The association between hepatic viral infections and cancers: A cross-sectional study in the Taiwan adult population

doi:10.21203/rs.3.rs-3343153/v1

Background

Hepatitis B (HBV) and hepatitis C (HCV) viruses are diseases of global public health concern and are associated with liver cancer. Recent studies have revealed associations between hepatic viral infections and extrahepatic cancers. This study aimed to explore the associations between hepatitis B and C viruses and cancer at baseline in the Taiwan Biobank database while controlling for a wide range of confounding variables.

Methods

In a cross-sectional study of adults aged > 20 years, we compared the distribution of demographic factors, lifestyle, and comorbidities between viral and nonviral hepatic groups using the chi-square test. Univariate and multivariate logistic regressions were performed to observe the associations between hepatitis B and C viral infections and cancers by estimating the odds ratio (OR) and 95% confidence interval (CI). Multivariate regression analysis was adjusted for sociodemographic factors, lifestyle, and comorbidities.

Results

From the database, 2,955 participants were identified as having HCV infection, 15,305 as having HBV infection, and 140,108 as the nonviral group. HBV infection was associated with an increased likelihood of liver cancer (adjusted OR (aOR) = 7.09, 95% CI = 3.48–14.44, P < 0.001) and ovarian cancer (aOR = 3.86, 95% CI = 1.68–8.88, P = 0.002). HCV infection was observed to increase the likelihood of liver cancer (aOR = 4.69, 95% CI = 1.34–16.36, P = 0.015), ovarian cancer (aOR = 5.19, 95% CI = 1.17–22.97, P = 0.030), and kidney cancer (aOR = 10.27, 95% CI = 2.06–52.25, P = 0.005).

Conclusion

Our findings suggest that hepatic viral infections are associated with intra- and extrahepatic cancers. However, being cross-sectional, causal inferences cannot be made. A recall-by-genotype study is recommended to further investigate the causality of these associations.

Hepatitis B virus

Hepatitis C virus

Cancer

Adults

Cross-sectional study

Viral hepatitis infections are a global public health concern, with hepatic viruses B and C leading to chronic illness in millions around the world. Globally, it is estimated that 354 million individuals are infected with hepatitis B virus (HBV) or hepatitis C virus (HCV)¹. In particular, the World Health Organization (WHO) estimates that 296 million people worldwide were living with chronic HBV infection, contributing to approximately 820,000 deaths in 2019². On the other hand, 58 million people are estimated to be living with chronic HCV infection globally, and 290,000 deaths attributed to HCV infection were reported in 2019 attributed to HCV infection³. In Taiwan, the prevalence of HBV is estimated to be approximately 9.7% in the adult population born before implementation of the vaccination program⁴.

Before the implementation of the vaccination program, the prevalence of HBV was projected to be between 15–20% in the general population in Taiwan⁵, with the major routes of spread being vertical and horizontal transmission in early life⁶. Due to the mass vaccination campaign introduced in 1984, the HBV prevalence decreased from 10.5–0.8% in 2007 among children7. Approximately 2–5% of the population was estimated to be infected with HCV ^8–10, with a higher prevalence rate exhibited in the early 1980s, mainly attributed to the use of intravenous injections that were not properly sterilized⁸. HBV and HCV infections are the most common contributors to liver diseases, such as cirrhosis, liver cancer, and viral hepatitis-related deaths¹.

The current literature reveals that HBV and HCV are related to the development of both hepatocellular carcinoma and extrahepatic cancers. Such associations have been observed in different cancer types, such as colorectal cancer^11–13, gallbladder and extrahepatic bile duct cancer^12,14, pancreatic cancer^12–14, renal cancer¹², ovarian cancer¹², stomach cancer¹³, oral cancer¹³, anus cancer¹⁴, skin cancer¹⁴, and non-Hodgkin’s lymphoma^12–14. Some inverse associations have been reported in uterine and prostate cancers¹⁴. The reported findings vary among studies and are therefore not entirely conclusive^11–14. A number of studies were limited by insufficient control of environmental and behavioral confounders, small sample sizes, inadequate control of cancer-specific risk factors, and misclassification bias from the use of diagnostic tests with low sensitivity. This presents a need to explore these associations in large databases with sufficient control for sociodemographic, lifestyle, behavioral, and cancer-specific confounders.

Cancer is the leading cause of death in the Taiwanese population¹⁵. Therefore, it is imperative to explore the associations between hepatic viral infections and cancer to gain a deeper understanding of the associations, patterns, and risk factors relevant to the Taiwanese population. The Taiwan Biobank (TWB) presents a great opportunity to explore the associations between hepatic viral infections and cancers due to its large sample size, wide range of cancer-specific risk factors, and comprehensive ascertainment of HBV and HCV infections. Therefore, the main objective of this study was to explore the association between hepatic viral infections (HBV and HCV) and cancer at baseline using the TWB.

Study population and design

The TWB is an ongoing prospective study comprising adults aged 20 to 70 years at the time of enrollment. It currently has over 160,000 participants with a target of enrolling up to 200,000 participants recruited from different regions all over Taiwan. The database contains comprehensive information on the phenotypes of the consenting participants obtained at the baseline and follow-up visits through a structured questionnaire and physical and biomarker measurements¹⁶. This study employed a cross-sectional design to explore the baseline associations between different cancer types and hepatic viral infections with data collected from 2012 to 2022. A total of 163886 participants were included in the study. We excluded participants with missing or unclear information on HBV and HCV measurements (n = 2,232) and the required covariates (n = 2,924). The final sample size was 158370 participants. Of these, 2955 had HCV alone, 15305 had HBV alone, 362 had HCV/HBV dual infection, and the nonviral hepatitis group comprised 140108 participants (Fig. 1). The data provided were deidentified.

Data

The database contains sociodemographic variables, such as age, sex, marital status, highest education level, residential area, income status, maternal and paternal origin, and anthropometric measurements, such as body weight and height. Sex was considered a binary variable (male and female) defined by birth characteristics. Age (in years) was categorized as < 50, 50–59, and ≥ 60 years. An individual’s marital status was considered single, married, or separated. The highest education levels were ‘junior high school and below’, ‘senior high school’, and ‘college and above’. Participant residences were classified as either ‘urban’ or ‘rural,’ based on their residential degree of urbanization. Maternal and paternal origins were grouped into ‘Hakka’, ‘Hokkien’, and ‘others’. Body mass index (BMI) was computed and categorized into low (< 18.5 kg/m²), normal (18.5–24.0 kg/m²), and ‘overweight and above’ (> 24.0 kg/m²). Income status was classified into three categories: <30,000, 30,000–60,000, and ≥ 60,000 National Taiwan dollars (NTD)¹⁷. Alcohol consumption status was categorized as ‘No’ for never drinkers and ‘Yes’ for previous and current drinkers. Smoking experience was regarded as ‘No’ for never smokers and ‘Yes’ for previous and current smokers. Exercise regularity was considered ‘No’ for participants without the habit of regular exercise and ‘Yes’ for those who had incorporated regular exercise. Betel nut experience was considered ‘No’ for those who reported never chewing betel nuts and ‘Yes’ for those who had previous or current experience. Information on comorbidities, such as hypertension, hyperlipidemia, and diabetes, was obtained from the survey. A family history of cancer was considered either ‘yes’ or ‘no’ based on the information provided from the survey.

Ascertainment of hepatic viral infections and cancers

Ascertainment of HBV status was performed through an immunological test of hepatitis B surface antigen (HBsAg) using electrochemiluminescence immunoassay (ECLIA) (Roche Diagnostics GmbH, Mannheim, Germany), a highly sensitive test. ‘Positive’ or ‘reactive’ results were considered HBsAg positive, and ‘negative’ or ‘nonreactive’ results were considered HBsAg negative. HCV serostatus was ascertained using the HCV antibody test, which was also performed using the ECLIA test. Cancer ascertainment was obtained from the information collected in the survey questionnaire. If a participant reported more than one cancer, the primary cancer was considered the first cancer type. Cancers whose frequency was below 10 were grouped together in the category ‘Other’.

Statistical analysis

This study examined the association between cancer and hepatic viral infections (HBV and HCV) at the baseline visit using the TWB database. The comparison of demographic factors, lifestyle, and comorbidities between the viral and nonviral hepatic groups was performed using the chi-square test. Hepatitis infection status was categorized into no infection, HBV infection and HCV infection. Logistic regression analysis was performed at both the univariate and multivariate levels by estimating the odds ratio (OR) and 95% confidence interval (CI). Adjustments were made for covariates that showed significant differences in distribution at the multivariate level. In the initial analysis of the HBV group, comparisons were made between the nonviral and HBV-infected groups (including both HBV alone and HBV-HCV coinfection). Similar considerations were made in the analysis of the HCV group. A sensitivity analysis was carried out in which the dual infection group was dropped and hepatitis viral groups were treated as HBV alone and HCV alone. Additionally, HCV infection was adjusted in the multivariate analysis of HBV infection and vice versa in the sensitivity analysis. All statistical analyses were performed using SAS software (version 9.4; SAS Institute).

Demographic characteristics

A total of 158,370 participants took part in the study. Of these, 15,305 (9.7%) had HBV infection alone, 2,955 (1.9%) had HCV infection alone, 362 (0.23%) had a dual infection of both HBV and HCV, and 140108 (88.4%) were in the nonviral group. From the primary comparison of characteristics between the HBV-infected and control groups, significant differences were observed in the following variables: age group, sex, education level, marital status, maternal and paternal origin, residence, BMI, income level, family history of cancer, alcohol drinking, smoking experience, betel nut experience, exercise regularity, hyperlipidemia, and diabetes (Table I). Compared with the nonviral hepatitis group, participants in the HBV infection group were generally more likely to be female, of Hokkien maternal and paternal origin, urban residents, within the BMI category ‘overweight and obese’, with a family history of cancer, smoking experience, and diabetes. Participants with HBV infection were also more likely to be in the age group 50–59 years, with a maximum education level of senior high school, and with income status > 60,000 NTD (Table I).

Table I. Distribution of socio-demographic, behavioral factors, and comorbidities between the HBV and nonviral groups

	No HBV		HBV infected
	(N=140108)		(N=15667)
Variables	N	(%)^a	N	(%)^b	P^c
Sex					<0.0001
Male	50186	(35.82)	6524	(41.64)
Female	89922	(64.18)	9143	(58.36)
Age group					<0.0001
<50	411	(0.29)	3	(0.02)
50-59	72857	(52.00)	8067	(51.49)
≥60	66840	(47.71)	7597	(48.49)
Education level					<0.0001
Junior high school and below	15507	(11.07)	1941	(12.39)
Senior high school	38342	(27.37)	4744	(30.28)
College	86259	(61.57)	8982	(57.33)
Marital status					<0.0001
Single	25130	(17.94)	1977	(12.27)
Married	97528	(69.61)	11767	(75.11)
Separated	17450	(12.45)	1912	(12.62)
Maternal origin					<0.0001
Hokkien	106720	(76.17)	12715	(81.16)
Hakka	21458	(15.32)	2231	(14.24)
Others	11930	(8.51)	721	(4.60)
Paternal origin					<0.0001
Hokkien	98244	(70.12)	11741	(74.94)
Hakka	20071	(14.33)	2036	(13.00)
Others	21793	(15.55)	1890	(12.06)
Residence					<0.0001
Rural	45065	(32.16)	4719	(30.12)
Urban	95043	(67.84)	10948	(69.88)
BMI					0.0043
Low	4999	(3.57)	495	(3.16)
Normal	68616	(48.97)	7576	(48.36)
Overweight and above	66493	(47.46)	7596	(48.48)
Income (NTD)					<0.0001
<30,000	83927	(59.90)	9656	(61.63)
30,000-60,000	37401	(26.69)	3786	(24.17)
≥60,000	18780	(13.40)	2225	(14.20)
Alcohol drinking					0.0038
No	127981	(91.34)	14203	(90.66)
Yes	12127	(8.66)	1464	(9.34)
Family history of cancer					<0.0001
No	90053	(64.27)	9258	(59.09)
Yes	50055	(35.73)	6409	(40.91)
Smoking experience					<0.0001
No	113291	(80.86)	12348	(78.82)
Yes	26817	(19.14)	3319	(21.18)
Betel nut experience					<0.0001
No	132435	(94.52)	14591	(93.13)
Yes	7673	(5.48)	1076	(6.87)
Exercise regularity					0.0608
No	85587	(61.09)	9691	(61.86)
Yes	54521	(38.91)	5976	(38.14)
Hypertension					0.9195
No	60055	(42.86)	6722	(42.91)
Yes	80053	(57.14)	8945	(57.09)
Hyperlipidemia					<0.0001
No	115400	(82.37)	13246	(84.55)
Yes	24708	(17.63)	2421	(15.45)
Diabetes					0.0327
No	88170	(62.93)	9723	(62.06)
Yes	51938	(37.07)	5944	(37.94)

Abbreviations: HBV, Hepatitis B Virus; BMI, Body Mass Index; NTD, National Taiwan Dollar.

^a: Percentages among the none HBV and/or HCV infected participants

^b: Percentages among the HBV infected participants

^c: Comparing the Non-viral and HBV infected group

Comparing the HCV-infected group and the control group, significant differences were observed for the variables age group, education level, marital status, maternal and paternal origin, residence, BMI, income level, family history of cancer, alcohol drinking, smoking experience, betel nut experience, exercise regularity, hypertension, and diabetes (Table II). Participants who were infected with HCV were most likely to be above 50 years old, having completed at least senior high school, married, of Hokkien origin, residing in urban areas, earning less than 30,000 NTD, and having a family history of cancer (Table II).

Table II. Distribution of socio-demographic, behavioral factors, and comorbidities between the HCV and nonviral groups.

	No HCV		HCV-infected
	(N=140108)		(N=3317)
Variables	N	(%)^a	N	(%)^b	P^c
Sex					0.1754
Male	50186	(35.82)	1226	(36.96)
Female	89922	(64.18)	2091	(63.04)
Age group					<0.0001
<50	411	(0.29)	0	(0.00)
50-59	72857	(52.00)	1029	(31.02)
≥60	66840	(47.71)	2288	(68.98)
Education level					<0.0001
Junior high school and below	15507	(11.07)	933	(28.13)
Senior high school	38342	(27.37)	1120	(33.77)
College	86259	(61.57)	1264	(38.11)
Marital status					<0.0001
Single	25130	(17.94)	292	(8.80)
Married	97528	(69.61)	2353	(70.94)
Separated	17450	(12.45)	672	(20.26)
Maternal origin					<0.0001
Hokkien	106720	(76.17)	2773	(83.60)
Hakka	21458	(15.32)	359	(10.82)
Others	11930	(8.51)	185	(5.58)
Paternal origin					<0.0001
Hokkien	98244	(70.12)	2559	(77.15)
Hakka	20071	(14.33)	375	(11.31)
Others	21793	(15.55)	383	(11.55)
Residence					<0.0001
Rural	45065	(32.16)	751	(22.64)
Urban	95043	(67.84)	2566	(77.36)
BMI					<0.0001
Low	4999	(3.57)	98	(2.95)
Normal	68616	(48.97)	1515	(45.67)
Overweight and above	66493	(47.46)	1704	(51.37)
Income (NTD)					<0.0001
<30,000	83927	(59.90)	2372	(71.51)
30,000-60,000	37401	(26.69)	610	(18.39)
≥60,000	18780	(13.40)	335	(10.10)
Alcohol drinking					<0.0001
No	127981	(91.34)	2876	(86.70)
Yes	12127	(8.66)	441	(13.30)
Family history of cancer					<0.0001
No	90053	(64.27)	1904	(57.40)
Yes	50055	(35.73)	1413	(42.60)
Smoking experience					<0.0001
No	113291	(80.86)	2439	(73.53)
Yes	26817	(19.14)	878	(26.47)
Betel nut experience					<0.0001
No	132435	(94.52)	2966	(89.42)
Yes	7673	(5.48)	351	(10.58)
Exercise regularity					<0.0001
No	85587	(61.09)	1823	(54.96)
Yes	54521	(38.91)	1494	(45.04)
Hypertension					0.0350
No	60055	(42.86)	1361	(41.03)
Yes	80053	(57.14)	1956	(58.97)
Hyperlipidemia					0.0793
No	115400	(82.37)	2771	(83.54)
Yes	24708	(17.63)	546	(16.46)
Diabetes					<0.0001
No	88170	(62.93)	1929	(58.15)
Yes	51938	(37.07)	1388	(41.85)

Abbreviations: HCV, Hepatitis C Virus; BMI, Body Mass Index; NTD, National Taiwan Dollar.

^a: Percentages among the none HBV and/or HCV infected participants

^b: Percentages among the HCV infected participants

^c: Comparing the Non-viral and HCV infected groups

Association between hepatic viral infections and cancer

Univariate analysis revealed that HBV was associated with both liver cancer (OR = 8.39, 95% CI = 4.15–16.98, P < 0.001) and ovarian cancer (OR = 4.15, 95% CI = 1.81–9.47, P = 0.001). Interestingly, after adjusting for age group, sex, education level, marital status, maternal and paternal origin, residence, BMI, income level, family history of cancer, alcohol consumption, smoking experience, betel nut experience, hyperlipidemia, and diabetes, the associations between HBV infection and liver (adjusted odds ratio (aOR) = 6.76, 95% CI = 3.32–13.77, P < 0.001) and ovarian (aOR = 3.80, 95% CI = 1.65–8.74, P = 0.002) cancer remained statistically significant (Table III).

Table III. Association between Hepatitis B infection and cancer

	No HBV		HBV- infected
Cancer sites	N	‱	N	‱	OR	95% CI	P	aOR^*	95% CI	P
Liver	16	1.14	15	9.57	8.39	4.15-16.98	<0.001	6.76	3.32-13.77	<0.001
Lung	46	3.28	2	1.28	0.39	0.09-1.60	0.191	0.35	0.08-1.43	0.142
Breast ^a	257	28.58	31	33.91	1.19	0.82-1.72	0.368	1.07	0.73-1.55	0.739
Gastric	9	0.64	1	0.64	0.99	0.13-7.84	0.995	0.73	0.09-5.83	0.769
Colorectal	64	4.57	8	5.11	1.12	0.54-2.33	0.766	1.00	0.48-2.09	0.999
Nasopharyngeal	16	1.14	2	1.28	1.12	0.26-4.86	0.882	0.88	0.20-3.88	0.870
Prostate ^b	22	4.38	1	1.53	0.35	0.05-2.59	0.304	0.33	0.05-2.49	0.285
Cervical ^a	141	15.68	20	21.87	1.40	0.87-2.23	0.163	1.25	0.78-2.01	0.353
Ovarian ^a	19	2.11	8	8.75	4.15	1.81-9.47	0.001	3.80	1.65-8.74	0.002
Uterine ^a	48	5.34	8	8.75	1.64	0.78-3.47	0.196	1.51	0.71-3.21	0.280
Oral	22	1.57	1	0.64	0.41	0.06-3.02	0.379	0.35	0.05-2.57	0.299
Bone	10	0.71	2	1.28	1.79	0.39-8.16	0.453	1.55	0.34-7.15	0.571
Non-Hodgkin’s	33	2.36	3	1.91	0.81	0.25-2.65	0.732	0.73	0.22-2.40	0.608
Thyroid	62	4.43	10	6.38	1.44	0.74-2.81	0.282	1.28	0.66-2.51	0.468
Skin	12	0.86	1	0.64	0.75	0.10-5.73	0.778	0.68	0.09-5.23	0.709
Kidney	6	0.43	2	1.28	2.98	0.60-14.77	0.181	2.90	0.57-14.72	0.198
Brain	8	0.57	2	1.28	2.24	0.48-10.53	0.309	1.76	0.37-8.35	0.480
Bladder	13	0.93	0	0.00	-	-	-	-	-	-
Other^c	42	3.00	1	0.64	0.21	0.03-1.55	0.126	0.19	0.03-1.42	0.106

Abbreviations: HBV, Hepatitis B Virus; OR, Odds Ratio; CI, Confidence Interval, aOR; Adjusted Odds ratio.

^*: Adjusted for age group, sex, education level, marital status, maternal and paternal origin, residence, BMI, income level, family history of cancer, alcohol drinking, smoking experience, betel nut experience, hyperlipidemia, and diabetes

^a: Females only

^b: Males only

^c: Other; throat cancer, retroperitoneal cancer, testicular cancer, neuroblastoma, cholangiocarcinoma, thymus cancer, spleen cancer, gall bladder cancer, ureteral cancer, vaginal cancer, esophageal cancer, bone marrow cancer and cancer of the head and neck.

Analysis of HCV infection revealed significant associations with liver cancer (OR=7.93, 95% CI=2.31-27.22, P=0.001), ovarian cancer (OR=4.53, 95% CI=1.06-19.46, P=0.042), and kidney cancer (OR=14.09, 95% CI=2.84-69.83, P=0.001) during the univariate analysis. Upon incorporation of necessary adjustments for significant covariates, HCV infection was still observed to be associated with liver cancer (aOR=4.33, 95% CI=1.23-15.22, P=0.022), ovarian cancer (aOR=4.83, 95% CI=1.08-21.59, P=0.039), and kidney cancer (aOR=14.09, 95% CI=2.84-69.83, P=0.039). (Table IV)

Table IV: Association between HCV infection and cancers

	No HCV		HCV- infected
Cancer sites	N	‱	N	‱	OR	95% CI	P	aOR^*	95% CI	P
Liver	16	1.14	3	9.04	7.93	2.31-27.22	0.001	4.33	1.23-15.22	0.022
Lung	46	3.28	2	6.03	1.84	0.45-7.57	0.400	1.38	0.33-5.74	0.661
Breast ^a	257	28.58	5	23.91	0.84	0.36-2.03	0.693	0.66	0.28-1.63	0.372
Gastric	9	0.64	0	0.00	-	-	-	-	-	-
Colorectal	64	4.57	1	3.01	0.66	0.09-4.76	0.680	0.44	0.06-3.17	0.412
Nasopharyngeal	16	1.14	0	0.00	-	-	-	-	-	-
Prostate ^b	22	4.38	1	8.17	1.86	0.25-13.82	0.543	1.27	0.17-9.55	0.817
Cervical ^a	141	15.68	4	21.87	1.22	0.45-3.30	0.694	1.00	0.37-2.72	0.993
Ovarian ^a	19	2.11	2	9.56	4.53	1.06-19.46	0.042	4.83	1.08-21.59	0.039
Uterine ^a	48	5.34	0	0.00	-	-	-	-	-	-
Oral	22	1.57	0	0.00	-	-	-	-	-	-
Bone	10	0.71	1	3.01	4.23	0.54-33.01	0.170	2.98	0.57-24.20	0.307
Non-Hodgkin’s	33	2.36	0	0.00	-	-	-	-	-	-
Thyroid	62	4.43	1	3.01	0.68	0.10-4.91	0.705	0.58	0.08-4.23	0.592
Skin	12	0.86	1	3.01	3.52	0.46-27.09	0.226	3.61	0.46-28.56	0.223
Kidney	6	0.43	2	6.03	14.09	2.84-69.83	0.001	11.60	2.21-60.99	0.039
Brain	8	0.57	0	0.00	-	-	-	-	-	-
Bladder	13	0.93	0	0.00	-	-	-	-	-	-
Other^c	42	3.00	0	0.00	-	-	-	-	-	-

Abbreviations: HBV, Hepatitis B Virus; OR, Odds Ratio; CI, Confidence Interval, aOR; Adjusted Odds ratio.

^*: Adjusted for age group, education level, marital status, maternal and paternal origin, residence, BMI, income level, family history of cancer, alcohol drinking, smoking experience, betel nut experience, exercise regularity, hypertension, and diabetes.

^a: Females only

^b: Males only

^c:Other; throat cancer, retroperitoneal cancer, testicular cancer, neuroblastoma, cholangiocarcinoma, thymus cancer, spleen cancer, gall bladder cancer, ureteral cancer, vaginal cancer, esophageal cancer, bone marrow cancer and cancer of the head and neck.

Sensitivity analysis

Table V shows the association between HBV and cancer after the omission of the dual infection group. In both the univariate and multivariate analyses, significant associations remained for liver cancer (aOR=7.47, 95% CI=3.68-15.19, P<0.001) and ovarian cancer (aOR=3.86, 95% CI=1.68-8.88, P=0.002).

Table V: The association between HBV ‘alone’ and cancer

	No HBV		HBV only
Cancers	N	‱	N	‱	OR	95% CI	P	aOR^*	95% CI	P
Liver	16	1.14	15	9.80	8.59	4.25-17.38	<0.001	7.47	3.68-15.19	<0.001
Lung	46	3.28	2	1.31	0.40	0.10-1.64	0.202	0.36	0.09-1.50	0.162
Breast ^a	257	28.58	30	33.61	1.18	0.81-1.72	0.400	1.06	0.73-1.56	0.756
Gastric	9	0.64	1	0.65	1.02	0.13-8.03	0.987	0.85	0.11-6.71	0.875
Colorectal	64	4.58	8	5.23	1.14	0.55-2.39	0.719	1.06	0.51-2.21	0.886
Nasopharyngeal	16	1.14	2	1.31	1.14	0.26-4.98	0.857	0.96	0.22-4.20	0.956
Prostate ^b	22	4.38	1	1.57	0.36	0.05-2.65	0.315	0.34	0.05-2.56	0.297
Cervical ^a	141	15.68	18	20.16	1.29	0.79-2.10	0.314	1.16	0.71-1.90	0.561
Ovarian ^a	19	2.11	8	8.96	4.25	1.89-9.70	0.001	3.86	1.68-8.88	0.002
Uterine and corpus ^a	48	5.34	8	8.96	1.68	0.79-3.55	0.175	1.57	0.74-3.23	0.864
Oral	22	1.57	1	0.65	0.42	0.06-3.09	0.391	0.37	0.05-2.72	0.325
Bone	10	0.71	1	0.65	0.92	0.12-7.15	0.933	0.83	0.11-6.52	0.861
Non-Hodgkin’s	33	2.36	3	1.96	0.83	0.26-2.71	0.761	0.75	0.23-2.46	0.639
Thyroid	62	4.43	10	6.54	1.48	0.76-2.88	0.253	1.27	0.65-2.48	0.486
Skin	12	0.86	1	0.65	0.76	0.10-5.87	0.795	0.69	0.09-5.35	0.726
Kidney	6	0.43	2	1.31	3.05	0.62-15.12	0.172	3.03	0.38-8.54	0.464
Brain	8	0.57	2	1.31	2.29	0.48-10.78	0.295	1.79	0.38-8.54	0.464
Bladder	13	1.21	0	-	-	-	-	-	-	-
Other ^c	42	3.00	1	0.65	0.22	0.03-1.58	0.132	0.20	0.03-1.46	0.112

Abbreviations: HBV, Hepatitis B Virus; OR, Odds Ratio; aOR, Adjusted Odds Ratio; CI, Confidence Interval.

^*: Adjusted for age group, sex, education level, marital status, maternal and paternal origin, residence, BMI, income level, family history of cancer, alcohol drinking, smoking experience, betel nut experience, exercise regularity, hyperlipidemia, and diabetes.

^a: Females only

^b: Males only

^c: Other; throat cancer, retroperitoneal cancer, testicular cancer, neuroblastoma, cholangiocarcinoma, thymus cancer, spleen cancer, gall bladder cancer, ureteral cancer, vaginal cancer, esophageal cancer, bone marrow cancer and cancer of the head and neck.

Similarly, for HCV infection, both the univariate and multivariate analyses showed that the association remained for liver cancer (aOR=4.80, 95% CI=1.38-16.74, P=0.014), ovarian cancer (aOR=5.19, 95% CI=1.17-22.97, P=0.030), and kidney cancer (aOR=11.98, 95% CI=2.32-61.84, P=0.003) (Table VI).

Table VI: Association between HCV ‘alone’ and cancer

	No		HCV only
Cancers	N	‱	N	‱	OR	95% CI	P	aOR^*	95% CI	P
Liver	16	1.14	3	10.15	8.90	2.59-30.55	0.001	4.80	1.38-16.74	0.014
Lung	46	3.28	2	6.77	2.06	0.50-8.50	0.316	1.58	0.38-6.68	0.530
Breast^a	257	28.58	4	21.33	0.75	0.28-2.01	0.562	0.59	0.22-1.58	0.291
Gastric	9	0.64	0	0.00	-	-	-	-	-	-
Colorectal	64	4.57	1	3.38	0.74	0.10-5.34	0.766	0.50	0.07-3.63	0.493
Nasopharyngeal	16	1.14	0	0.00	-	-	-	-	-	-
Prostate^b	22	4.38	1	9.26	2.12	0.29-15.69	0.464	1.44	0.19-10.83	0.725
Cervical^a	141	15.68	2	10.67	0.68	0.17-2.75	0.590	0.55	0.13-2.22	0.397
Ovarian^a	19	2.11	2	10.67	5.05	1.18-21.71	0.029	5.19	1.17-22.97	0.030
Uterine^a	48	3.43	0	0.00	-	-	-	-	-	-
Oral	22	1.57	0	0.00	-	-	-	-	-	-
Bone	10	0.71	0	0.00	-	-	-	-	-	-
Non-Hodgkin’s	33	2.36	0	0.00	-	-	-	-	-	-
Thyroid	62	4.43	1	3.38	0.77	0.11-5.52	0.791	0.66	0.09-4.76	0.676
Skin	12	0.86	1	3.38	3.95	0.51-30.40	0.187	3.54	0.45-28.08	0.232
Kidney	6	0.43	2	6.77	15.82	3.19-78.39	0.001	11.98	2.32-61.84	0.003
Brain	8	0.57	0	0.00	-	-	-	-	-	-
Bladder	13	0.93	0	0.00	-	-	-	-	-	-
Other ^c	42	3.00	0	0.00	-	-	-	-	-	-

Abbreviations: HBV, Hepatitis B Virus; OR, Odds Ratio; aOR, Adjusted Odds Ratio; CI, Confidence Interval.

^*: Adjusted for age group, sex, education level, marital status, maternal and paternal origin, residence, BMI, income level, family history of cancer, alcohol drinking, smoking experience, betel nut experience, exercise regularity, hyperlipidemia, and diabetes.

^a: Females only

^b: Males only

^c: Other; throat cancer, retroperitoneal cancer, testicular cancer, neuroblastoma, cholangiocarcinoma, thymus cancer, spleen cancer, gall bladder cancer, ureteral cancer, vaginal cancer, esophageal cancer, bone marrow cancer and cancer of the head and neck.

In the current study, we observed that hepatitis viral infections were associated not only with liver cancer but also with some extrahepatic cancer types. In particular, the extrahepatic cancers observed to be associated with HCV infection were ovarian and kidney cancers, whereas those with HBV infection were ovarian cancer. In the sensitivity analysis, the same associations were observed between HBV and HCV infections and cancer. This finding reinforces the robustness of our findings.

A few recent studies have examined the association between HBV infection and intra- and extrahepatic cancer. In these studies, the association with liver cancer was consistent, but the associated extrahepatic cancers varied among different studies. A study by Kamiza et al. revealed associations between HBV infection and an increased likelihood of hepatocellular carcinoma and ovarian cancer¹², similar to our study. He additionally reported associations between colorectal cancer, gallbladder and extrahepatic bile duct cancer, pancreatic cancer, renal cancer, and non-Hodgkin’s lymphoma using the Taiwan National Health Insurance Research Database (NHIRD) in a retrospective cohort study¹². Similar findings were observed by Spradling et al., who demonstrated a higher incidence of ovarian and hepatocellular cancers among HBV-infected participants in a cohort study in the United States. Other incident extrahepatic cancers included gastric, cholangiocarcinoma, neuroendocrine, and non-Hodgkin cancers¹⁸. A Chinese-based longitudinal study revealed associations between HBV infection and the risk of liver cancer, stomach cancer, colorectal cancer, oral cancer, pancreatic cancer, and lymphoma in a prospective cohort study using a nested case‒control study¹³. The extrahepatic associations revealed in this study are in contrast to our findings. Another study on the elderly population in the United States reported significant associations between HBV infection and an increased risk of stomach cancer, cancer of the anus, liver cancer, intrahepatic bile duct cancer, nasopharynx cancer, and myelodysplastic syndrome¹⁴. All the above studies showed consistent associations with liver cancer but different extrahepatic cancer types.

Several studies have examined the relationship between HCV infection and various types of cancer. Our findings are consistent with those of Kamiza et al., who observed significant associations between liver and ovarian cancer. The author also revealed associations with other extrahepatic cancers, such as gallbladder and extrahepatic bile duct cancers, and non-Hodgkin’s lymphoma¹². Another study revealed significant associations between HCV infection and the risk of renal cancer in a hospital-based cohort study conducted in southeastern Michigan¹⁹, consistent with our study. Similarly, a Taiwanese study based on the NHIRD revealed an association between kidney cancer and HCV infection²⁰. A large study of the Canadian population revealed an elevated risk of some extrahepatic cancers associated with HCV infection, including liver, anal, esophageal, larynx, lung, and oral cancer²¹. Similarly, the associations with HCV examined in the above studies revealed significant associations with liver cancer and various extrahepatic cancers.

The coherent findings with the Taiwanese-based studies could be attributed to the fact that the studies were carried out in the same population group with similar exposures, lifestyle behaviors, diet, and genetic patterns. Otherwise, both HBV and HCV are known to be risk factors for liver cancer, and this association is expected. The inconsistencies observed could be attributed to differences in study designs, database types, populations, control of different confounders, and different analytical strategies. All the above studies used longitudinal study designs, unlike the current study. The different populations explored have different risk factors due to differences in diet patterns, lifestyle behaviors, environmental exposures, and comorbidities, making it imperative to observe different extrahepatic manifestations.

HBV and HCV are oncogenic viruses, particularly in liver cancer²². The oncogenic role of viruses in hepatocytes is believed to be both direct and indirect. The direct mechanism is by forming covalently closed circular deoxyribonucleic acid (cccDNA) structures in hepatocytes, leading to chronic injury and inflammation^23,24, and indirectly by altering cellular signal transduction pathways^23,25,26. However, few studies have explored the mechanism of carcinogenesis of HBV and HCV in extracellular cancers. Song et al. reported the presence of HBV DNA and hepatitis B X protein in stomach and pancreatic cancer tissues but not in lung cancer tissues¹³. The presence of HCV ribonucleic acid (RNA) has also been detected in ovarian cancer tissue^27,28. Nucleic acids and core proteins of HCV have also been isolated from kidney tissue^{29, 30}. HCV RNA was isolated in 65% of the glomerular tissue analyzed, and HCV core protein was identified in 77.5% of the tubules and glomeruli²⁹. The presence of these biomarkers in extrahepatic cancer tissues could indicate the likelihood of viral replication in these cells, leading to chronic inflammation and cancer development.

This study provides evidence of an association between hepatic viral infections (HBV and HCV) and both hepatic and extrahepatic cancer. However, this study had several strengths and limitations. The first strength of this study was the use of a large database covering a wide geographic location of the Taiwanese population. Second, the study used a highly sensitive method for the diagnosis of HCV and HBV cases, ECLIA, which has a sensitivity greater than 99% and a specificity of 100%³¹. This implies a high diagnostic accuracy for HBV and HCV infections. In addition, the study controlled for a wide range of confounding variables, including sociodemographics, lifestyle behaviors, and comorbidities, providing an opportunity to control a wide range of risk factors.

Our study had some limitations. Being cross-sectional in nature, we were unable to infer causality due to the limitations of the study design. The study only presents the likely association between hepatic viral infections and cancers and an opportunity to explore them further. Second, the generalizability of the study may be limited because of the small number of cancer events in the baseline study. However, this is validated by the fact that associations with liver cancer were observed to be significant (HBV and HCV are known risk factors for hepatocellular cancer)^32-34. The findings of the study were also observed to be consistent with previous research^12,19,20. Third, the influence of likely confounding from other viral infections such as human immunodeficiency virus³⁵ and human papilloma virus^36,37 could not be ruled out. Finally, the cases of cancer in the TWB database were based on a survey, which may not be the most accurate way to diagnose cancer. Future studies should consider linking this database to other databases, such as the cancer registry or the NHIRD, to ensure a more comprehensive diagnosis of cancer. However, these cancer results can be relied upon because patients are less likely to lie about their cancer status³⁸.

In conclusion, hepatic viral infections (HBV and HCV) were not only associated with an increased likelihood of hepatocellular cancer but also with extrahepatic cancers such as ovarian and kidney cancers. The TWB database provides a great opportunity to investigate these associations further in a longitudinal study due to the large sample size, long follow-up period, and potential for controlling a wide range of likely confounding variables.

aOR: Adjusted odds ratio; BMI: Body mass index; CI: Confidence interval; DNA: Deoxyribonucleic acid; ECLIA: Electrochemiluminescence assay; HBV: HBsAg: Hepatitis B surface antigen; Hepatitis B virus; HCV: Hepatitis C virus; OR: Odds ratio; NHIRD: National health insurance research database; NTD: National Taiwan dollar; RNA: Ribonucleic acid; TWB: Taiwan biobank; WHO: World Health Organization.

Ethics approval and consent to participate

This study was reviewed and approved by the Institutional Review Board of Taipei Medical University and Hospital Research Ethics Committee (TMU-JIRB No.: N202005033, N202304079). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements, however the TWB obtains consent from all participants at the point of recruitment.

Consent for publication

Not applicable

Availability of data and materials

The data that support the findings of this study are not openly available due to licenses\restrictions and can be available from the Taiwan Biobank upon submission of a formal proposal. Requests to access these datasets should be directed to [email protected]. .

Competing interests

The authors declare that they have no competing interests.

Funding

The current research is without funding support.

Authors’ contributions

M.M. and C.C.Y. conceptualized the study. M.M., F.H.S., M.J.S., and C.C.Y. contributed to the methodology. M.M., F.H.S., M.J.S., and C.C.Y. conducted the formal analysis. M.M., F.H.S., M.J.S., and C.C.Y. conducted the investigation. M.M., F.H.S., M.J.S., A.B.K. and C.C.Y. wrote the original draft. M.M., F.H.S., M.J.S., A.B.K. and C.C.Y. reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.

Acknowledgments

The authors would like to thank the Taiwan Biobank for approving the application to access the data.

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No competing interests reported.

The association between hepatic viral infections and cancers: A cross-sectional study in the Taiwan adult population

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

INTRODUCTION

MATERIALS AND METHODS

Study population and design

Data

Ascertainment of hepatic viral infections and cancers

Statistical analysis

RESULTS

Demographic characteristics

Association between hepatic viral infections and cancer

DISCUSSION

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1