J Pathol Transl Med.  2019 Jan;53(1):40-49. 10.4132/jptm.2018.11.29.

Prognostic Impact of Fusobacterium nucleatum Depends on Combined Tumor Location and Microsatellite Instability Status in Stage II/III Colorectal Cancers Treated with Adjuvant Chemotherapy

• Oh HJ
• Kim JH
• Bae JM
• Kim HJ
• Cho NY
• Kang GH

• KMID: 2437577
• DOI: http://doi.org/10.4132/jptm.2018.11.29

Abstract

BACKGROUND
This study aimed to investigate the prognostic impact of intratumoral Fusobacterium nucleatum in colorectal cancer (CRC) treated with adjuvant chemotherapy.
METHODS
F. nucleatum DNA was quantitatively measured in a total of 593 CRC tissues retrospectively collected from surgically resected specimens of stage III or high-risk stage II CRC patients who had received curative surgery and subsequent oxaliplatin-based adjuvant chemotherapy (either FOLFOXor CAPOX). Each case was classified into one of the three categories: F. nucleatum-high, -low, or -negative.
RESULTS
No significant differences in survival were observed between the F.nucleatum-high and -low/negative groups in the 593 CRCs (p = .671). Subgroup analyses according to tumor location demonstrated that disease-free survival was significantly better in F.nucleatum-high than in -low/negative patients with non-sigmoid colon cancer (including cecal, ascending, transverse, and descending colon cancers; n = 219; log-rank p = .026). In multivariate analysis, F. nucleatum was determined to be an independent prognostic factor in non-sigmoid colon cancers (hazard ratio, 0.42; 95% confidence interval, 0.18 to 0.97; p = .043). Furthermore, the favorable prognostic effect of F. nucleatum-high was observed only in a non-microsatellite instability-high (non-MSI-high) subset of non-sigmoid colon cancers (log-rank p = 0.014), but not in a MSI-high subset (log-rank p = 0.844), suggesting that the combined status of tumor location and MSI may be a critical factor for different prognostic impacts of F. nucleatum in CRCs treated with adjuvant chemotherapy.
CONCLUSIONS
Intratumoral F. nucleatum load is a potential prognostic factor in a non-MSI-high/non-sigmoid/non-rectal cancer subset of stage II/III CRCs treated with oxaliplatin-based adjuvant chemotherapy.

Keyword

Colorectal neoplasms; Fusobacterium; Gastrointestinal microbiome; Prognosis

MeSH Terms

Chemotherapy, Adjuvant*
Colon, Descending
Colonic Neoplasms
Colorectal Neoplasms*
Disease-Free Survival
DNA
Fusobacterium nucleatum*
Fusobacterium*
Gastrointestinal Microbiome
Humans
Microsatellite Instability*
Microsatellite Repeats*
Multivariate Analysis
Prognosis
Retrospective Studies
DNA

Figure

• 

  Fig. 1. Different proportions of Fusobacterium nucleatum–high vs F. nucleatum–low/negative colorectal cancers according to tumor location bowel subsites.

• 

  Fig. 2. Kaplan-Meier survival analysis, including subgroup analysis according to tumor location. (A) No significant difference in disease-free survival was evident between Fusobacterium nucleatum–high and –low/negative subgroups in the overall 593 stage II/III colorectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy. (B) The F. nucleatum–high subgroup was significantly associated with better disease-free survival in non-sigmoid colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (n=219). (C) In sigmoid colon and rectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy (n=374), the F. nucleatum–high subgroup shows a tendency toward worse disease-free survival without statistical significance.

• 

  Fig. 3. Kaplan-Meier survival analysis, including subgroup analysis according to combined tumor location and microsatellite instability (MSI) status. (A) The Fusobacterium nucleatum–high subgroup was significantly associated with better disease-free survival in an MSS/MSI-low subset of non-sigmoid colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (n=185). (B) No significant survival difference according to F. nucleatum status was observed in an MSI-high subset of non-sigmoid colon cancer patients treated with oxaliplatinbased adjuvant chemotherapy (n=31). (C) There is a tendency toward worse survival in the F. nucleatum–high subgroup without statistical significance in an MSS/MSI-low subset of sigmoid colon or rectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy (n= 360). (D) No significant survival difference according to F. nucleatum status was observed in an MSI-high subset of sigmoid colon or rectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy (n=9).

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