Immunogenic characteristics of microsatellite instability-low esophagogastric junction adenocarcinoma based on clinicopathological, molecular, immunological and survival analyses

Yu Imamura, Tasuku Toihata, Ikumi Haraguchi, Yoko Ogata, Manabu Takamatsu, Aya Kuchiba, Norio Tanaka, Osamu Gotoh, Seiichi Mori, Yuichiro Nakashima, Eiji Oki, Masaki Mori, Yoshinao Oda, Kenichi Taguchi, Manabu Yamamoto, Masaru Morita, Naoya Yoshida, Hideo Baba, Shinji Mine, Souya NunobeTakeshi Sano, Tetsuo Noda, Masayuki Watanabe

Research output: Contribution to journalArticlepeer-review

Abstract

Microsatellite instability (MSI) is categorized by mutation frequency: high MSI (MSI-H), low MSI (MSI-L) and microsatellite stable (MSS). MSI-H tumors have a distinct immunogenic phenotype, with immunotherapies using checkpoint inhibitors already approved for the treatment of MSI-H gastroesophageal adenocarcinoma (GEA); this is not observed for MSI-L or MSS. Here, we tested the hypothesis that MSI-L tumors are also a distinct phenotype and potentially immunogenic. MSI-PCR assays (BAT25, BAT26, BAT40, D2S123, D5S346 and D17S250) were performed on 363 Epstein-Barr virus-negative, surgically resected esophagogastric junction (EGJ) adenocarcinoma samples. Tumors were characterized as MSI-H (≥2 markers), MSI-L (1 marker) or MSS (0 markers). CD8+ cell counts, PD-L1 and HER2 expression levels, TP53 mutations, epigenetic alterations and prognostic significance were also examined. All pathological and molecular experiments were conducted using serial, whole-tumor sections of chemo-naïve surgical specimens. MSI-H and MSI-L were assigned to 28 (7.7%) and 24 (6.6%) cases, respectively. Compared to MSS cases, MSI-L cases had significantly higher intratumoral CD8+ cell infiltration (P =.048) and favorable EGJ cancer-specific survival (multivariate hazard ratio = 0.35, 95% CI, 0.12-0.82; P =.012). MSI-L tumors were also significantly associated with TP53-truncating mutations as compared to MSI-H (P =.009) and MSS (P =.012) cases, and this trend was also observed in GEA data from The Cancer Genome Atlas (TCGA). Indel mutational burden among TCGA MSI-L tumors was significantly higher than that of MSS tumors (P =.016). These results suggest that MSI-L tumors may have a distinct tumor phenotype and be potentially immunogenic in EGJ adenocarcinoma.

Original languageEnglish
Pages (from-to)1260-1275
Number of pages16
JournalInternational Journal of Cancer
Volume148
Issue number5
DOIs
Publication statusAccepted/In press - 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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