Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST)

BMC Cancer

Margherita Nannini¹  Annalisa Astolfi²  Milena Urbini²  Valentina Indio²  Donatella Santini⁵  Michael C Heinrich⁴  Christopher L Corless³  Claudio Ceccarelli⁵  Maristella Saponara²  Anna Mandrioli¹  Cristian Lolli¹  Giorgio Ercolani⁶  Giovanni Brandi¹  Guido Biasco²  Maria A Pantaleo² 

[1] Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy

[2] “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna, Italy

[3] Department of Pathology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

[4] Portland VA Medical Center and Knight Cancer Institute, and Division of Hematology and Oncology, Oregon Health & Science University Portland, Portland, OR, USA

[5] Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

[6] Transplant, General and Emergency Surgery Department, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

关键词: Quadruple^WT;    RAS;    SDHA;    Succinate dehydrogenase;    PDGFRA;    KIT;    Wild-type;    Gastrointestinal stromal tumors (GIST);   

Others  :  1121056
DOI  :  10.1186/1471-2407-14-685

 received in 2014-01-23, accepted in 2014-09-17,  发布年份 2014

【 摘 要 】

Background

About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813–3825, 2004; Hematol Oncol Clin North Am 23:15–34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).

In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadruple^WT or KIT^WT/PDGFRA^WT/SDH^WT/RAS-P^WT) remains undefined. The aim of this study is to investigate the genomic profile of KIT^WT/PDGFRA^WT/SDH^WT/RAS-P^WT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes.

Methods

We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KIT^WT/PDGFRA^WT/SDH^WT and SDHB^IHC+/SDHA^IHC+, 2 KIT^WT/PDGFRA^WT/SDHA^mut and SDHB^IHC-/SDHA^IHC- and 12 cases of KIT^mut or PDGFRA^mut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KIT^WT/PDGFRA^WTSDHA^mut GIST and 19 KIT^mut or PDGFRA^mut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis.

Results

We found that both cases of quadruple^WT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadruple^WT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG).

Conclusion

We report for the first time an integrated genomic picture of KIT^WT/PDGFRA^WT/SDH^WT/RAS-P^WT GIST, using massively parallel sequencing and gene expression analyses, and found that quadruple^WT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadruple^WT GIST represent another unique group within the family of gastrointestintal stromal tumors.

【 授权许可】

   
2014 Nannini et al.; licensee BioMed Central Ltd.

【 图 表 】

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