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Cancer gene profiling explores the possible precision medicine for diffuse-type gastric adenocarcinoma

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Abstract

Diffuse type gastric cancer (DGC), a pathological subtype, is one of the most common malignant solid tumors, and mortality of this tumor is not negligible, especially in early-onset cancer patients. In fact, affirmative personalized treatments based on gene profile have not been established yet. The aim of this study was to provide the possible genotype-matched treatment for DGC through comprehensive examination of genomic variants and analysis of clinicopathological characteristics. We retrospectively studied 23 formalin-fixed, paraffin-embedded samples of patients diagnosed as DGC between January 2003 and December 2015 at the Department of Cancer Pathology, Hokkaido University Graduate School of Medicine. The cases were divided into two groups: early-onset (< 50 years old) and elderly-onset (≥ 50 years old) DGC groups. We performed targeted genomic sequencing using a 163 cancer-related gene panel. The sequencing data were analyzed using an original bioinformatics pipeline called GenomeJack and were clinicopathologically evaluated. Intestinal metaplasia and atrophy were highly observed in the adjacent non-cancerous mucosa in the elderly-onset DGC group compared with those in the early-onset DGC group. The number of somatic variants was significantly higher in the elderly-onset DGC group than in the early-onset DGC group. Fifteen patients (65.2%) harbored at least one genomic alteration of the potential target for genotype-matched treatment. In addition, one patient with hypermutation phenotype was diagnosed as Lynch syndrome due to MLH1 mutation, suggesting the sensitivity for the treatment with immune checkpoint inhibitors. Not only does our study demonstrated the potential utility of the targeted genomic sequencing approach for making informed therapeutic decisions, but it also sheds light on DGC pathogenesis and progression.

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Abbreviations

GC:

Gastric cancer

NGS:

Next generation sequencing

EBV:

Epstein-barr virus

DGC:

Diffuse type of gastric cancer

FFPE:

Formalin-fixed, paraffin embedded

TNM:

Tumor-node-metastasis

IHC:

Immunohistochemical

PARP:

Poly ADP-ribose polymerase

HDAC:

Histone deacetylase

EZH2:

Enhancer of zeste homolog 2

BTK:

Bruton’s tyrosine kinase

HER2:

Human epidermal growth factor receptor 2

CDK:

Cyclin-dependent kinase

FGFR:

Fibroblast growth factor receptor

mTOR:

Mammalian target of rapamycin

ASPP:

Apoptosis-stimulating protein of p53

SHP2:

Src homology 2 domain containing protein tyrosine phosphatase 2

FAK:

Focal adhesion kinase

LOH:

Loss of heterozygosity

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Funding

This research is (partially) supported by the Program for an Integrated Database of Clinical and Genomic Information from Japan Agency for Medical Research and development (JP19ck0106406), AMED and also by Japan Society for the Promotion of Science (Grant Nos. 1 7 K 1 0 8 5 5, 1 7 K T 0 0 4 6).

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Authors and Affiliations

  1. Division of Endoscopy, Hokkaido University Hospital, Nishi-5, Kita-14, Kita-ku, Sapporo, 060-8648, Japan

    Marin Ishikawa

  2. Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Nishi-7, Kita-15, Kita-ku, Sapporo, 060-8638, Japan

    Marin Ishikawa & Shinya Tanaka

  3. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Shinnomachi 35, Shinjuku-ku, Tokyo, 160-8582, Japan

    Hideyuki Hayashi & Hiroshi Nishihara

  4. Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Nishi-7, Kita-15, Kita-ku, Sapporo, 060-8638, Japan

    Naoya Sakamoto

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  1. Marin Ishikawa
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Correspondence to Hiroshi Nishihara.

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Ishikawa, M., Hayashi, H., Sakamoto, N. et al. Cancer gene profiling explores the possible precision medicine for diffuse-type gastric adenocarcinoma. Med Oncol 37, 10 (2020). https://doi.org/10.1007/s12032-019-1327-4

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