Molecular subtype switching in early-stage gastric cancers with multiple occurrences
Multiple gastric cancers at the same time (synchronous) or recurrence after 1 year (metachronous) are frequently encountered. Since their genetic profiles were not well elucidated, we molecularly subtyped the genetic events of synchronous and metachronous early-stage gastric cancers.
We studied mismatch repair (MMR) genes in 84 tumors from 31 patients (15 synchronous and 16 metachronous) by immunohistochemistry. We performed microsatellite instability analysis and targeted sequencing of 58 significantly mutated genes (SMGs) in 35 tumors from thirteen patients. Genomic data from TCGA were used for comparisons with advanced-stage cancers.
Among the 31 patients, at least one deficient-MMR (dMMR) tumor was observed in eight (26%). Of eight patients, seven showed a mixture of proficient-MMR (pMMR) and dMMR tumors. The one case with only dMMR had six recurrent tumors within 2 years. To further subtype, we sequenced 58 SMGs in 35 samples (25 pMMR and 10 dMMR) from thirteen patients. In 35 samples, 163 mutations were identified, but none matched in almost cases, strongly indicating different clonal origins, whether synchronous or metachronous occurrences. Of the 25 pMMR cases, 1 belonged to Epstein–Barr virus (EBV), 24 belonged to chromosomal instability (CIN) subtypes. Of the thirteen cases, repetitive CIN, a mixture of CIN and MSI, a mixture of CIN and EBV, and repetitive MSI were observed in nine (70%), two (15%), one (8%) and one (8%), respectively.
Despite multiple tumors occurring in the same patient simultaneously or several years apart, clonal origin was totally different. ‘Switching’ or ‘mixing’ of dMMR and pMMR, EBV or CIN occurred, which had clinical relevance with regard to immunotherapy.
KeywordsGastric cancer Multiple cancer Mutation Microsatellite instability Mismatch repair
Significantly mutated genes
Epstein–Barr virus encoded small mRNA’s
Endoscopic submucosal dissection
The Cancer Genome Atlas
International Cancer Genome Consortium
Catalog of Somatic Mutations in Cancer
This study was supported by a Grant-in-Aid for Genome Research Project from Yamanashi Prefecture (to M.O. and Y.H.), The Japan Society for the Promotion of Science (JSPS) KAKENHI Early-Career Scientists (Grant Number JP18K16292 to Y.H.), Research Grant for Young Scholars (to Y.H.), The YASUDA Medical Foundation (to Y.H.) and The Uehara Memorial Foundation (to Y.H.). We thank all medical and ancillary hospital staff and the patients for consenting to participate. We also thank Kanoko Sano, Saki Hiraga, Shunsuke Watanabe, and Eri Ishii for technical support. Finally, we thank James P. Mahaffey, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflicts of interest.
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