Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer

BMC Gastroenterology

Andreas H Marx²  Guido Sauter²  Ronald Simon²  Carsten Bokemeyer¹  Jakob R Izbicki³  Maximillian Bockhorn³  Asad Kutup³  Patrick Lebok²  Carsten Seeschaaf²  Phillip Stahl² 

[1] II Med. Klinik, Oncology, Hematology with section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

关键词: Heterogeneity tissue microarray;    Gastric cancer;    Gene amplification;    CCND1;    MYC;    EGFR;    HER2;   

Others  :  1121705
DOI  :  10.1186/s12876-015-0231-4

 received in 2014-10-09, accepted in 2015-01-13,  发布年份 2015

【 摘 要 】

Background

Intra-tumor heterogeneity is a potential cause for failure of targeted therapy in gastric cancer, but the extent of heterogeneity of established (HER2) or potential (EGFR, CCND1) target genes and prognostic gene alterations (MYC) had not been systematically studied.

Methods

To study heterogeneity of these genes in a large patient cohort, a heterogeneity tissue microarray was constructed containing 0.6 mm tissue cores from 9 different areas of the primary gastric cancers of 113 patients and matched lymph node metastases from 61 of these patients. Dual color fluorescence in-situ hybridization was performed to assess amplification of HER2, EGFR, CCND1 and MYC using established thresholds (ratio ≥ 2.0). Her2 immunohistochemistry (IHC) was performed in addition.

Results

Amplification was found in 17.4% of 109 interpretable cases for HER2, 6.4% for EGFR, 17.4% for CCND1, and 24.8% for MYC. HER2 amplification was strongly linked to protein overexpression by IHC in a spot-by-spot analysis (p < 0.0001). Intra-tumor heterogeneity was found in the primary tumors of 9 of 19 (47.3%) cancers with HER2, 8 of 17 (47.0%) cancers with CCND1, 5 of 7 (71.4%) cancers with EGFR, and 23 of 27 (85.2%) cancers with MYC amplification. Amplification heterogeneity was particularly frequent in case of low-level amplification (<10 gene copies). While the amplification status was often different between metastases, unequivocal intra-tumor heterogeneity was not found in individual metastases.

Conclusion

The data of our study demonstrate that heterogeneity is common for biomarkers in gastric cancer. Given that both TMA tissue cores and clinical tumor biopsies analyze only a small fraction of the tumor bulk, it can be concluded that such heterogeneity may potentially limit treatment decisions based on the analysis of a single clinical cancer biopsy.

【 授权许可】

   
2015 Stahl et al.; licensee BioMed Central.

【 图 表 】

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