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Open Access 01-12-2018 | Case report

Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene

Authors: Deniss Sõritsa, Hindrek Teder, Retlav Roosipuu, Hannes Tamm, Triin Laisk-Podar, Pille Soplepmann, Alan Altraja, Andres Salumets, Maire Peters

Published in: BMC Medical Genetics | Issue 1/2018

Abstract

Background

Benign metastasizing leiomyoma (BML) is an orphan neoplasm commonly characterized by pulmonary metastases consisting of smooth muscle cells. Patients with BML have usually a current or previous uterine leiomyoma, which is therefore suggested to be the most probable source of this tumour. The purpose of this case report was to determine the possible genetic grounds for pulmonary BML.

Case presentation

We present a case report in an asymptomatic 44-year-old female patient, who has developed uterine leiomyoma with subsequent pulmonary BML. Whole exome sequencing (WES) was used to detect somatic mutations in BML lesion. Somatic single nucleotide mutations were identified by comparing the WES data between the pulmonary metastasis and blood sample of the same BML patient. One heterozygous somatic mutation was selected for validation by Sanger sequencing. Clonality of the pulmonary metastasis and uterine leiomyoma was assessed by X-chromosome inactivation assay.

Conclusions

We describe a potentially deleterious somatic heterozygous mutation in bone morphogenetic protein 8B (BMP8B) gene (c.1139A > G, Tyr380Cys) that was identified in the pulmonary metastasis and was absent from blood and uterine leiomyoma, and may play a facilitating role in the metastasizing of BML. The clonality assay confirmed a skewed pattern of X-chromosome inactivation, suggesting monoclonal origin of the pulmonary metastases.

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Rivera JA, Christopoulos S, Small D, Trifiro M. Hormonal manipulation of benign metastasizing leiomyomas: report of two cases and review of the literature. J Clin Endocrinol Metab. 2004;89(7):3183–8.CrossRefPubMed

Abell MR, Littler ER. Benign metastasizing uterine leiomyoma. Multiple lymph nodal metastases. Cancer. 1975;36(6):2206–13.CrossRefPubMed

Kayser K, Zink S, Schneider T, Dienemann H, Andre S, Kaltner H, et al. Benign metastasizing leiomyoma of the uterus: documentation of clinical, immunohistochemical and lectin-histochemical data of ten cases. Virchows Arch. 2000;437(3):284–92.CrossRefPubMed

Abu-Rustum NR, Curtin JP, Burt M, Jones WB. Regression of uterine low-grade smooth-muscle tumors metastatic to the lung after oophorectomy. Obstet Gynecol. 1997;89(5 Pt 2):850–2.CrossRefPubMed

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.CrossRefPubMed

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. 2014;33(2):140–5.CrossRefPubMed

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. 2006;19(1):130–40.CrossRefPubMed

Wu RC, Chao AS, Lee LY, Lin G, Chen SJ, Lu YJ, et al. Massively parallel sequencing and genome-wide copy number analysis revealed a clonal relationship in benign metastasizing leiomyoma. Oncotarget. 2017;8(29):47547–54.CrossRefPubMedPubMedCentral

Styer AK, Rueda BR. The epidemiology and genetics of uterine Leiomyoma. Best Pract Res Clin Obstet Gynaecol. 2016;34:3–12.CrossRefPubMed

10.

Lee HJ, Choi J, Kim KR. Pulmonary benign metastasizing leiomyoma associated with intravenous leiomyomatosis of the uterus: clinical behavior and genomic changes supporting a transportation theory. Int J Gynecol Pathol. 2008;27(3):340–5.CrossRefPubMed

11.

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.CrossRefPubMed

12.

Viljanen AA, Viljanen BC, Halttunen PK, Kreus KE. Pulmonary diffusing capacity and volumes in healthy adults measured with the single breath technique. Scand J Clin Lab Invest Suppl. 1982;159:21–34.CrossRefPubMed

13.

Laisk T, Haller-Kikkatalo K, Laanpere M, Jakovlev U, Peters M, Karro H, et al. Androgen receptor epigenetic variations influence early follicular phase gonadotropin levels. Acta Obstet Gynecol Scand. 2010;89(12):1557–63.CrossRefPubMed

14.

Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–99.CrossRefPubMed

15.

Hull ML, Escareno CR, Godsland JM, Doig JR, Johnson CM, Phillips SC, et al. Endometrial-peritoneal interactions during endometriotic lesion establishment. Am J Pathol. 2008;173(3):700–15.CrossRefPubMedPubMedCentral

16.

Beck MM, Biswas B, D'Souza A, Kumar R. Benign metastasising leiomyoma after hysterectomy and bilateral salpingo-oophorectomy. Hong Kong Med J. 2012;18(2):153–5.PubMed

17.

Tietze L, Gunther K, Horbe A, Pawlik C, Klosterhalfen B, Handt S, et al. Benign metastasizing leiomyoma: a cytogenetically balanced but clonal disease. Hum Pathol. 2000;31(1):126–8.CrossRefPubMed

18.

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.CrossRefPubMedPubMedCentral

19.

Hodge JC, Morton CC. Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. Hum Mol Genet. 2007;16 Spec No 1:R7–13.CrossRefPubMed

20.

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.CrossRefPubMedPubMedCentral

21.

Taftaf R, Starnes S, Wang J, Shipley R, Namad T, Khaled R, et al. Benign metastasizing leiomyoma: a rare type of lung metastases-two case reports and review of the literature. Case Rep Oncol Med. 2014;2014:842801.PubMedPubMedCentral

22.

Hague WM, Abdulwahid NA, Jacobs HS, Craft I. Use of LHRH analogue to obtain reversible castration in a patient with benign metastasizing leiomyoma. Br J Obstet Gynaecol. 1986;93(5):455–60.CrossRefPubMed

23.

Jacobson TZ, Rainey EJ, Turton CW. Pulmonary benign metastasising leiomyoma: response to treatment with goserelin. Thorax. 1995;50(11):1225–6.CrossRefPubMedPubMedCentral

24.

Guo X, Wang XF. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 2009;19(1):71–88.CrossRefPubMedPubMedCentral

25.

Ehata S, Yokoyama Y, Takahashi K, Miyazono K. Bi-directional roles of bone morphogenetic proteins in cancer: another molecular Jekyll and Hyde? Pathol Int. 2013;63(6):287–96.CrossRefPubMed

26.

Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, et al. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis. 2014;1(1):87–105.CrossRefPubMedPubMedCentral

27.

Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vazquez MJ, et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell. 2012;149(4):871–85.CrossRefPubMedPubMedCentral

28.

Wisnieski F, Leal MF, Calcagno DQ, Santos LC, Gigek CO, Chen ES, et al. BMP8B is a tumor suppressor gene regulated by Histone Acetylation in gastric cancer. J Cell Biochem. 2017;118(4):869–77.CrossRefPubMed

29.

Cheng Z, Cui W, Ding Y, Liu T, Liu W, Qin Y, et al. BMP8B mediates the survival of pancreatic cancer cells and regulates the progression of pancreatic cancer. Oncol Rep. 2014;32(5):1861–6.CrossRefPubMed

30.

Mima K, Fukagawa T, Kurashige J, Takano Y, Uchi R, Ueo H, et al. Gene expression of bone morphogenic protein 8B in the primary site, peripheral blood and bone marrow of patients with gastric cancer. Oncol Lett. 2013;6(2):387–92.CrossRefPubMedPubMedCentral

31.

Cai YR, Diao XL, Wang SF, Zhang W, Zhang HT, Su Q. X-chromosomal inactivation analysis of uterine leiomyomas reveals a common clonal origin of different tumor nodules in some multiple leiomyomas. Int J Oncol. 2007;31(6):1379–89.PubMed

32.

Medikare V, Kandukuri LR, Ananthapur V, Deenadayal M, Nallari P. The genetic bases of uterine fibroids; a review. J Reprod Infertil. 2011;12(3):181–91.PubMedPubMedCentral

33.

Haberal A, Kayikcioglu F, Caglar GS, Cavusoglu D. Leiomyomatosis peritonealis disseminata presenting with intravascular extension and coexisting with endometriosis: a case report. J Reprod Med. 2007;52(5):422–4.PubMed

34.

Mahmoud MS, Desai K, Nezhat FR. Leiomyomas beyond the uterus; benign metastasizing leiomyomatosis with paraaortic metastasizing endometriosis and intravenous leiomyomatosis: a case series and review of the literature. Arch Gynecol Obstet. 2015;291(1):223–30.CrossRefPubMed

Title: Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene
Authors: Deniss Sõritsa
Hindrek Teder
Retlav Roosipuu
Hannes Tamm
Triin Laisk-Podar
Pille Soplepmann
Alan Altraja
Andres Salumets
Maire Peters
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-018-0537-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene

Abstract

Background

Case presentation

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Case presentation

Conclusions

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