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Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype

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Abstract

Purpose

Rhabdomyosarcoma (RMS), which is the most common pediatric soft tissue sarcoma, is classified into two major histologic subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). RMS is occasionally reported to be the second neoplasm of hereditary retinoblastoma. Osteosarcoma is known as the most common second neoplasm of hereditary retinoblastoma, and tumorigenesis of osteosarcoma has been proven in previous studies to be related to the RB gene (RB1) alteration. Therefore, there might be a correlation between the tumorigenesis of RMS and RB1 alteration.

Methods

We examined the RB protein (pRB) expression and RB1 alteration such as allelic imbalance (gain or loss) and homozygous deletion, using immunohistochemistry, microsatellite makers, and quantitative real-time PCR in 57 sporadic RMS.

Results

Allelic imbalance was more frequently detected in ERMS (13/27), than in ARMS (3/20) (P = 0.04). Homozygous deletion on the protein-binding pocket domain of RB1 was found in 6 of 27 ERMS and in 2 of 20 ARMS (P = 0.24). Furthermore, immunohistochemical pRB labeling indexes (LI) in 31 ERMS (median value, 31%) were significantly reduced in comparison with those observed in 26 ARMS (median value, 85%) (P < 0.0001).

Conclusions

Our results support the assertion that tumorigenesis of RMS may be associated with RB1 alteration especially in ERMS, as previously reported for osteosarcoma. As for the RB pathway, each subtype of RMS may have a different tumorigenesis. In addition, immunohistochemical pRB LI may have the potential to be a useful ancillary tool in the differential diagnosis of RMS subtypes.

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Abbreviations

RMS:

Rhabdomyosarcoma

ERMS:

Embryonal rhabdomyosarcoma

ARMS:

Alveolar rhabdomyosarcoma

RB1:

Retinoblastoma gene

pRB:

Retinoblastoma protein

LI:

Labeling index

AI:

Allelic imbalance

References

  • Aerts I, Pacquement H, Doz F, Mosseri V, Desjardins L, Sastre X, Michon J, Rodriguez J, Schlienger P, Zucker JM, Quintana E (2004) Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Eur J Cancer 40:1522–1529

    Article  PubMed  Google Scholar 

  • Asakura A, Rudnicki MA (2003) Rhabdomyosarcomagenesis-Novel pathway found. Cancer Cell 4:421–422

    Article  PubMed  CAS  Google Scholar 

  • Aveyard JS, Knowles MA (2004) Measurement of relative copy number of CDKN2A/ARF and CDKN2B in bladder cancer by real-time quantitative PCR and multiplex ligation-dependent probe amplification. J Mol Diagn 6:356–365

    PubMed  CAS  Google Scholar 

  • Berggren P, Kumar R, Sakano S, Hemminki L, Wada T, Steineck G, Adolfsson J, Larsson P, Norming U, Wijkstrom H, Hemminki K (2003) Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res 9:235–242

    PubMed  CAS  Google Scholar 

  • Bergthorsson JT, Agnarsson BA, Gudbjartsson T, Magnusson K, Thoroddsen A, Palsson B, Bjornsson J, Stefansson K, Gulcher J, Einarsson GV, Amundadottir LT, Barkardottir RB (2006) A genome-wide study of allelic imbalance in human testicular germ cell tumors using microsatellite markers. Cancer Genet Cytogenet 164:1–9

    Article  PubMed  CAS  Google Scholar 

  • Bridge JA, Liu J, Qualman SJ, Suijkerbuijk R, Wenger G, Zhang J, Wan X, Baker KS, Sorensen P, Barr FG (2002) Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer 33:310–321

    Article  PubMed  CAS  Google Scholar 

  • Gordon T, McManus A, Anderson J, Min T, Swansbury J, Pritchard-Jones K, Shipley J; United Kingdom Children’s Cancer Study Group; United Kingdom Cancer Cytogenetics Group (2001) Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study. Med Pediatr Oncol 36:259–267

    Article  PubMed  CAS  Google Scholar 

  • Helman LJ, Meltzer P (2003) Mechanisms of sarcoma development. Nat Rev Cancer 3:685–694

    Article  PubMed  CAS  Google Scholar 

  • Hostein I, Andraud-Fregeville M, Guillou L, Terrier-Lacombe MJ, Deminiere C, Ranchere D, Lussan C, Longavenne E, Bui NB, Delattre O, Coindre JM (2004) Rhabdomyosarcoma: value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype: an analysis of 109 paraffin-embedded specimens. Cancer 101:2817–2824

    Article  PubMed  CAS  Google Scholar 

  • Jin L, Majerus J, Oliveira A, Inwards CY, Nascimento AG, Burgart LJ, Lloyd RV (2003) Detection of fusion gene transcripts in fresh-frozen and formalin-fixed paraffin-embedded tissue sections of soft-tissue sarcomas after laser capture microdissection and rt-PCR. Diagn Mol Pathol 12:224–230

    Article  PubMed  CAS  Google Scholar 

  • Koi M, Johnson LA, Kalikin LM, Little PF, Nakamura Y, Feinberg AP (1993) Tumor cell growth arrest caused by subchromosomal transferable DNA fragments from chromosome 11. Science 260:361–364

    Article  PubMed  CAS  Google Scholar 

  • Labuhn M, Jones G, Speel EJ, Maier D, Zweifel C, Gratzl O, Van Meir EG, Hegi ME, Merlo A (2001) Quantitative real-time PCR does not show selective targeting of p14(ARF) but concomitant inactivation of both p16(INK4A) and p14(ARF) in 105 human primary gliomas. Oncogene 20:1103–1109

    Article  PubMed  CAS  Google Scholar 

  • Li M, Squire JA, Weksberg R (1998) Molecular genetics of Wiedemann-Beckwith syndrome. Am J Med Genet 79:253–259

    Article  PubMed  CAS  Google Scholar 

  • Loh WE Jr, Scrable HJ, Livanos E, Arboleda MJ, Cavenee WK, Oshimura M, Weissman BE (1992) Human chromosome 11 contains two different growth suppressor genes for embryonal rhabdomyosarcoma. Proc Natl Acad Sci USA 89:1755–1759

    Article  PubMed  CAS  Google Scholar 

  • Nishimura T, Nishida N, Komeda T, Fukuda Y, Ikai I, Yamaoka Y, Nakao K (2006) Genome-wide semiquantitative microsatellite analysis of human hepatocellular carcinoma: discrete mapping of smallest region of overlap of recurrent chromosomal gains and losses. Cancer Genet Cytogenet 167:57–65

    Article  PubMed  CAS  Google Scholar 

  • Parham DM, Barr FG (2002a) Alveolar rhabdomyosarcoma. In: Fletcher CDM, Unni KK, Mertens F (eds) WHO classification of tumours, pathology and genetics of tumours of soft tissue and bone. IARG Press, Lyon, pp 150–152

    Google Scholar 

  • Parham DM, Barr FG (2002b) Embryonal rhabdomyosarcoma. In: Fletcher CDM, Unni KK, Mertens F (eds) WHO classification of tumours, pathology and genetics of tumours of soft tissue and bone. IARG Press, Lyon, pp 146–149

    Google Scholar 

  • Polito P, Dal Cin P, Sciot R, Brock P, Van Eyken P, Van den Berghe H (1999) Embryonal rhabdomyosarcoma with only numerical chromosome changes. Case report and review of the literature. Cancer Genet Cytogenet 109:161–165

    Article  PubMed  CAS  Google Scholar 

  • Raymond AK, Ayala AG, Knuutila S (2002) Conventional osteosarcoma. In: Fletcher CDM, Unni KK, Mertens F (eds) WHO classification of tumours, pathology and genetics of tumours of soft tissue and bone. IARG Press, Lyon, pp 264–270

    Google Scholar 

  • Scrable HJ, Witte DP, Lampkin BC, Cavenee WK (1987) Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. Nature 329:645–647

    Article  PubMed  CAS  Google Scholar 

  • Takahira T, Oda Y, Tamiya S, Yamamoto H, Kobayashi C, Izumi T, Ito K, Iwamoto Y, Tsuneyoshi M (2005) Alterations of the RB1 gene in dedifferentiated liposarcoma. Mod Pathol 18:1461–1470

    Article  PubMed  CAS  Google Scholar 

  • Tateishi U, Hasegawa T, Miyakawa K, Sumi M, Moriyama N (2003) CT and MRI features of recurrent tumors and second primary neoplasms in pediatric patients with retinoblastoma. Am J Roentgenol 181:879–884

    Google Scholar 

  • Wadayama B, Toguchida J, Shimizu T, Ishizaki K, Sasaki MS, Kotoura Y, Yamamuro T (1994) Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res 54:3042–3048

    PubMed  CAS  Google Scholar 

  • Xia SJ, Pressey JG, Barr FG (2002) Molecular pathogenesis of rhabdomyosarcoma. Cancer Biol Ther 1:97–104

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The English used in this manuscript was revised by KN International (http://www.kninter.com/).

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Authors and Affiliations

  1. Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan

    Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomonari Takahira & Masazumi Tsuneyoshi

  2. Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan

    Yukiko Takahashi, Tatsuro Tajiri, Tomoaki Taguchi & Sachiyo Suita

Authors
  1. Kenichi Kohashi
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  2. Yoshinao Oda
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  3. Hidetaka Yamamoto
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  4. Sadafumi Tamiya
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  5. Tomonari Takahira
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  6. Yukiko Takahashi
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  7. Tatsuro Tajiri
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  8. Tomoaki Taguchi
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  9. Sachiyo Suita
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  10. Masazumi Tsuneyoshi
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Corresponding author

Correspondence to Yoshinao Oda.

Additional information

This study was supported by a Grant-in-Aid for Scientific Research (C) (no. 18590332) from the Japan Society for the Promotion of Science, Tokyo, Japan.

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Kohashi, K., Oda, Y., Yamamoto, H. et al. Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype. J Cancer Res Clin Oncol 134, 1097–1103 (2008). https://doi.org/10.1007/s00432-008-0385-3

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  • DOI: https://doi.org/10.1007/s00432-008-0385-3

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