Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer

Koichiro Haruki; Keisuke Kosumi; Tsuyoshi Hamada; Tyler S Twombly; Juha P Väyrynen; Sun A Kim; Yohei Masugi; Zhi Rong Qian; Kosuke Mima; Yoshifumi Baba; Annacarolina da Silva; Jennifer Borowsky; Kota Arima; Kenji Fujiyoshi; Mai Chan Lau; Peilong Li; Chunguang Guo; Yang Chen; Mingyang Song; Jonathan A Nowak; Reiko Nishihara; Katsuhiko Yanaga; Xuehong Zhang; Kana Wu; Susan Bullman; Wendy S Garrett; Curtis Huttenhower; Jeffrey A Meyerhardt; Marios Giannakis; Andrew T Chan; Charles S Fuchs; Shuji Ogino

doi:10.1002/path.5381

Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer

J Pathol. 2020 Apr;250(4):397-408. doi: 10.1002/path.5381. Epub 2020 Feb 3.

Authors

Koichiro Haruki^{1

2}, Keisuke Kosumi¹, Tsuyoshi Hamada¹, Tyler S Twombly¹, Juha P Väyrynen^{1

3

4}, Sun A Kim¹, Yohei Masugi¹, Zhi Rong Qian^{1

5}, Kosuke Mima¹, Yoshifumi Baba¹, Annacarolina da Silva¹, Jennifer Borowsky^{1

6}, Kota Arima¹, Kenji Fujiyoshi¹, Mai Chan Lau¹, Peilong Li¹, Chunguang Guo¹, Yang Chen¹, Mingyang Song^{7

8

9}, Jonathan A Nowak¹, Reiko Nishihara^{1

7

10

11}, Katsuhiko Yanaga², Xuehong Zhang¹², Kana Wu^{7

10

12}, Susan Bullman^{3

13}, Wendy S Garrett^{3

13

14}, Curtis Huttenhower^{11

13}, Jeffrey A Meyerhardt³, Marios Giannakis^{3

13

15}, Andrew T Chan^{8

9

12

14}, Charles S Fuchs^{16

17

18}, Shuji Ogino^{1

10

13

19}

Affiliations

¹ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
³ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴ Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
⁵ Scientific Research Center and Digestive Disease Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, PR China.
⁶ Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Yale Cancer Center, New Haven, CT, USA.
¹⁷ Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁸ Smilow Cancer Hospital, New Haven, CT, USA.
¹⁹ Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA.

Abstract

Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow-up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long-interspersed nucleotide element-1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1-low cases, BECN1-intermediate and BECN1-high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29-0.99) and 0.31 (95% confidence interval, 0.16-0.60), respectively (P_trend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (P_trend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (P_trend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: Colorectal neoplasms; Immunology; Microbiology; Microbiome; Molecular pathological epidemiology; Tumour microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Autophagy / genetics*
Biomarkers, Tumor / genetics
Carcinogenesis / genetics
Carcinogenesis / pathology
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / immunology
Female
Fusobacterium nucleatum / genetics*
Fusobacterium nucleatum / immunology
Humans
Male
Microsatellite Instability
Mutation / genetics
Tumor Microenvironment / genetics*

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding