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Diversity of Clinical Implication of B-Cell Translocation Gene 1 Expression by Histopathologic and Anatomic Subtypes of Gastric Cancer

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Abstract

Background

Genetic signatures may differ by histopathologic and anatomic subtypes of gastric cancer (GC). B-cell translocation gene 1 (BTG1) was identified as one of genes downregulated in GC tissues from our microarray data.

Aims

To evaluate the clinical implications of BTG1 expression in GC and the genetic diversity among GC subtypes.

Methods

BTG1 mRNA expression was analyzed in GC cell lines and 233 pairs of surgical specimens. The mutational and methylation status of BTG1 in GC cell lines was analyzed, and immunohistochemistry was conducted to determine the distribution of BTG1. The pattern and prognostic significance of BTG1 expression were correlated with the three proposed GC subtypes.

Results

BTG1 mRNA was downregulated in 82 % of GC cell lines and in 88 % of clinical GC tissues. Promoter hypermethylation events or sequence mutations were not detected in GC cell lines. The pattern of BTG1 expression as observed by immunohistochemistry was consistent with that of its mRNA. Downregulation of BTG1 mRNA in GCs was significantly associated with shorter disease-specific and recurrence-free survival. Multivariate analysis of disease-specific survival identified downregulation of BTG1 transcription as an independent prognostic factor. BTG1 mRNA expression was more strongly suppressed in proximal nondiffuse and diffuse GC compared with distal nondiffuse GC, and subgroup analysis revealed that BTG1 downregulation led to adverse prognosis, specifically in patients with proximal nondiffuse and diffuse GC.

Conclusions

Altered expression of BTG1 is a potential biomarker for carcinogenesis and progression of GC, particularly for proximal nondiffuse and diffuse GC.

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Conflict of interest

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Authors and Affiliations

  1. Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Mitsuro Kanda, Hisaharu Oya, Shuji Nomoto, Hideki Takami, Dai Shimizu, Ryoji Hashimoto, Satoshi Sueoka, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara & Yasuhiro Kodera

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  1. Mitsuro Kanda
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Correspondence to Mitsuro Kanda.

Electronic supplementary material

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10620_2014_3477_MOESM1_ESM.tif

Supplemental Fig. 1 A Mutational analysis of BTG1. Mutations were not detected using HRM analysis in BTG1 exons 1 and 2. B Methylation analysis of the BTG1 promoter in GC cell lines. Representative chromatograms of bisulfite sequence analysis, showing absence of promoter hypermethylation (TIFF 6925 kb)

10620_2014_3477_MOESM2_ESM.tif

Supplemental Fig. 2 A Even when patients were subdivided according to UICC staging (stages I–II and III–IV), BTG1 mRNA expression in GC tissues was significantly lower in proximal nondiffuse and diffuse GCs compared with distal GC. B Survival of patients with stage II/III GC. When the analysis was limited to cases with or without BTG1 mRNA downregulation in GC tissues, prognosis was similar among the three GC subtypes in patients without downregulation of BTG1 mRNA expression, whereas proximal nondiffuse and diffuse GCs were significantly associated with shorter survival in patients with downregulation of BTG1 mRNA expression (TIFF 6034 kb)

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Kanda, M., Oya, H., Nomoto, S. et al. Diversity of Clinical Implication of B-Cell Translocation Gene 1 Expression by Histopathologic and Anatomic Subtypes of Gastric Cancer. Dig Dis Sci 60, 1256–1264 (2015). https://doi.org/10.1007/s10620-014-3477-8

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  • DOI: https://doi.org/10.1007/s10620-014-3477-8

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