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J Neurol Surg B Skull Base 2017; 78(04): 346-352
DOI: 10.1055/s-0037-1601320
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable β-catenin Overexpression and a β-catenin Mutation

Andrew C. Birkeland   *
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Sarah J. Burgin   *
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Megan Yanik
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Megan V. Scott
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Carol R. Bradford
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
2   Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Jonathan B. McHugh
3   Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Scott A. McLean
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Stephen E. Sullivan
4   Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Jacques E. Nor
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
Erin L. McKean   †
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
,
J. Chad Brenner   †
1   Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States
2   Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
› Author Affiliations
Further Information

Publication History

20 November 2016

12 February 2017

Publication Date:
27 March 2017 (online)

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Abstract

Objective Sinonasal teratocarcinosarcomas are rare, aggressive tumors of the skull base. Treatment options are limited and outcomes are poor. Little is known in regard to the genetic factors regulating these tumors. Characterization of actionable molecular alterations in these tumors could provide potentially successful therapeutic options.

Methods We performed targeted exome sequencing on an index sinonasal teratocarcinosarcoma specimen to identify potential driver mutations. We performed immunohistochemical stains for β-catenin on paraffin-embedded tissue on the index tumor and a subsequent teratocarcinosarcoma. Online databases of cancer mutations (Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas) were accessed.

Results We identified an activating p.S45F mutation in β-catenin in our index sinonasal teratocarcinosarcoma. This mutation results in constitutive signaling in the Wnt/β-catenin pathway. We confirmed β-catenin overexpression and nuclear localization via immunohistochemistry in the index tumor and a second patient. The p.S45F activating mutation was found in a variety of solid tumors, and accounts for 3.3 to 10.4% of all known β-catenin mutations.

Conclusion We identified a potential driver mutation in β-catenin in a sinonasal teratocarcinosarcoma, resulting in β-catenin overexpression. These findings suggest a role for the Wnt/β-catenin pathway in sinonasal teratocarcinosarcoma tumorigenesis and a role for anti-β-catenin targeted therapy.

Keywords

CTNNB1 - Wnt - pathogenetics - sinonasal teratocarcinosarcoma - teratocarcinosarcoma - β-catenin

* These authors contributed equally to this work.


† These are cosenior authors.


Supplementary Material

 

  • References

  • 1 Misra P, Husain Q, Svider PF, Sanghvi S, Liu JK, Eloy JA. Management of sinonasal teratocarcinosarcoma: a systematic review. Am J Otolaryngol 2014; 35 (01) 5-11
    CrossrefPubMedSearch in Google Scholar
  • 2 Fatima SS, Minhas K, Din NU, Fatima S, Ahmed A, Ahmad Z. Sinonasal teratocarcinosarcoma: a clinicopathologic and immunohistochemical study of 6 cases. Ann Diagn Pathol 2013; 17 (04) 313-318
    CrossrefPubMedSearch in Google Scholar
  • 3 Wei S, Carroll W, Lazenby A, Bell W, Lopez R, Said-Al-Naief N. Sinonasal teratocarcinosarcoma: report of a case with review of literature and treatment outcome. Ann Diagn Pathol 2008; 12 (06) 415-425
    CrossrefPubMedSearch in Google Scholar
  • 4 Su YY, Friedman M, Huang CC, Wilson M, Lin HC. Sinonasal teratocarcinosarcoma. Am J Otolaryngol 2010; 31 (04) 300-303
    CrossrefPubMedSearch in Google Scholar
  • 5 Birkeland AC, Brenner JC. Personalizing medicine in head and neck squamous cell carcinoma: The rationale for combination therapies. Med Res Arch 2015; 2015 (03)
    PubMedSearch in Google Scholar
  • 6 Birkeland AC, Ludwig ML, Meraj TS, Brenner JC, Prince ME. The tip of the iceberg: clinical implications of genomic sequencing projects in head and neck cancer. Cancers (Basel) 2015; 7 (04) 2094-2109
    CrossrefPubMedSearch in Google Scholar
  • 7 Birkeland AC, Uhlmann WR, Brenner JC, Shuman AG. Getting personal: head and neck cancer management in the era of genomic medicine. Head Neck 2016; 38 (Suppl. 01) E2250-E2258
    CrossrefPubMedSearch in Google Scholar
  • 8 Giefing M, Wierzbicka M, Szyfter K. , et al. Moving towards personalised therapy in head and neck squamous cell carcinoma through analysis of next generation sequencing data. Eur J Cancer 2016; 55: 147-157
    CrossrefPubMedSearch in Google Scholar
  • 9 Birkeland AC, Yanik M, Tillman BN. , et al. Identification of targetable ERBB2 aberrations in head and neck squamous cell carcinoma. JAMA Otolaryngol Head Neck Surg 2016; 142 (06) 559-567
    Search in Google Scholar
  • 10 Tillman BN, Yanik M, Birkeland AC. , et al. Fibroblast growth factor family aberrations as a putative driver of head and neck squamous cell carcinoma in an epidemiologically low-risk patient as defined by targeted sequencing. Head Neck 2016; 38 (Suppl. 01) E1646-E1652
    CrossrefPubMedSearch in Google Scholar
  • 11 Warrick JI, Hovelson DH, Amin A. , et al. Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma. Virchows Arch 2015; 466 (03) 297-311
    CrossrefPubMedSearch in Google Scholar
  • 12 Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38 (16) e164
    Search in Google Scholar
  • 13 Forbes SA, Beare D, Gunasekaran P. , et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res 2015; 43 (Database issue): D805-D811
    CrossrefPubMedSearch in Google Scholar
  • 14 Weinstein JN, Collisson EA, Mills GB. , et al; Cancer Genome Atlas Research Network. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 2013; 45 (10) 1113-1120
    CrossrefPubMedSearch in Google Scholar
  • 15 Ludwig ML, Birkeland AC, Hoesli R, Swiecicki P, Spector ME, Brenner JC. Changing the paradigm: the potential for targeted therapy in laryngeal squamous cell carcinoma. Cancer Biol Med 2016; 13 (01) 87-100
    PubMedSearch in Google Scholar
  • 16 Michmerhuizen NL, Birkeland AC, Bradford CR, Brenner JC. Genetic determinants in head and neck squamous cell carcinoma and their influence on global personalized medicine. Genes Cancer 2016; 7 (5-6): 182-200
    PubMedSearch in Google Scholar
  • 17 Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol 2013; 59 (05) 1107-1117
    CrossrefPubMedSearch in Google Scholar
  • 18 Arend RC, Londoño-Joshi AI, Straughn Jr JM, Buchsbaum DJ. The Wnt/b-catenin pathway in ovarian cancer: a review. Gynecol Oncol 2013; 131 (03) 772-779
    CrossrefPubMedSearch in Google Scholar
  • 19 Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst 2014; 106 (01) djt356
    CrossrefPubMedSearch in Google Scholar
  • 20 Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997; 275 (5307): 1790-1792
    CrossrefPubMedSearch in Google Scholar
  • 21 Morin PJ, Sparks AB, Korinek V. , et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997; 275 (5307): 1787-1790
    CrossrefPubMedSearch in Google Scholar
  • 22 Liu J, Pan S, Hsieh MH. , et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A 2013; 110 (50) 20224-20229
    CrossrefPubMedSearch in Google Scholar
  • 23 Hamada S, Futamura N, Ikuta K. , et al. CTNNB1 S45F mutation predicts poor efficacy of meloxicam treatment for desmoid tumors: a pilot study. PLoS One 2014; 9 (05) e96391
    CrossrefPubMedSearch in Google Scholar
  • 24 Colombo C, Miceli R, Lazar AJ. , et al. CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study. Cancer 2013; 119 (20) 3696-3702
    CrossrefPubMedSearch in Google Scholar
  • 25 Conley BA, Doroshow JH. Molecular analysis for therapy choice: NCI MATCH. Semin Oncol 2014; 41 (03) 297-299
    CrossrefPubMedSearch in Google Scholar
  • 26 Tsimberidou AM, Wen S, Hong DS. , et al. Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analyses. Clin Cancer Res 2014; 20 (18) 4827-4836
    CrossrefPubMedSearch in Google Scholar
  • 27 Delgado ER, Yang J, So J. , et al. Identification and characterization of a novel small-molecule inhibitor of b-catenin signaling. Am J Pathol 2014; 184 (07) 2111-2122
    CrossrefPubMedSearch in Google Scholar
  • 28 Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci 2014; 105 (09) 1087-1092
    CrossrefPubMedSearch in Google Scholar