Germline variants in patients diagnosed with pediatric soft tissue sarcoma
DOI:
https://doi.org/10.2340/1651-226X.2024.40730Keywords:
Soft tissue sarcoma, pathogenic germline variants, hereditary, MYO3A, MYO5B, CHD1LAbstract
Background: While soft tissue sarcomas affect younger patients, few studies have assessed the distribution of underlying pathogenic germline variants.
Patients and methods: We retrospectively identified all pediatric and young adult patients (0–22 years) at Haukeland University Hospital, Norway (1981–2019), through clinical and pathological records. We identified n = 46 eligible patients. From these 46 patients, adequate material representing normal tissue was available for n = 41 cases (n = 24 diagnosed with rhabdomyosarcoma, 9 with synovial sarcomas, 2 with Ewing sarcomas, and 6 without further classification), with matching tumor tissue for n = 40. Normal tissue samples were analyzed for germline pathogenic variants (PVs) by targeted sequencing of 360 cancer genes.
Results: Out of the 41 analyzed cases, we found PVs or likely PVs in 7 (17%). These variants were found in TP53, MUTYH, FANCC, DICER1, FANCA, MYO3A, and MYO5B. Supporting the causality of these PVs, four cases revealed loss of heterozygosity (LOH) of the wild-type allele in the tumor tissue, one patient with a PV in DICER1 had a second somatic variant in DICER1, and a patient with a PV in TP53 had the altered allele amplified in the tumor. For three out of five with available family history, a history of other cancers in relatives was recorded. Among genes with variants of uncertain significance, CHD1L was of particular interest, revealing a stop-gain and a missense variant.
Interpretation: A high fraction of young patients with soft tissue sarcoma harbor PVs. Among the genes affected, we substantiate a potential role of MYO5B and propose a potential role for MYO3A.
Downloads
References
Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2(1):14.
https://doi.org/10.1186/2045-3329-2-14 DOI: https://doi.org/10.1186/2045-3329-2-14
Lu Y, Ek WE, Whiteman D, Vaughan TL, Spurdle AB, Easton DF, et al. Most common ‘sporadic’ cancers have a significant germline genetic component. Hum Mol Genet. 2014;23(22):6112–8.
https://doi.org/10.1093/hmg/ddu312 DOI: https://doi.org/10.1093/hmg/ddu312
Skapek SX, Ferrari A, Gupta AA, Lupo PJ, Butler E, Shipley J, et al. Rhabdomyosarcoma. Nat Rev Dis Primers. 2019;5:1.
https://doi.org/10.1038/s41572-018-0051-2 DOI: https://doi.org/10.1038/s41572-018-0051-2
Martin-Giacalone BA, Weinstein PA, Plon SE, Lupo PJ. Pediatric rhabdomyosarcoma: epidemiology and genetic susceptibility. J Clin Med. 2021;10(9):2028.
https://doi.org/10.3390/jcm10092028 DOI: https://doi.org/10.3390/jcm10092028
Arora RS, Alston RD, Eden TO, Geraci M, Birch JM. The contrasting age-incidence patterns of bone tumours in teenagers and young adults: implications for aetiology. Int J Cancer. 2012;131(7):1678–85.
https://doi.org/10.1002/ijc.27402 DOI: https://doi.org/10.1002/ijc.27402
Schneider KW, Cost NG, Schultz KAP, Svihovec S, Suttman A. Germline predisposition to genitourinary rhabdomyosarcoma. Transl Androl Urol. 2020;9(5):2430–40.
https://doi.org/10.21037/tau-20-76 DOI: https://doi.org/10.21037/tau-20-76
Kim J, Light N, Subasri V, Young EL, Wegman-Ostrosky T, Barkauskas DA, et al. Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma. JCO Precis Oncol. 2021;5:75–87.
https://doi.org/10.1200/PO.20.00218 DOI: https://doi.org/10.1200/PO.20.00218
Li H, Sisoudiya SD, Martin-Giacalone BA, Khayat MM, Dugan-Perez S, Marquez-Do DA, et al. Germline cancer predisposition variants in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group. J Natl Cancer Inst. 2021;113(7):875–83.
https://doi.org/10.1093/jnci/djaa204 DOI: https://doi.org/10.1093/jnci/djaa204
Walsh T, Gulsuner S, Lee MK, Troester MA, Olshan AF, Earp HS, et al. Inherited predisposition to breast cancer in the Carolina Breast Cancer Study. Npj Breast Cancer. 2021;7(1):6.
https://doi.org/10.1038/s41523-020-00214-4 DOI: https://doi.org/10.1038/s41523-020-00214-4
Narod SA, Hawkins MM, Robertson CM, Stiller CA. Congenital anomalies and childhood cancer in Great Britain. Am J Hum Genet. 1997;60(3):474–85.
Merks JHM, Caron HN, Hennekam RCM. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet Part A. 2005;134A(2):132–43.
https://doi.org/10.1002/ajmg.a.30603 DOI: https://doi.org/10.1002/ajmg.a.30603
Jongmans MCJ, Loeffen J, Waanders E, Hoogerbrugge PM, Ligtenberg MJL, Kuiper RP, et al. Recognition of genetic predisposition in pediatric cancer patients: an easy-to-use selection tool. Eur J Med Genet. 2016;59(3):116–25.
https://doi.org/10.1016/j.ejmg.2016.01.008
Yang P, Grufferman S, Khoury MJ, Schwartz AG, Kowalski J, Ruymann FB, et al. Association of childhood rhabdomyosarcoma with neurofibromatosis type I and birth defects. Genet Epidemiol. 1995;12(5):467–74.
https://doi.org/10.1016/j.ejmg.2016.01.008 DOI: https://doi.org/10.1016/j.ejmg.2016.01.008
Lupo PJ, Schraw JM, Desrosiers TA, Nembhard WN, Langlois PH, Canfield MA, et al. Association between birth defects and cancer risk among children and adolescents in a population-based assessment of 10 million live births. JAMA Oncol. 2019;5(8):1150–8.
https://doi.org/10.1002/gepi.1370120504 DOI: https://doi.org/10.1002/gepi.1370120504
Brockschmidt A, Chung B, Weber S, Fischer DC, Kolatsi-Joannou M, Christ L, et al. CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT). Nephrol Dialysis Transplant. 2012;27(6):2355–64.
https://doi.org/10.1001/jamaoncol.2019.1215 DOI: https://doi.org/10.1001/jamaoncol.2019.1215
Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, et al. Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 2014;85(6):1429–33.
https://doi.org/10.1093/ndt/gfr649 DOI: https://doi.org/10.1093/ndt/gfr649
Venizelos A, Elvebakken H, Perren A, Nikolaienko O, Deng W, Lothe IMB, et al. The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocrine-related Cancer. 2022;29(1):1–14. DOI: https://doi.org/10.1530/ERC-21-0152
https://doi.org/10.1038/ki.2013.508 DOI: https://doi.org/10.1038/ki.2013.508
Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G, Van Loo P, et al. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med. 2015;21(7):751–9.
https://doi.org/10.1038/nm.3886 DOI: https://doi.org/10.1038/nm.3886
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.
https://doi.org/10.1038/gim.2015.30
Nakken S, Saveliev V, Hofmann O, Moller P, Myklebost O, Hovig E. Cancer Predisposition Sequencing Reporter (CPSR): a flexible variant report engine for high-throughput germline screening in cancer. Int J Cancer. 2021;149(11):1955–60. DOI: https://doi.org/10.1002/ijc.33749
https://doi.org/10.1038/gim.2015.30 DOI: https://doi.org/10.1038/gim.2015.30
Yang H, Wang K. Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protocols. 2015;10(10):1556–66.
https://doi.org/10.1038/nprot.2015.105 DOI: https://doi.org/10.1038/nprot.2015.105
Jones D, Raine KM, Davies H, Tarpey PS, Butler AP, Teague JW, et al. cgpCaVEManWrapper: simple execution of CaVEMan in order to detect somatic single nucleotide variants in NGS sata. Curr Protoc Bioinformatics. 2016;56:15.10.1–18.
https://doi.org/10.1002/cpbi.20 DOI: https://doi.org/10.1002/cpbi.20
Raine KM, Hinton J, Butler AP, Teague JW, Davies H, Tarpey P, et al. cgpPindel: identifying somatically acquired insertion and deletion events from paired end sequencing. Curr Protoc Bioinformatics. 2015;52:15.7.1–2.
https://doi.org/10.1002/0471250953.bi1507s52 DOI: https://doi.org/10.1002/0471250953.bi1507s52
Shen R, Seshan VE. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016;44(16):e131.
https://doi.org/10.1093/nar/gkw520 DOI: https://doi.org/10.1093/nar/gkw520
Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R, Rosenberg M, et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 2014;4(2):216–31.
https://doi.org/10.1158/2159-8290.CD-13-0639 DOI: https://doi.org/10.1158/2159-8290.CD-13-0639
Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, et al. From flies’ eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci U S A. 2002;99(11):7518–23.
https://doi.org/10.1073/pnas.102091699 DOI: https://doi.org/10.1073/pnas.102091699
Muller T, Hess MW, Schiefermeier N, Pfaller K, Ebner HL, Heinz-Erian P, et al. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008;40(10):1163–5.
https://doi.org/10.1038/ng.225
Capasso M, Montella A, Tirelli M, Maiorino T, Cantalupo S, Iolascon A. Genetic predisposition to solid pediatric cancers. Front Oncol. 2020;10:590033.
https://doi.org/10.1038/ng.225 DOI: https://doi.org/10.1038/ng.225
Gillani R, Camp SY, Han S, Jones JK, Chu H, O’Brien S, et al. Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes. Am J Hum Genet. 2022;109(6):1026–37.
https://doi.org/10.3389/fonc.2020.590033 DOI: https://doi.org/10.3389/fonc.2020.590033
Roland JT, Bryant DM, Datta A, Itzen A, Mostov KE, Goldenring JR. Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. Proc Natl Acad Sci U S A. 2011;108(7):2789–94. DOI: https://doi.org/10.1073/pnas.1010754108
https://doi.org/10.1016/j.ajhg.2022.04.007 DOI: https://doi.org/10.1016/j.ajhg.2022.04.007
Akhavanfard S, Padmanabhan R, Yehia L, Cheng FX, Eng C. Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors. Nat Commun. 2020;11(1):2206.
https://doi.org/10.1038/s41467-020-16067-1 DOI: https://doi.org/10.1038/s41467-020-16067-1
Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373(24):2336–46.
https://doi.org/10.1056/NEJMoa1508054 DOI: https://doi.org/10.1056/NEJMoa1508054
Additional Files
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2023 Synnøve Yndestad, Hans Kristian Haugland, Dorota Goplen, Dorota Wojcik, Stian Knappskog, Per Eystein Lønning
This work is licensed under a Creative Commons Attribution 4.0 International License.
