Abstract
The objective of the present study was to investigate the association between human T‐lymphotropic virus type‐1 (HTLV‐1) infection and cancer risk in a longitudinal study. The study population consisted of 2729 atomic bomb survivors in Nagasaki Prefecture, Japan, who had no previous history of cancer at baseline. The baseline survey, including analysis of antibody to HTLV‐1, took place during 1985–1987 and follow‐up was performed until the end of 2001. There were 553 incident cases of malignant neoplasms during the observation period. After adjustment for sex, age and other variables, HTLV‐1 infection was not associated with the risk of developing cancers of all sites, excluding adult T‐cell leukemia (rate ratio 1.0, 95% confidence interval [CI] 0.76–1.4), stomach, colon and rectum, lung, female breast or other minor sites, but was associated with increased risk of liver cancer (rate ratio 2.1, 95%CI 1.0–4.6). The point estimate of the rate ratio for thyroid cancer was 3.0, but this was not significantly higher than 1 because of the small number of events (n = 11) and low prevalence of HTLV‐1 seropositivity. These findings support the idea that HTLV‐1 infection is not associated with an increased general cancer risk. Confounding by hepatitis C virus (HCV) and the interaction between HTLV‐1 and HCV may explain the increased risk of liver cancer among HTLV‐1 carriers. Further follow‐up may be required to determine if HTLV‐1 carriers are at increased risk of thyroid cancer. (Cancer Sci 2006; 97: 535– 539)
Human T‐cell lymphotropic virus type‐1 (HTLV‐1), the first retrovirus discovered in humans, causes an aggressive form of T‐cell malignancy, termed adult T‐cell leukemia/lymphoma (ATL), chronic inflammatory disorders including tropical spastic paraparesis/HTLV‐1‐associated myelopathy (TSP/HAM) and uveitis.( 1 , 2 ) This virus is endemic in Southwestern Japan, the Caribbean basin, South America, Central and West Africa, the Middle East and the Pacific region.( 1 , 2 ) It is believed that mother‐to‐child infection through breast‐feeding, but not sexual or blood‐borne transmission in adulthood, leads to the development of ATL. For this reason, an intervention program to prevent the vertical transmission of HTLV‐1, consisting of screening of pregnant women and recommending carrier mothers not to breast‐feed their babies, has been performed in endemic areas in Japan.( 3 ) In obtaining informed consent from each carrier mother, valid information on the magnitude of the health risks associated with HTLV‐1 infection is indispensable because breast‐feeding in itself has beneficial health effects for both mothers (reduction of breast cancer risk)( 4 ) and infants (nutrition, immunological protection, formation of mother‐to‐child bonding and promotion of psychological development).
Epidemiological studies have shown that the crude incidence or mortality rate of ATL is around 50–200 cases/100 000 persons‐years, and the lifetime risk is roughly 1–6% among HTLV‐1 carriers, with male predominance in Japan.( 5 , 6 , 7 ) The incidence rate and the lifetime risk of HAM have been reported to be around 3.1 cases/100 000 persons‐years and 0.25%, respectively.( 8 ) However, it remains controversial whether or not HTLV‐1 carriers are at an increased risk of malignancies other than ATL. Several retrospective case‐referent studies and case reports suggested that HTLV‐1 was associated with cancers of various organs without any organ specificity,( 9 , 10 ) lung (small‐cell type),( 11 ) cervix uteri,( 12 , 13 ) and vagina.( 12 ) In addition, neurofibromas,( 14 , 15 ) adrenal medullary tumors( 16 ) and mammary carcinomas( 17 ) frequently occurred in mice or rats transgenic for the HTLV‐1 tax or pX gene, which encodes the trans‐acting viral factor p40tax. In contrast, in our previous 7‐year prospective study in an HTLV‐I endemic area of Nagasaki Prefecture, Japan (total population of 4297), HTLV‐I carriers were not at an increased risk of total cancers, but at reduced risk of gastric cancer.( 18 ) To evaluate the consistency of the findings, we examined the association of HTLV‐1 infection with the risk of developing malignant neoplasms with the 15.4‐year follow‐up of another cohort.
Materials and Methods
Study population
Since 1958, 7564 subjects (3374 men and 4190 women) have received biennial health examinations at least once in Nagasaki, Japan, as part of the Atomic Bomb Casualty Commission (ABCC)‐Radiation Effects Research Foundation (RERF) follow‐up program. A detailed description of this program (Adult Health Study [AHS]) has been published in another report.( 19 ) A total of 1196 men and 1894 women (aged 39–92 years at baseline) received the AHS examination and assay of HTLV‐1 antibody during an approximately 2‐year period from 1985 to 1987. The significantly shortened survival associated with HTLV‐1 seropositivity and HTLV‐1 antibody titer observed in this population has been reported elsewhere.( 20 ) The study protocol was reviewed and approved by the Clinical Research Ethical Committee of the Tokushima University Hospital.
Assay of HTLV‐1 antibody
Serum antibody to HTLV‐1 was analyzed by the indirect immunofluorescence method, using the adult T‐cell leukemia cell line (MT‐1 and MT‐2) as antigen cells, as described previously.( 21 ) Briefly, cell smears were treated with diluted human serum at 37°C for 30 min, and subsequently with fluorescein isothiocyanate‐labeled goat antihuman IgG at 37°C for 30 min. Then, the cell smears were examined with fluorescence microscopy. The antibody titer was determined for all but one HTLV‐1 seropositive subject by serial dilution of the sera, and defined as the maximum dilution at which fluorescence‐positive cells were identified.
Information on other variables
Trained nurses inquired about the study participants’ smoking and drinking habits at the time of the AHS examinations. Data on these health habits were not obtained for 219 subjects who had not been interviewed. Therefore, data from the initial survey of the ABCC‐RERF follow‐up program were alternatively used for 181 of these 219 subjects. No information on lifestyle was available for the remaining 38 subjects. Body mass index (BMI) was measured in 3043 subjects at the time of the health examination. Between 1993 and 1995, trained nurses asked 2046 of 3090 subjects how many times and when they had received blood transfusions.( 22 , 23 ) In addition, hepatitis virus C (HCV) antibody (Abbott HCV‐PHA 2nd Generation, Dynabott, Tokyo) and hepatitis B virus (HBV) surface antigen (HBs‐Ag) (reversed passive hemagglutination, Maisel HBsAg, Institute of Immunology, Tokyo) were measured for 1884 subjects between 1993 and 1995.
Examination of the incidence of cancer
Since 1958, the RERF has run a population‐based cancer registry in Nagasaki City, under the supervision of the Nagasaki City Medical Association Tumor Statistics Committee, to accurately determine cancer incidence among atomic bomb survivors.( 24 ) The cancer registry was extended to the whole of Nagasaki Prefecture in January 1985. Previous history and incidence of cancer were examined by record linkage with the data file of this cancer registry. A total of 192 subjects had a history of cancer before the time of blood drawing for HTLV‐1 antibody assay during 1985–1987. In addition, 169 subjects were living outside Nagasaki Prefecture at the time of the baseline health examination. After excluding these 361 subjects, the remaining 2729 subjects were defined as the target population and were followed from the time of the baseline survey to the date of the first diagnosis of cancer, death or transfer, or December 31, 2001, whichever came first. Twenty‐two persons who had moved out of the prefecture during the observation period were treated as censored cases. The median follow‐up period was 15.4 years (total of 35 556 person‐years).
Statistical analysis
The significance of the difference in the baseline characteristics between HTLV‐1 seropositive and seronegative subjects was evaluated using the Wilcoxon rank sum test, Student's t‐test or the χ2 test, depending on the distribution of the data. In the analysis of cancer incidence, the Cox regression model was used to estimate the rate ratios (RR) and their Wald type 95% confidence interval (CI) for overall and site‐specific cancers associated with HTLV‐1 infection.( 25 ) The assumption of constant hazard ratio was checked by assessing the significance of the interaction between HTLV‐1 seropositivity and log (time). The potential confounding effects of sex, age, BMI (<20, 20–26.9, 27), smoking (non‐smoker, current or ex‐smoker) and drinking habits (non‐drinker, current or ex‐drinker) were adjusted by incorporating the indicator or continuous variables in the model. Statistical analyses were performed using SAS (version 8.2) and STATA (release 4) software packages, and all P‐values reported were two‐sided.
Results
Table 1 presents the background characteristics of the study population by sex and HTLV‐1 antibody status. The proportion of HTLV‐1 seropositive subjects was 8.2% for men and 8.5% for women. In men, the median age at enrollment was 3 years older (P = 0.01), the percentage of current or ex‐smokers was higher (P = 0.09), and that of current or ex‐drinkers was lower (P = 0.04) among seropostitive subjects as compared to seronegative subjects. In women, the proportion of current or ex‐smokers was higher (P = 0.01) among the HTLV‐1 carriers than non‐carriers. Information about the history of blood transfusion, HBs‐Ag and HCV antibody was not presented because of the large number of missing data. As has been previously reported,( 21 ) there was no association between HTLV‐1 seropositivity and effective atomic bomb radiation dose, suggesting that the radiation exposure was not a confounding variable for the association between HTLV‐1 and cancer risk (data not shown).
Table 1.
Background characteristics of the study subjects according to HTLV‐I seropositivity (Nagasaki, Japan, 1985–1987)
| Men | P‐value | Women | P‐value | |||
|---|---|---|---|---|---|---|
| (–) | (+) | (–) | (+) | |||
| No. of subjects | 986 | 88 | 1515 | 140 | ||
| Age (years) † , ‡ | 57 (39–92) | 60 (46–87) | 0.01 | 58 (39–90) | 59 (40–92) | 0.66 |
| 30–39 (%) | 2 (0.2) | 0 (0.0) | 2 (0.1) | 0 (0.0) | ||
| 40–49 | 173 (17.5) | 3 (3.4) | 181 (11.9) | 20 (14.3) | ||
| 50–59 | 418 (42.4) | 41 (46.6) | 669 (44.2) | 52 (37.1) | ||
| 60–69 | 174 (17.6) | 22 (25.0) | 410 (27.1) | 40 (28.6) | ||
| 70–79 | 170 (17.2) | 13 (14.8) | 175 (11.6) | 19 (13.6) | ||
| 80–89 | 44 (4.5) | 9 (10.2) | 75 (5.0) | 7 (5.0) | ||
| 90–99 | 5 (0.5) | 0 (0.0) | 3 (0.2) | 2 (1.4) | ||
| Body mass index (kg/m2) § , ¶ | 22.0 (2.9) | 22.3 (2.3) | 0.42 | 23.0 (3.3) | 22.9 (3.8) | 0.92 |
| Smoking (%) †† | ||||||
| Non‐smoker | 247 (25.3) | 15 (17.0) | 0.09 | 1343 (89.7) | 113 (82.5) | 0.01 |
| Current or ex‐smoker | 731 (74.7) | 73 (83.0) | 155 (10.3) | 24 (17.5) | ||
| Drinking (%) †† | ||||||
| Non‐drinker | 268 (27.4) | 33 (37.5) | 0.04 | 1256 (83.8) | 110 (80.3) | 0.28 |
| Current or ex‐drinker | 710 (72.6) | 55 (62.5) | 242 (16.2) | 27 (19.7) | ||
Median (range).
‡ Wilcoxon rank sum test.
§ Mean (SD).
Two sample t‐test.
χ2 test.
During the observation period, 553 incident cases of cancer occurred (Table 2). The most common organ was the stomach (n = 106), followed by the colon and rectum (n = 91), lung (n = 59), liver (n = 50) and female breast (n = 45). Two cases of ATL (one in each sex) developed among 228 HTLV‐1 carriers (2836 person‐years), with a crude incidence rate of 0.71 cases/1000 person‐years (95% CI 0.09–2.55). Table 2 also shows the RR of developing cancer associated with HTLV‐1 seropositivity. On the whole, the sex‐ and age‐adjusted RR did not materially change after further adjustment for smoking and drinking habits and BMI, although additional adjustment was difficult for some organs because of the small number of cases. HTLV‐1 infection was not associated with an increased risk of developing cancers of all sites, and all sites excluding ATL (RR 1.0, 95% CI 0.76–1.4). In addition, there was no significantly increased risk of cancer of the stomach (rather protective, RR 0.62), colon and rectum, lung, female breast, or other minor sites. Conversely, the risk of liver cancer, 86% of which consisted of hepatocellular carcinoma (HCC), was elevated among carriers than among non‐carriers (RR 2.1 95% CI 1.0–4.6). The trend for the association between the HTLV‐1 antibody titer and the risk of liver cancer was statistically significant (P = 0.047), with an RR of 1.6 (95% CI 0.57–4.5) for the low titer group (<320) and an RR of 3.2 (95% CI 1.1–9.0) for the high titer group (320). The point estimate of the RR for thyroid cancer was 3.0, but this was not significantly higher than 1 because of the small number of events (n = 11) and low prevalence of HTLV‐1 seropositivity. An additional adjustment for radiation dose yielded an essentially similar RR for all and site‐specific cancers (data not shown).
Table 2.
Incident cases of malignant neoplasms and rate ratios (RR) associated with HTLV‐I seropositivity (Nagasaki, Japan, 1985‐7‐2001)
| Site (ICDO‐T) | Men | Women | No. of events | RR † | 95% CI | No. of events | RR | 95% CI | ||
|---|---|---|---|---|---|---|---|---|---|---|
| (–) | (+) | (–) | (+) | |||||||
| All sites | 265 | 29 | 239 | 20 | 553 | 1.1 | 0.81–1.4 | 547 | 1.1 ‡ | 0.80–1.4 |
| All sites excluding ATL § | 265 | 28 | 239 | 19 | 551 | 1.0 | 0.77–1.4 | 545 | 1.0 ‡ | 0.76–1.4 |
| Major sites | ||||||||||
| Stomach (C160–C169) | 59 | 4 | 41 | 2 | 106 | 0.66 | 0.29–1.5 | 104 | 0.62 ¶ | 0.27–1.4 |
| Colon, rectum (C180–C189) | 50 | 3 | 35 | 3 | 91 | 0.81 | 0.35–1.9 | 91 | 0.80 ‡ | 0.35–1.8 |
| Liver (C220–C221) | 24 | 5 | 18 | 3 | 50 | 2.2 | 1.0–4.8 | 50 | 2.1 ¶ | 1.0–4.6 |
| Lung (C340–C349) | 32 | 4 | 21 | 2 | 59 | 1.2 | 0.53–2.9 | 59 | 1.1 ¶ | 0.49–2.7 |
| Breast (C500–C509) | 0 | 0 | 41 | 4 | 45 | 1.1 | 0.38–3.0 | 44 | 1.0 †† | 0.37–2.9 |
| Minor sites | ||||||||||
| Lip, oral cavity, pharynx (C000–C149) | 5 | 1 | 4 | 0 | 10 | 1.3 | 0.17–10.4 | – | – | – |
| Esophagus (C150–C159) | 6 | 2 | 2 | 0 | 10 | 3.1 | 0.65–14.7 | – | – | – |
| Gallbladder, bile duct (C239–C249) | 8 | 0 | 13 | 0 | 21 | 0.0 | – | – | – | – |
| Pancreas (C250–C259) | 10 | 1 | 8 | 1 | 20 | 1.1 | 0.26–4.9 | 20 | 1.1 ¶ | 0.25–4.6 |
| Bone marrow (C421) | 8 | 2 | 5 | 0 | 15 | 1.7 | 0.38–7.4 | 15 | 1.6 ¶ | 0.36–7.1 |
| Skin (C440–C449) | 11 | 0 | 13 | 0 | 24 | 0.0 | – | – | – | – |
| Cervix uteri (C530–C539) | – | – | 5 | 1 | 6 | – | – | – | – | – |
| Prostate gland (C619) | 16 | 1 | – | – | 17 | 0.69 | 0.09–5.2 | 17 | 0.78 ‡‡ | 0.10–6.0 |
| Bladder (C670–C679) | 11 | 2 | 4 | 0 | 17 | 1.5 | 0.33–6.4 | 17 | 1.3 ¶ | 0.30–5.9 |
| Kidney (C649, C659) | 2 | 0 | 5 | 0 | 7 | – | – | – | – | – |
| Thyroid gland (C739) | 2 | 0 | 7 | 2 | 11 | 2.7 | 0.58–12.5 | 11 | 3.0 ¶ | 0.65–14.2 |
Adjusted for sex and age or age alone (reference = HTLV‐I seronegative subjects).
‡ Adjusted for sex, age, body mass index, and smoking and drinking habits.
§ Two ATL cases were excluded.
¶ Adjusted for sex, age, and smoking and drinking habits.
†† Adjusted for age, body mass index, and smoking and drinking habits.
‡‡ Adjusted for age, and smoking and drinking habits. CI, confidence interval; ICDO‐T, International Classification of Diseases for Oncology‐Topography.
Discussion
The results of the present study indicate that HTLV‐1 seropositivity was not associated with an increased risk of overall cancers, and the point estimate of the RR (1.0) was almost identical to that of our previous study (0.98).( 18 ) A case‐control study performed in Kumamoto, Japan, reported a higher HTLV‐1 seroprevalence among cancer patients without a history of transfusion than healthy blood donors.( 9 ) However, information on transfusion history is usually based on recall, and the possibility of misclassification may not be completely ruled out. Our earlier study on another cohort also showed that the more frequent reported history of cancers among HTLV‐1 carriers was associated with transfusion.( 18 ) Thus, retrospective data on the association between HTLV‐1 infection and cancer risk should be interpreted with caution in terms of the temporal relationship between exposure and outcome, and prospective analysis may be essential. Our results provide stronger evidence than the retrospective data in terms of causal inference, and hence, we conclude that HTLV‐1 carriers are not at an increased risk of overall cancers.
In in vitro experiments, transfection of the tax gene is capable of transforming rat fibroblasts,( 1 ) and in in vivo experiments using transgenic mice or rats carrying the HTLV‐1 tax or the pX gene, a variety of malignancies other than leukemia/lymphoma frequently occurred,( 14 , 15 , 16 , 17 ) indicating that tax is an oncogenic protein. However, these results from transgenic animals cannot be directly extrapolated to humans because they are different from natural infection in terms of organ specificity for tax or pX mRNA expression, depending on the promoters used to construct transgenes. In humans, HTLV‐1 mainly infects CD4+ T‐cells, although a receptor of HTLV‐1, glucose transporter (GLUT‐1), is ubiquitously expressed on vertebrate cells.( 26 ) Conversely, tax or pX mRNA was expressed broadly( 15 , 17 ) or mainly in muscles( 14 ) in these transgenic animals.
HTLV‐1 carriers were at a 2.1‐fold higher risk of liver cancer than non‐carriers. The first explanation for this result is the confounding by HCV. HCV is a strong risk factor for HCC among atomic bomb survivors,( 27 ) and has the same routes of transmission as HTLV‐1, such as blood transfusion and vertical transmission.( 28 ) The percentage of those who were HCV antibody seropositive was higher among HTLV‐1 carriers than among non‐carriers, for whom data on the HCV antibody were obtained (data not shown). However, we do not exclude the possibility that the increased RR of liver cancer was, at least in part, due to the positive interaction between HCV and HTLV‐1. In the present study population, there was a significant dose‐response relationship between the serum HTLV‐1 antibody titers and the risk of liver cancer. Serum HTLV‐1 antibody titers reflect HTLV‐1 proviral DNA levels in the peripheral blood, which may be genetically determined by the cytotoxic T lymphocyte response to HTLV‐1,( 29 ) and there is no evidence that subjects infected with HTLV‐1 during adulthood have a higher proviral load than vertically infected persons in the steady state.( 30 ) Therefore, it seems unlikely that HCV carriers were more frequent among HTLV‐1 carriers with high antibody titers than among those with low titers, and the significant dose‐response relationship between the HTLV‐1 antibody titer and the risk of liver cancer cannot be explained by confounding of HCV alone. It was also reported that infection with HTLV‐1 inhibited the elimination of HCV in interferon‐treated and non‐treated subjects.( 31 ) Furthermore, a synergistic effect of coinfection with HCV and HTLV‐1 on the risk of developing chronic liver disease and death from liver cancer has been reported in Miyazaki, Japan.( 32 )
The point estimate of RR for gastric cancer was rather protective (0.62). However, the RR was not significantly lower than 1, probably because of the small number of cases (n = 104) and the low prevalence of HTLV‐1 seropositivity in the source population (8.4%). In our previous study, we pointed out a significantly reduced risk of stomach cancer among HTLV‐1 carriers (RR 0.42, 95% CI 0.17–0.99),( 18 ) and proposed the lower prevalence of Helicobacter pylori (Hp) infection( 33 ) as one of the possible biological mechanisms. As has been reported for carriers of human immunodeficiency virus type 1,( 34 ) mildly weakened inflammatory response among HTLV‐1 carriers( 35 ) might provide an unsuitable intragastric environment for sustained Hp infection.
The point estimate of the RR for developing thyroid cancer was high (3.0), although this was not significantly higher than 1 because of the small number of events (n = 11). It is of interest that autoimmune thyroiditis is considered a preneoplastic lesion of papillary thyroid carcinoma( 36 ) and HTLV‐1 was reported to be associated with autoimmune thyroiditis.( 37 ) Thus, continued follow‐up may be required to determine if HTLV‐1 carriers are at increased risk of thyroid cancer.
It is of concern whether or not the current results are generalizable to other HTLV‐1 infected populations. The sex‐ and age‐specific prevalence of HTLV‐1 seropositivity in the present study population seems somewhat different from that of other endemic areas, which usually increase with age and is higher among females than among males in the age range 40 years or older.( 1 , 2 ) This suggests that transmission other than natural infection, that is, blood transfusion, was more frequent among the study population. If this is the case, the average age at HTLV‐1 infection may be older and the duration of infection may be shorter in the current study population than in other HTLV‐1 endemic populations. Early age at infection is known to be an important risk factor for virus‐associated malignancies, such as ATL( 1 , 2 ) and HBV‐induced HCC.( 38 ) Thus, such a difference might partially explain the reason for the lack of association between HTLV‐1 infection and cancer incidence. Nevertheless, the present result is consistent with that of our previous study in another typical HTLV‐1 endemic area,( 18 ) and supports the idea that HTLV‐1 infection is not associated with an increased general cancer risk. This information may be particularly beneficial when counseling pregnant women and voluntary blood donors who turn out to be HTLV‐1 seropositive. Further follow‐up may be needed to determine if HTLV‐1 infection is associated with increased risk of thyroid cancer.
Acknowledgments
The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a private, non‐profit foundation funded by the Japanese Ministry of Health, Labour and Welfare (MHLW) and the US Department of Energy (DOE), the latter through the National Academy of Sciences. This publication was supported by RERF Research Protocols RP #18–61 and 1–85.
References
- 1. IARC. Human T‐cell lymphotropic viruses. In. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 67: Human Immunodeficiency Viruses and Human T‐cell lymphotropic viruses. Lyon: IARC,1996; 261–390. [PMC free article] [PubMed] [Google Scholar]
- 2. Mueller NE, Blattner WA. Retroviruses‐human T‐cell lymphotropic virus. In: Evans AS, Kaslow RA, eds. Viral Infections of Humans. Epidemiology and Control, 4th edn. New York and London: Plenum, 1997; 785–813. [Google Scholar]
- 3. Hino S. Primary prevention of adult T cell leukemia (ATL) in Nagasaki, Japan by refraining from breast‐feeding. Gann Monograph Cancer Res 2003; 50: 241–51. [Google Scholar]
- 4. Collaborative Group on Hormonal Factors in Breast Cancer . Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet 2002; 360: 187–95. [DOI] [PubMed] [Google Scholar]
- 5. Tajima K, Kuroishi T. Estimation of rate of incidence of ATL among ATLV (HTLV‐I) carriers in Kyushu, Japan. Jpn J Clin Oncol 1985; 15: 423–30. [PubMed] [Google Scholar]
- 6. Cleghorn FR, Manns A, Falk R et al. Effect of human T‐lymphotropic virus type I infection on non‐Hodgkin's lymphoma incidence. J Natl Cancer Inst 1995; 87: 1009–14. [DOI] [PubMed] [Google Scholar]
- 7. Arisawa K, Soda M, Endo S et al. Evaluation of adult T‐cell leukemia/lymphoma incidence and its impact on non‐Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer 2000; 85: 319–24. [DOI] [PubMed] [Google Scholar]
- 8. Kaplan JE, Osame M, Kubota H et al. The risk of the development of HTLV‐I‐associated myelopathy/tropical spastic paraparesis among persons infected with HTLV‐I. J Acquir Immune Defic Syndr 1990; 3: 1096–101. [PubMed] [Google Scholar]
- 9. Asou N, Kumagai T, Uekihara S et al. HTLV‐I seroprevalence in patients with malignancy. Cancer 1986; 58: 903–7. [DOI] [PubMed] [Google Scholar]
- 10. Kozuru M, Uike N, Muta K, Goto T, Suehiro Y, Nagano M. High occurrence of primary malignant neoplasms in patients with adult T‐cell leukemia/lymphoma, their siblings, and their mothers. Cancer 1996; 78: 1119–24. [DOI] [PubMed] [Google Scholar]
- 11. Matsuzaki H, Asou N, Kawaguchi Y et al. Human T‐cell leukemia virus type 1 associated with small cell lung cancer. Cancer 1990; 66: 1763–8. [DOI] [PubMed] [Google Scholar]
- 12. Miyazaki K, Yamaguchi K, Tohya T, Ohba T, Takatsuki K, Okamura H. Human T‐cell leukemia virus type I infection as an oncogenic and prognostic risk factor in cervical and vaginal carcinoma. Obstet Gynecol 1991; 77: 107–10. [PubMed] [Google Scholar]
- 13. Strickler HD, Rattray C, Escoffery C et al. Human T‐cell lymphotropic virus type I and severe neoplasia of the cervix in Jamaica. Int J Cancer 1995; 61: 23–6. [DOI] [PubMed] [Google Scholar]
- 14. Nerenberg M, Hinrichs SH, Reynolds RK, Khoury G, Jay G. The tat gene of human T‐lymphotropic virus type 1 induces mesechymal tumors in transgenic mice. Science 1987; 237: 1324–9. [DOI] [PubMed] [Google Scholar]
- 15. Iwakura Y, Tosu M, Yoshida E et al. Augmentation of c‐fos and c‐jun expression in transgenic mice carrying the human T‐cell leukemia virus type‐I tax gene. Virus Genes 1994; 9: 161–70. [DOI] [PubMed] [Google Scholar]
- 16. Green JE, Baird AM, Hinrichs SH, Klintworth GK, Jay G. Adrenal medullary tumors and iris proliferation in a transgenic mouse model of neurofibromatosis. Am J Pathol 1992; 140: 1401–10. [PMC free article] [PubMed] [Google Scholar]
- 17. Yamada S, Ikeda H, Yamazaki H et al. Cytokine‐producing mammary carcinomas in transgenic rats carrying the pX gene of human T‐lymphotropic virus type I. Cancer Res 1995; 55: 2524–7. [PubMed] [Google Scholar]
- 18. Arisawa K, Sobue T, Yoshimi I et al. Human T‐lymphotropic virus type‐I infection, survival and cancer risk in southwestern Japan: a prospective cohort study. Cancer Causes Control 2003; 14: 889–96. [DOI] [PubMed] [Google Scholar]
- 19. Atomic Bomb Casualty Commission. Research plan for joint ABCC‐NIH Adult Health Study in Hiroshima and Nagasaki, Japan. Hiroshima and Nagasaki: ABCC Technical Report, 1962; 11–62. [Google Scholar]
- 20. Arisawa K, Soda M, Akahoshi M et al. Human T‐lymphotropic virus type‐I infection, antibody titers and cause‐specific mortality among atomic‐bomb survivors. Jpn J Cancer Res 1998; 89: 797–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Matsuo T, Nakashima E, Carter RL et al. Anti‐Human T‐lymphotropic virus type‐I antibodies in atomic‐bomb survivors. J Radiat Res, 1995; 36: 8–16. [DOI] [PubMed] [Google Scholar]
- 22. Fujiwara S, Kusumi S, Cologne J, Akahoshi M, Kodama K, Yoshizawa H. Prevalence of anti‐hepatitis C virus antibody and chronic liver disease among atomic bomb survivors. Radiat Res 2000; 154: 12–19. [DOI] [PubMed] [Google Scholar]
- 23. Fujiwara S, Sharp GB, Cologne JB et al. Prevalence of hepatitis B virus infection among atomic bomb survivors. Radiat Res 2003; 159: 780–6. [DOI] [PubMed] [Google Scholar]
- 24. Soda M, Ikeda T. Japan, Nagasaki Prefecture. In: Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, eds. Cancer Incidence in Five Continents, vol. VII. Lyon: IARC Scientific Publications, 1997; 390–3. [Google Scholar]
- 25. Collett D. Modelling Survival Data in Medical Research. London: Chapman & Hall, 1994; 253–65. [Google Scholar]
- 26. Manel N, Kim FJ, Kinet S, Taylor N, Sitbon M, Battini JL. The ubiquitous glucose transporter GLUT‐1 is a receptor for HTLV. Cell 2003; 115: 449–59. [DOI] [PubMed] [Google Scholar]
- 27. Sharp GB, Lagarde F, Mizuno T et al. Relationship of hepatocellular carcinoma to soya food consumption: a cohort‐based, case‐control study in Japan. Int J Cancer 2005; 115: 290–5. [DOI] [PubMed] [Google Scholar]
- 28. Okamoto M, Nagata I, Murakami J et al. Prospective reevaluation of risk factors in mother‐to‐child transmission of hepatitis C virus: high virus load, vaginal delivery, and negative anti‐NS4 antibody. J Infect Dis 2000; 182: 1511–14. [DOI] [PubMed] [Google Scholar]
- 29. Jeffery KJ, Usuku K, Hall SE et al. HLA alleles determine human T‐lymphotropic virus‐I (HTLV‐I) proviral load and the risk of HTLV‐I‐associated myelopathy. Proc Natl Acad Sci USA 1999; 96: 3848–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Tanaka G, Okayama A, Watanabe T et al. The clonal expansion of human T lymphotropic virus type 1‐infected T cells: a comparison between seroconverters and long‐term carriers. J Infect Dis 2005; 191: 1140–7. [DOI] [PubMed] [Google Scholar]
- 31. Kishihara Y, Furusyo N, Kashiwagi K, Mitsutake A, Kashiwagi S, Hayashi J. Human T lymphotropic virus type 1 infection influences hepatitis C virus clearance. J Infect Dis 2001; 184: 1114–9. [DOI] [PubMed] [Google Scholar]
- 32. Boschi‐Pinto C, Stuver S, Okayama A et al. A follow‐up study of morbidity and mortality associated with hepatitis C virus infection and its interaction with human T lymphotropic virus type I in Miyazaki, Japan. J Infect Dis 2000; 181: 35–41. [DOI] [PubMed] [Google Scholar]
- 33. Isomoto H, Mizuta Y, Fukushima K et al. Low prevalence of Helicobacter pylori in individuals with HTLV‐I infection. Eur J Gastroenterol Hepatol 1999; 11: 497–502. [DOI] [PubMed] [Google Scholar]
- 34. Cacciarelli AG, Marano BJ Jr, Gualtieri NM et al. Lower Helicobacter pylori infection and peptic ulcer disease prevalence in patients with AIDS and suppressed CD4 counts. Am J Gastroenterol 1996; 91: 1783–4. [PubMed] [Google Scholar]
- 35. Welles SL, Tachibana N, Okayama A et al. Decreased reactivity to PPD among HTLV‐I carriers in relation to virus and hematologic status. Int J Cancer 1994; 56: 337–40. [DOI] [PubMed] [Google Scholar]
- 36. Okayasu I, Fujiwara M, Hara Y, Tanaka Y, Rose NR. Association of chronic lymphocytic thyroiditis and thyroid papillary carcinoma. A study of surgical cases among Japanese, and white and African Americans. Cancer 1995; 76: 2312–18. [DOI] [PubMed] [Google Scholar]
- 37. Akamine H, Takasu N, Komiya I et al. Association of HTLV‐I with autoimmune thyroiditis in patients with adult T‐cell leukaemia (ATL) and in HTLV‐I carriers. Clin Endocrinol 1996; 45: 461–6. [DOI] [PubMed] [Google Scholar]
- 38. Hsieh CC, Tzonou A, Zavitsanos X, Kaklamani E, Lan SJ, Trichopoulos D. Age at first establishment of chronic hepatitis B virus infection and hepatocellular carcinoma risk. A birth order study. Am J Epidemiol 1992; 136: 1115–19. [DOI] [PubMed] [Google Scholar]