High tumor mutation burden indicates a poor prognosis in patients with intrahepatic cholangiocarcinoma

Table 1 Clinical characteristics of the study population

Characteristics	All patients (n = 412)
	Number (n)	Percent (%)
Age, yr
Median	63
Range	18-88
< 65	188	45.6
≥ 65	224	54.4
Gender
Female	190	46.1
Male	222	53.9
BMI
Median	27.5
Range	17.6-59.8
< 28	191	46.4
≥ 28	217	52.7
TMB, mut/Mb
Median	2.5
Range	0-51.6
≤ 3.1	239	58.0
> 3.1	140	34.0
CA19-9
< 40 U/mL	121	29.4
≥ 40 U/mL	192	46.6
Chronic viral hepatitis
Negative	379	92.0
Positive	33	8.0
Tumor resection
Resected	203	49.3
Unresected	209	50.7
Tumor grade
Well differentiated	15	3.6
Moderately differentiated	231	56.1
Poorly differentiated	146	35.4
Disease progression
Solitary liver tumor	148	35.9
Multifocal liver disease	86	20.9
Metastatic disease	178	43.2
Smoking status
Never smoked	202	49.0
Former smoker	166	40.3
Current smoker	41	10.0

BMI: Body mass index; TMB: Tumor mutation burden.

Table 2 Grouping analysis of the relationship between tumor mutation burden and overall survival

	Median survival (mo)		Log-rank test
	TMB-high	TMB-low	HR	P value
Tumor grade
Well differentiated	- (n = 5)	56.1 (n = 10)	0.64 (0.15-2.27)	0.582
Moderately differentiated	26.5 (n = 79)	42.5 (n = 134)	1.46 (1.02-2.08)	0.026
Poorly differentiated	20.2 (n = 52)	29.8 (n = 82)	1.72 (1.11-2.66)	0.007
Disease progression
Solitary liver tumor	55.1 (n = 44)	69.4 (n = 93)	1.42 (0.85-2.38)	0.140
Multifocal liver disease	24.4 (n = 31)	40.6 (n = 46)	1.85 (1.00-3.43)	0.026
Metastatic disease	15.5 (n = 65)	15.8 (n = 100)	1.17 (0.83-1.66)	0.357
Tumor resection
Resected	36.6 (n = 67)	61.5 (n = 127)	1.77 (1.17-2.66)	0.002
Unresected	17.5 (n = 73)	17.7 (n = 112)	1.13 (0.81-1.59)	0.461

TMB: Tumor mutation burden.

Table 3 Univariable and multivariable analysis of overall survival

	Univariable			Multivariable
	HR	95%CI	P value	HR	95%CI	P value
Age, yr
< 65
≥ 65	0.96	0.76-1.21	0.7286	1.16	0.84-1.61	0.3662
Gender
Female
Male	1.27	1.00-1.61	0.0424	1.27	0.94-1.72	0.1145
BMI
< 28
≥ 28	0.80	0.63-1.00	0.0536	0.84	0.62-1.132	0.2517
TMB, mut/Mb
Low (≤ 3.1)
High (> 3.1)	1.47	1.13-1.91	0.002	1.43	1.05-1.96	0.0240
CA19-9
< 40 U/mL
≥ 40 U/mL	1.79	1.37-2.33	< 0.0001	1.78	1.28-2.46	0.0005
Chronic viral hepatitis
Negative
Positive	1.19	0.78-1.83	0.3667	1.72	1.01-2.95	0.0468
Tumor resection
Resected
Unresected	3.09	2.39-3.99	< 0.0001	2.58	1.72-3.88	< 0.0001
Tumor grade
Well differentiated
Moderately differentiated	2.01	1.19-3.39	0.0471	1.08	0.49-2.38	0.8489
Poorly differentiated	2.26	1.34-3.80	0.0211	1.15	0.52-2.57	0.7298
Disease progression
Solitary liver tumor
Multifocal liver disease	2.26	1.53-3.36	< 0.0001	1.47	0.86-2.52	0.1587
Metastatic disease	3.79	2.87-5.01	< 0.0001	2.55	1.55-4.20	0.0002
Smoking status
Never smoked
Former smoker	1.02	0.80-1.31	0.8591	0.94	0.69-1.29	0.7077
Current smoker	1.03	0.69-1.52	0.8971	1.64	0.98-2.73	0.0587

BMI: Body mass index; TMB: Tumor mutation burden; CI: Confidence interval.