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Virchows Archiv

, Volume 471, Issue 3, pp 329–336 | Cite as

Intratumoral Fusobacterium nucleatum abundance correlates with macrophage infiltration and CDKN2A methylation in microsatellite-unstable colorectal carcinoma

  • Hye Eun Park
  • Jung Ho Kim
  • Nam-Yun Cho
  • Hye Seung Lee
  • Gyeong Hoon Kang
Original Article

Abstract

Fusobacterium nucleatum (Fn), a specific species of gut microbiota, has been suggested to be enriched in the microsatellite instability-high (MSI-H) molecular subtype of colorectal carcinomas (CRCs). However, the clinicopathologic and molecular factors that interact with Fn in MSI-H CRCs are poorly understood. In this study, 16S ribosomal RNA gene DNA sequence of Fn was quantitatively measured by real-time polymerase chain reaction in tumor DNA samples from a total of 160 surgically resected MSI-H CRC tissues. Each case was classified into one of the three categories based on the Fn DNA amount: Fn-high, Fn-low, and Fn-negative. The clinicopathologic and molecular associations of Fn in MSI-H CRCs were statistically analyzed. Among the 160 MSI-H CRC samples, 15 (9%), 92 (58%), and 53 (33%) cases were Fn-high, Fn-low, and Fn-negative, respectively. Compared with Fn-low/negative tumors, Fn-high MSI-H CRCs were significantly associated with a high density of CD68+ tumor-infiltrating macrophages (P = 0.019) and promoter CpG island hypermethylation of the CDKN2A (p16) gene (P = 0.008). There were also tendencies toward associations of Fn-high with the BRAF V600E mutation (P = 0.047) and active Crohn-like lymphoid reactions (P = 0.052) in MSI-H CRCs. However, Fn-high was not significantly associated with CD3+ T cell density, CD163+ M2 macrophage density or PD-L1 expression status. In conclusion, high amounts of intratumoral Fn are correlated with increased macrophage infiltration and CDKN2A promoter methylation in MSI-H CRCs.

Keywords

Colorectal cancer Fusobacterium nucleatum Gut microbiota Tumor-associated macrophage Microsatellite instability 

Notes

Acknowledgements

We thank Professor Katsuhiko Nosho, from the Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Japan, for his kind instruction regarding the protocol of real-time PCR for Fusobacterium nucleatum. This study was supported by the National Research Foundation of Korea grant funded by the Korea government (Ministry of Science, ICT and Future Planning) (2016R1C1B2010627), a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Korea government (Ministry of Education) (2016R1D1A1A02937130), National Research Foundation of Korea grants funded by the Korea government (Ministry of Science, ICT and Future Planning) (2011-0030049 and 2016M3A9B6026921), and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Korea government (Ministry of Health and Welfare) (HI14C1277).

Compliance with ethical standards

This study was approved by the institutional review board of Seoul National University Hospital (IRB No. 1203-072-402). Under the condition of retrospective archival tissue collection and patient data anonymization, our study was exempted from the acquisition of informed consent from patients.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2017_2171_MOESM1_ESM.pdf (32 kb)
Supplementary Fig. S1 (PDF 32 kb)
428_2017_2171_MOESM2_ESM.pdf (205 kb)
Supplementary Table S1 (PDF 205 kb)

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Copyright information

© Springer-Verlag GmbH Deutschland 2017

Authors and Affiliations

  1. 1.Department of Pathology, Seoul National University HospitalSeoul National University College of MedicineSeoulRepublic of Korea
  2. 2.Laboratory of Epigenetics, Cancer Research InstituteSeoul National University College of MedicineSeoulRepublic of Korea
  3. 3.Department of PathologySeoul National University Bundang HospitalSeongnamRepublic of Korea
  4. 4.Department of PathologySeoul National University College of MedicineSeoulRepublic of Korea

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