.org/10.1038/nbt.2514.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lin J, Song X, Liu C. Pelvic intravascular leiomyomatosis associated with benign pulmonary metastasizing leiomyoma: clinicopathologic, clonality, and copy number variance analysis. Int J Gynecol Pathol Off J Int Soc Gynecol Pathol. 2014;33(2):140–5.  https://doi.org/10.1097/PGP.0b013e31828def26.CrossRefGoogle Scholar
  13. 13.
    Tatebe S, Oka K, Kuraoka S, Yatabe Y. Benign metastasizing leiomyoma of the lung: potential role of low-grade malignancy. Thorac Cardiovasc Surg. 2009;57(3):180–3.  https://doi.org/10.1055/s-2008-1038637.CrossRefPubMedGoogle Scholar
  14. 14.
    Gal AA, Brooks JS, Pietra GG. Leiomyomatous neoplasms of the lung: a clinical, histologic, and immunohistochemical study. Mod Pathol Off J US Can Acad Pathol Inc. 1989;2(3):209–16.Google Scholar
  15. 15.
    Nucci MR, Drapkin R, Dal Cin P, Fletcher CD, Fletcher JA. Distinctive cytogenetic profile in benign metastasizing leiomyoma: pathogenetic implications. Am J Surg Pathol. 2007;31(5):737–43.  https://doi.org/10.1097/01.pas.0000213414.15633.4e.CrossRefPubMedGoogle Scholar
  16. 16.
    Anderson LN, Cotterchio M, Knight JA, Borgida A, Gallinger S, Cleary SP. Genetic variants in vitamin d pathway genes and risk of pancreas cancer; results from a population-based case-control study in ontario, Canada. PLoS One. 2013;8(6):e66768.  https://doi.org/10.1371/journal.pone.0066768.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Moon H, Ju HL, Chung SI, Cho KJ, Eun JW, Nam SW, et al. Transforming growth factor beta promotes liver tumorigenesis in mice via upregulation of snail. Gastroenterology. 2017.  https://doi.org/10.1053/j.gastro.2017.07.014.Google Scholar
  18. 18.
    Blevins-Primeau AS, Sun D, Chen G, Sharma AK, Gallagher CJ, Amin S, et al. Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Can Res. 2009;69(5):1892–900.  https://doi.org/10.1158/0008-5472.CAN-08-3708.CrossRefGoogle Scholar
  19. 19.
    de Haas EC, Zwart N, Meijer C, Nuver J, Boezen HM, Suurmeijer AJ, et al. Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(11):1817–23.  https://doi.org/10.1200/JCO.2007.14.1606.CrossRefGoogle Scholar
  20. 20.
    Makinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 2011;334(6053):252–5.  https://doi.org/10.1126/science.1208930.CrossRefPubMedGoogle Scholar
  21. 21.
    Davies EM, Sheffield DA, Tibarewal P, Fedele CG, Mitchell CA, Leslie NR. The PTEN and Myotubularin phosphoinositide 3-phosphatases: linking lipid signalling to human disease. Sub Cell Biochem. 2012;58:281–336.  https://doi.org/10.1007/978-94-007-3012-0_8.CrossRefGoogle Scholar
  22. 22.
    Mizuno M, Nawa A, Nakanishi T, Yatabe Y. Clinical benefit of endocrine therapy for benign metastasizing leiomyoma. Int J Clin Oncol. 2011;16(5):587–91.  https://doi.org/10.1007/s10147-010-0156-4.CrossRefPubMedGoogle Scholar
  23. 23.
    Abramson S, Gilkeson RC, Goldstein JD, Woodard PK, Eisenberg R, Abramson N. Benign metastasizing leiomyoma: clinical, imaging, and pathologic correlation. AJR Am J Roentgenol. 2001;176(6):1409–13.  https://doi.org/10.2214/ajr.176.6.1761409.CrossRefPubMedGoogle Scholar
  24. 24.
    Lewis EI, Chason RJ, DeCherney AH, Armstrong A, Elkas J, Venkatesan AM. Novel hormone treatment of benign metastasizing leiomyoma: an analysis of five cases and literature review. Fertil Steril. 2013;99(7):2017–24.  https://doi.org/10.1016/j.fertnstert.2013.01.147.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fu X, Creighton CJ, Biswal NC, Kumar V, Shea M, Herrera S, et al. Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase. Breast Cancer Res BCR. 2014;16(5):430.  https://doi.org/10.1186/s13058-014-0430-x.CrossRefPubMedGoogle Scholar
  26. 26.
    Ottlakan A, Borda B, Lazar G, Tiszlavicz L, Furak J. Treatment decision based on the biological behavior of pulmonary benign metastasizing leiomyoma. J Thorac Dis. 2016;8(8):E672–6.  https://doi.org/10.21037/jtd.2016.06.61.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.Department of Second Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouPeople’s Republic of China
  2. 2.Department of Medical Oncology, The First Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouPeople’s Republic of China
  3. 3.Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang ProvinceZhejiang Provincial People’s HospitalHangzhouPeople’s Republic of China
  4. 4.Department of Thyroid and Breast SurgeryZhejiang Provincial People’s HospitalHangzhouPeople’s Republic of China

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