High-resolution Array CGH and Gene Expression Profiling of Alveolar Soft Part Sarcoma

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2014 Feb 5

PMID 24493828

Citations 15

Authors

Shamini Selvarajah

Saumyadipta Pyne

Eleanor Chen

Ramakrishna Sompallae

Azra H Ligon

Gunnlaugur P Nielsen

Glenn Dranoff

Edward Stack

Massimo Loda

Richard Flavin

Affiliations

Soon will be listed here.

Abstract

Purpose: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis.

Experimental Design: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL-TFE3 fusion and, hence, confirm the aCGH observations.

Results: FISH analysis identified the ASPL-TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation.

Conclusion: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS.

Citing Articles

ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs.

Sicinska E, Kola V, Kerfoot J, Taddei M, Al-Ibraheemi A, Hsieh Y Cancer Res. 2024; 84(14):2247-2264.

PMID: 38657118 PMC: 11250573. DOI: 10.1158/0008-5472.CAN-23-2115.

Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.

Phadnis S, Wang X, Daw N, Herzog C, Subbiah I, Zaky W ESMO Open. 2023; 8(6):101609.

PMID: 37879233 PMC: 10774869. DOI: 10.1016/j.esmoop.2023.101609.

ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma.

Tanaka M, Chuaychob S, Homme M, Yamazaki Y, Lyu R, Yamashita K Nat Commun. 2023; 14(1):1957.

PMID: 37029109 PMC: 10082046. DOI: 10.1038/s41467-023-37049-z.

Calreticulin Expression Controls Cellular Redox, Stemness, and Radiosensitivity to Function as a Novel Adjuvant for Radiotherapy in Neuroblastoma.

Chen C, Hu Y, Chien Y, Huang W, Wu C, Tsai C Oxid Med Cell Longev. 2023; 2023:8753309.

PMID: 36644580 PMC: 9839411. DOI: 10.1155/2023/8753309.

Alveolar soft-part sarcoma (ASPS) resembles a mesenchymal stromal progenitor: evidence from meta-analysis of transcriptomic data.

Stockwin L PeerJ. 2020; 8:e9394.

PMID: 32596059 PMC: 7307565. DOI: 10.7717/peerj.9394.

References

Guillou L, Lamoureux E, Masse S, Costa J . Alveolar soft-part sarcoma of the uterine corpus: histological, immunocytochemical and ultrastructural study of a case. Virchows Arch A Pathol Anat Histopathol. 1991; 418(5):467-71. DOI: 10.1007/BF01605935. View

Gasche J, Hoffmann J, Boland C, Goel A . Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells. Int J Cancer. 2011; 129(5):1053-63. PMC: 3110561. DOI: 10.1002/ijc.25764. View

Foschini M, Eusebi V . Alveolar soft-part sarcoma: a new type of rhabdomyosarcoma?. Semin Diagn Pathol. 1994; 11(1):58-68. View

Pesek M, Kopeckova M, Benesova L, Meszarosova A, Mukensnabl P, Bruha F . Clinical significance of hypermethylation status in NSCLC: evaluation of a 30-gene panel in patients with advanced disease. Anticancer Res. 2011; 31(12):4647-52. View

Gomez J, Amin M, Ro J, Linden M, Lee M, Zarbo R . Immunohistochemical profile of myogenin and MyoD1 does not support skeletal muscle lineage in alveolar soft part sarcoma. Arch Pathol Lab Med. 1999; 123(6):503-7. DOI: 10.5858/1999-123-0503-IPOMAM. View

Evans H . Alveolar soft-part sarcoma. A study of 13 typical examples and one with a histologically atypical component. Cancer. 1985; 55(4):912-7. DOI: 10.1002/1097-0142(19850215)55:4<912::aid-cncr2820550434>3.0.co;2-g. View

Ladanyi M, Lui M, Antonescu C, Meindl A, Argani P, Healey J . The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001; 20(1):48-57. DOI: 10.1038/sj.onc.1204074. View

Moelans C, Verschuur-Maes A, van Diest P . Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. J Pathol. 2011; 225(2):222-31. DOI: 10.1002/path.2930. View

Zong X, Yang H, Yu Y, Zou D, Ling Z, He X . Possible role of Pax-6 in promoting breast cancer cell proliferation and tumorigenesis. BMB Rep. 2011; 44(9):595-600. DOI: 10.5483/bmbrep.2011.44.9.595. View

10.

Semenza G . Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10):721-32. DOI: 10.1038/nrc1187. View

11.

Nakano H, Tateishi A, Imamura T, Miki H, Ohno T, Moue T . RT-PCR suggests human skeletal muscle origin of alveolar soft-part sarcoma. Oncology. 2000; 58(4):319-23. DOI: 10.1159/000012119. View

12.

Flandin P, Zhao Y, Vogt D, Jeong J, Long J, Potter G . Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron. 2011; 70(5):939-50. PMC: 3153409. DOI: 10.1016/j.neuron.2011.04.020. View

13.

Kiuru-Kuhlefelt S, El-Rifai W, Sarlomo-Rikala M, Knuutila S, Miettinen M . DNA copy number changes in alveolar soft part sarcoma: a comparative genomic hybridization study. Mod Pathol. 1998; 11(3):227-31. View

14.

Kobos R, Nagai M, Tsuda M, Merl M, Saito T, Lae M . Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein. J Pathol. 2013; 229(5):743-754. PMC: 4083568. DOI: 10.1002/path.4158. View

15.

Aulmann S, Longerich T, Schirmacher P, Mechtersheimer G, Penzel R . Detection of the ASPSCR1-TFE3 gene fusion in paraffin-embedded alveolar soft part sarcomas. Histopathology. 2007; 50(7):881-6. DOI: 10.1111/j.1365-2559.2007.02693.x. View

16.

Rosai J, Dias P, Parham D, Shapiro D, Houghton P . MyoD1 protein expression in alveolar soft part sarcoma as confirmatory evidence of its skeletal muscle nature. Am J Surg Pathol. 1991; 15(10):974-81. DOI: 10.1097/00000478-199110000-00008. View

17.

Wang N, Bacchi C, Jiang J, McNutt M, Gown A . Does alveolar soft-part sarcoma exhibit skeletal muscle differentiation? An immunocytochemical and biochemical study of myogenic regulatory protein expression. Mod Pathol. 1996; 9(5):496-506. View

18.

Argani P, Antonescu C, Illei P, Lui M, Timmons C, Newbury R . Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001; 159(1):179-92. PMC: 1850400. DOI: 10.1016/S0002-9440(10)61684-7. View

19.

Agundez M, Grau L, Palou J, Algaba F, Villavicencio H, Sanchez-Carbayo M . Evaluation of the methylation status of tumour suppressor genes for predicting bacillus Calmette-Guérin response in patients with T1G3 high-risk bladder tumours. Eur Urol. 2011; 60(1):131-40. DOI: 10.1016/j.eururo.2011.04.020. View

20.

Zhang X, Huang C, Chen J, Pankratz M, Xi J, Li J . Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell. 2010; 7(1):90-100. PMC: 2904346. DOI: 10.1016/j.stem.2010.04.017. View