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Genetic Predisposition to Sarcoma: What Should Clinicians Know?

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Pathogenic germline variants in the setting of several associated cancer predisposition syndromes (CPS) may lead to the development of sarcoma. We would consider testing for a CPS in patients with a strong family history of cancer, multiple primary malignancies, and/or pediatric/adolescent/young adult patients diagnosed with other malignancies strongly associated with CPS. When a CPS is diagnosed in a patient with sarcoma, additional treatment considerations and imaging options for those patients are required. This applies particularly to the use of radiation therapy, ionizing radiation with diagnostic imaging, and the use of alkylating chemotherapy. As data and guidelines are currently lacking for many of these scenarios, we have adopted a shared decision-making process with patients and their families. If the best chance for cure in a patient with CPS requires utilization of radiation therapy or alkylating chemotherapy, we discuss the risks with the patient but do not omit these modalities. However, if there are treatment options that yield equivalent survival rates, yet avoid these modalities, we elect for those options. Considering staging imaging and post-therapy evaluation for sarcoma recurrence, we avoid surveillance techniques that utilize ionizing radiation when possible but do not completely omit them when their use is indicated.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Vagher J, et al. Germline predisposition to soft tissue sarcoma. J Cancer Metastasis Treat. 2022;8:31. This reference is important as it has provided a detailed review of common soft tissue sarcomas related to cancer predisposition syndromes.

  2. Zhang J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373(24):2336–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chavarri-Guerra Y, et al. Genetic cancer predisposition syndromes among older adults. J Geriatr Oncol. 2020;11(7):1054–60.

    Article  PubMed  PubMed Central  Google Scholar 

  4. •• Kumamoto T, et al. Medical guidelines for Li–Fraumeni syndrome 2019, version 1.1. Int J Clin Oncol. 2021;26:2161–2178. This article is of major importance as it provides screening guidelines for LFS.

  5. Vogt A, et al. Multiple primary tumours: challenges and approaches, a review. ESMO Open. 2017;2(2): e000172.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Li H, et al. Germline cancer predisposition variants in pediatric rhabdomyosarcoma: a report from the children’s oncology group. JNCI J Natl Cancer Inst. 2021;113(7):875–883.

  7. Fair D, et al. TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children’s Oncology Group report. Pediatr Blood Cancer. 2023;70(9): e30413.

    Article  CAS  Google Scholar 

  8. Schultz KAP, et al. DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res. 2018;24(10):2251–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Apellaniz-Ruiz M, McCluggage WG, Foulkes WD. DICER1-associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: pathology, molecular genetics, and indications for molecular testing. Genes Chromosomes Cancer. 2021;60(3):217–33.

    Article  CAS  PubMed  Google Scholar 

  10. Martin-Giacalone BA, et al. Pediatric Rhabdomyosarcoma: epidemiology and genetic susceptibility. J Clin Med. 2021;10(9):2028.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Miller RW, Rubinstein JH. Tumors in Rubinstein-Taybi syndrome. Am J Med Genet. 1995;56(1):112–5.

    Article  CAS  PubMed  Google Scholar 

  12. Mussa A, et al. Cancer risk in Beckwith-Wiedemann syndrome: a systematic review and meta-analysis outlining a novel (epi)genotype specific histotype targeted screening protocol. J Pediatr. 2016;176:142–149 e1.

  13. Ducatman BS, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 1986;57(10):2006–21.

  14. Wong WW, et al. Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys. 1998;42(2):351–60.

    Article  CAS  PubMed  Google Scholar 

  15. Anghileri M, et al. Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution. Cancer: Interdiscip Int J Am Cancer Soc. 2006;107(5):1065–1074.

  16. Evans DG, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39(5):311–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stucky CC, et al. Malignant peripheral nerve sheath tumors (MPNST): the Mayo Clinic experience. Ann Surg Oncol. 2012;19(3):878–85.

    Article  PubMed  Google Scholar 

  18. Evans DG, Huson SM, Birch JM. Malignant peripheral nerve sheath tumours in inherited disease. Clin Sarcoma Res. 2012;2(1):17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Brohl AS, et al. Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma. Genet Med. 2017;19(8):955–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gillani R, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mirabello L, et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 2020;6(5):724–34.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Diessner BJ, et al. Nearly half of TP53 germline variants predicted to be pathogenic in patients with osteosarcoma are de novo: a report from the Children’s Oncology Group. JCO Precis Oncol. 2020;4:1187–95.

    Article  Google Scholar 

  23. Calvert GT, et al. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma. 2012;2012: 152382.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wong FL, et al. Cancer incidence after retinoblastoma: radiation dose and sarcoma risk. JAMA. 1997;278(15):1262–7.

    Article  CAS  PubMed  Google Scholar 

  25. Bougeard G, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33(21):2345–52.

    Article  CAS  PubMed  Google Scholar 

  26. Villani A, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011;12(6):559–67.

    Article  CAS  PubMed  Google Scholar 

  27. de Andrade KC, et al. Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol. 2021;22(12):1787–98.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kleinerman RA, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23(10):2272–9.

    Article  PubMed  Google Scholar 

  29. MacCarthy A, et al. Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951–2004. Br J Cancer. 2013;108(12):2455–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bright CJ, et al. Risk of soft-tissue sarcoma among 69 460 five-year survivors of childhood cancer in Europe. JNCI J Natl Cancer Inst. 2018;110(6): 649–660.

  31. Kleinerman RA, et al. Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst. 2007;99(1):24–31.

    Article  PubMed  Google Scholar 

  32. Hensley ML, et al. Genomic landscape of uterine sarcomas defined through prospective clinical sequencing. Clin Cancer Res. 2020;26(14):3881–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jonsson P, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571(7766):576–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kraft S, Fletcher CD. Atypical intradermal smooth muscle neoplasms: clinicopathologic analysis of 84 cases and a reappraisal of cutaneous “leiomyosarcoma.” Am J Surg Pathol. 2011;35(4):599–607.

    Article  PubMed  Google Scholar 

  35. Fallen T, et al. Desmoid tumors–a characterization of patients seen at Mayo Clinic 1976–1999. Fam Cancer. 2006;5(2):191–4.

    Article  PubMed  Google Scholar 

  36. Eaton KW, et al. Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer. 2011;56(1):7–15.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bourdeaut F, et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res. 2011;17(1):31–8.

    Article  CAS  PubMed  Google Scholar 

  38. Foulkes WD, et al. Cancer surveillance in Gorlin syndrome and rhabdoid tumor predisposition syndrome. Clin Cancer Res. 2017;23(12):e62–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schneppenheim R, et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet. 2010;86(2):279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nemes K, Bens S, Bourdeaut F. Rhabdoid tumor predisposition syndrome, 2017 Dec 7. GeneReviews®[Internet]. Seattle: University of Washington; 1993.

  41. Hirota S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.

    Article  CAS  PubMed  Google Scholar 

  42. Ponti G, et al. Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting. Oncol Rep. 2010;23(2):437–44.

    CAS  PubMed  Google Scholar 

  43. Postow MA, Robson ME. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin Sarcoma Res. 2012;2(1):16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chompret A, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. 2004;126(1):318–21.

    Article  CAS  PubMed  Google Scholar 

  45. Janeway KA, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011;108(1):314–8.

    Article  CAS  PubMed  Google Scholar 

  46. Miettinen M, et al. Succinate dehydrogenase deficient gists–a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric gists with predilection to young age. Am J Surg Pathol. 2011;35(11):1712.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zoller ME, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer. 1997;79(11):2125–31.

    Article  CAS  PubMed  Google Scholar 

  48. Yang XR, et al. T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet. 2009;41(11):1176–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Parry DM, et al. Clinical findings in families with chordoma with and without T gene duplications and in patients with sporadic chordoma reported to the surveillance, epidemiology, and end results program. J Neurosurg. 2020;134(5):1399–408.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kelley M, et al. Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma. Hum Genet. 2014;133(10):1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pillay N, et al. A common single-nucleotide variant in T is strongly associated with chordoma. Nat Genet. 2012;44(11):1185–7.

    Article  CAS  PubMed  Google Scholar 

  52. Yepes S, et al. Rare germline variants in chordoma-related genes and chordoma susceptibility. Cancers. 2021;13(11):2704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Young RJ, et al. Angiosarcoma. Lancet Oncol. 2010;11(10):983–91.

    Article  PubMed  Google Scholar 

  54. El Abiad JM, et al. Natural history of Ollier disease and Maffucci syndrome: patient survey and review of clinical literature. Am J Med Genet A. 2020;182(5):1093–103.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Blatt J, et al. Cancer risk in Klippel-Trenaunay syndrome. Lymphat Res Biol. 2019;17(6):630–6.

    Article  PubMed  Google Scholar 

  56. West JG, et al. BRCA mutations and the risk of angiosarcoma after breast cancer treatment. Clin Breast Cancer. 2008;8(6):533–7.

    Article  PubMed  Google Scholar 

  57. Kadouri L, et al. Genetic predisposition to radiation induced sarcoma: possible role for BRCA and p53 mutations. Breast Cancer Res Treat. 2013;140(1):207–11.

    Article  CAS  PubMed  Google Scholar 

  58. Calvete O, et al. The wide spectrum of POT1 gene variants correlates with multiple cancer types. Eur J Hum Genet. 2017;25(11):1278–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Calvete O, et al. A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families. Nat Commun. 2015;6:8383.

    Article  CAS  PubMed  Google Scholar 

  60. Anderson WJ, Doyle LA. Updates from the 2020 World Health Organization classification of soft tissue and bone tumours. Histopathology. 2021;78(5):644–57.

    Article  PubMed  Google Scholar 

  61. Frebourg T, et al. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. 2020;28(10):1379–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hampel H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70–87.

    Article  PubMed  Google Scholar 

  63. •• Waespe N, et al. Cancer predisposition syndromes as a risk factor for early second primary neoplasms after childhood cancer–a national cohort study. Eur J Cancer. 2021;145:71–80. This article is of major importance as it outlines the risks for secondary primary malignancies in pediatric patients in relation to their cancer predisposition syndrome.

  64. Stiller CA, et al. Subsequent cancers within 5 years from initial diagnosis of childhood cancer. Patterns and risks in the population of Great Britain. Pediatr Blood Cancer 2023;70(5): e30258.

  65. Eulo V, et al. Secondary sarcomas: biology, presentation, and clinical care. Am Soc Clin Oncol Educ Book. 2020;40:463–74.

    Article  Google Scholar 

  66. •• Hendrickson PG, et al. Radiation therapy and secondary malignancy in Li‐Fraumeni syndrome: a hereditary cancer registry study. Cancer Med. 2020;9(21): 7954–7963. This article is of major importance as it proved radiation therapy does not significantly increase the risk for second primary malignancies induced by RT in patients with LFS.

  67. Funato M, et al. Characteristics of Li-Fraumeni syndrome in Japan; a review study by the Special Committee of JSHT. Cancer Sci. 2021;112(7):2821–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kasper E, et al. Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations. Eur J Cancer. 2018;101:254–62.

    Article  CAS  PubMed  Google Scholar 

  69. • Clarke JE, et al. Radiologic screening and surveillance in hereditary cancers. Eur J Radiol Open. 2022;9: 100422. This article is of importance as it shows that imaging surveillance with whole body MRI is beneficial in patients with cancer predisposition syndromes.

  70. Reid JR. Ionizing radiation use and cancer predisposition syndromes in children. J Am Coll Radiol. 2018;15(9):1238–9.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Population Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    Jennie Vagher CGC, Casey J. Mehrhoff DO, MS & Luke D. Maese DO

  2. Division of Hematology/Oncology, Primary Children’s Hospital, University of Utah, 100 Mario Capecchi Dr, Salt Lake City, UT, 84113, USA

    Casey J. Mehrhoff DO, MS & Luke D. Maese DO

  3. Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

    Vaia Florou MD, MS

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  1. Jennie Vagher CGC
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  2. Casey J. Mehrhoff DO, MS
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  3. Vaia Florou MD, MS
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  4. Luke D. Maese DO
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CJM and JV are co-first authors

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Correspondence to Luke D. Maese DO.

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Jennie Vagher declares she has received payment or honoraria for participation in the National Society of Genetic Counselors AC.2022 and AAMDS Foundation 2023. Casey Mehrhoff declares she has no conflict of interest. Vaia Florou declares she has received consulting fees from Deciphera and Incyte. Luke Maese declares he has served as a consultant, received payment or honoraria for involvement with, and has participated on the Data Safety Monitoring or Advisory Board for Jazz Pharmaceuticals. Luke Maese also declares he has participated on the Data Safety Monitoring or Advisory Board for Servier Pharmaceuticals.

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Vagher, J., Mehrhoff, C.J., Florou, V. et al. Genetic Predisposition to Sarcoma: What Should Clinicians Know?. Curr. Treat. Options in Oncol. (2024). https://doi.org/10.1007/s11864-024-01192-6

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