Molecular cytology genotyping of primary and metastatic GI stromal tumors by using a custom two-gene targeted next-generation sequencing panel with therapeutic intent

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• 作者：Ferga C. Gleeson ; MD¹ ; ; Sarah E. Kerr ; MD² ; Benjamin R. Kipp ; MD² ; Jesse S. Voss ; MD² ; Douglas M. Minot ; MD² ; Zheng Jin Tu ; MD³ ; Michael R. Henry ; MD² ; George Vasmatzis ; MD⁴ ; John C. Cheville ; MD⁴ ; Konstantinos N. Lazaridis ; MD¹ ; ⁴ ; Michael J. Levy ; MD¹
• 关键词：FFPE ; formalin-fixed paraffin-embedded ; KIT ; mast/stem cell growth factor receptor Kit gene ; NGS ; next-generation sequencing ; PCR ; polymerase chain reaction ; PDGFRA ; platelet-derived growth factor receptor A ; SDH ; succinate dehydrogenase ; WT ; wild-type (no KIT or PDGFRA somatic mutation detected)
• 刊名：Gastrointestinal Endoscopy
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：84
• 期：6
• 页码：950-958.e3
• 全文大小：2115 K

文摘

In an era of precision medicine, customized genotyping of GI stromal tumors by screening for driver mutations will become the standard of care. The fidelity of genotype concordance between paired cytology smears and surgical pathology specimens is unknown. In patients with either primary or metastatic sporadic disease, we sought to determine the frequency of KIT and PDGFRA pathogenic alterations within such specimens, imatinib sensitivity, and the concordance of pathogenic alterations between paired specimens.

Methods

DNA obtained from cytology smears from 36 patients, 24 of whom had paired surgical pathology specimens, underwent targeted next-generation sequencing by using a custom panel to evaluate somatic mutations within KIT (exon 2, 9, 10, 11, 13, 14, 15, 17, 18) and PDGFRA (exon 12, 14, 15, 18) genes. Patients with KIT and PDGRFA wild-type genes completed the Qiagen Human Comprehensive Cancer GeneRead DNAseq Targeted Array V2.

Results

Genotyping revealed KIT and PDGFRA mutations in 68% and 15% of patients. The wild-type population did not harbor mutations in BRAF, RAS family, SDHB, SETD2, or NF1. Imatinib sensitivity based on the oncogenic kinase mutation prevalence was estimated to be 68%. Mutational concordance between paired cytology and surgical pathology specimens was 96%.

Conclusions

Our data have demonstrated the ability to stratify either primary or metastatic gastrointestinal stromal tumors by mutational subtype using a targeted next-generation sequencing 2 gene mutation panel. We highlight the ability to use cytology specimens obtained via minimally invasive techniques as a surrogate to surgical specimens given the high mutational landscape concordance between paired specimens.