Both environmental and intrinsic biologic factors influence the transformation of normal cells into malignant cells. Many genes increase susceptibility to cancer, and many single-gene disorders1 are associated with an increased incidence of cancer. Less evidence is available about biologic factors that might protect against malignancy, but in recent years the phenomenon of apoptosis has been shown to be an important mechanism in limiting cancer growth.2
Huntington disease (HD) is an autosomal dominant hereditary neurodegenerative disorder characterized by late onset (usually at age 35–45 years), involuntary choreiform movements, dementia, and intellectual decline, leading to death 15–20 years later.3 The mutation underlying HD is an expansion of a CAG trinucleotide repeat region that codes for a polyglutamine tract in huntingtin, the protein encoded by the HD gene.4 Neither the normal physiologic function of huntingtin nor the function of the mutated protein is known, but it has been suggested that the mutated protein has a gain of function leading to neuronal loss, primarily in the caudate nucleus. Further, evidence is emerging that the death of neurons is associated with apoptosis,5–7 and it has recently been shown that huntingtin with elongated polyglutamine tracts is susceptible to cleavage by apopain,8 an enzyme responsible for apoptosis in mammalian cells. It is therefore probable that huntingtin is involved in the apoptotic pathway.
In an earlier study9 of the causes of death of patients with Huntington disease, based on death certificates, we found that cancer was reported only rarely. The aim of the current study was to assess whether this observation is due to a low incidence of cancer among HD patients. We report a lower risk of cancer for individuals carrying the HD mutation than for their relatives with normal HD genes, suggesting that the lower incidence of cancer among HD patients is associated with the mutation and not with environmental factors. Further, we speculate that this finding is due to an apoptotic effect of huntingtin.
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All subjects affected by HD who had survived to at least age 45 years during the period 1943–1993, representing a total of 694 individuals, were identified in the files of the Danish Huntington Disease Registry at the University of Copenhagen, which contains fully updated information on families with HD in Denmark. The exact date of onset of disease was known in some but not all of the cases. Control subjects were also extracted from the files; they consisted of 695 healthy relatives who had been at 50% prior risk of HD and had reached at least age 55 years by 1993. This age was chosen because HD may start late in life. We used age specific risks based on life table analysis10 to estimate that only 7% of the healthy individuals in this group could be assumed to have been carriers of the HD gene. Finally, we included 182 individuals who had been analyzed for the HD mutation; 64 had an expanded CAG repeat sequence (>38 repeat units) and 118 had no CAG expansion.
All study subjects were linked to the Central Population Register and the National Death Certificate File for verification of name and date of birth and for information on vital status and migration. Information on the occurrence of cancer among the subjects was obtained through record linkage to the Danish Cancer Registry, which began reporting cancer incidence in 1943, including that of benign brain tumors and bladder papillomas.11 The period of follow-up for cancer occurrence began at age 45 years for subjects affected by HD, age 55 years for healthy relatives, or the date when the mutation analysis was performed for the remaining study subjects. It ended at the date of emigration, date of death, or the closing date of the study (December 31, 1993), whichever occurred first. Cancers were classified according to the modified Danish version of the International Classification of Diseases, 7th revision (ICD-7).12
The expected numbers of cancers were calculated by multiplying the number of person-years experienced by the study subjects by the age specific and gender specific cancer incidence rates for the population in 5-year age groups and calendar periods of observation. Standardized incidence ratios (SIRs), as a measure of relative risk, and 95% confidence intervals (CIs) were calculated, assuming a Poisson distribution of the observed numbers of cancers.13 The incidence of cancer was considered for the four study groups separately: HD patients, healthy at-risk relatives (comparison group), and genotyped subjects with and without an elongated CAG repeat sequence in the HD gene.
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The 694 HD patients had accrued 11,190 person-years of follow-up (average, 16.1 years; range, 1 month to 45 years). Overall, 55 cancers were observed and 88.0 were expected, yielding a significantly reduced SIR of 0.6 (Table 1). This inverse association was found for all the common cancers and groups of cancers, although none were significant individually. The largest deficit was seen for the group of digestive organs, with 14 observed cancers versus 23.1 expected (Table 1). Other major deficits were seen for cancers of the skin and respiratory tract, the latter of which was striking because many HD patients are heavy smokers. No tumors of the brain, the nervous system, the thyroid, bones, or connective tissue were seen.
Table 1. Observed and Expected Numbers of Malignant Neoplasms, Standardized Incidence Ratios, and Associated 95% Confidence Intervals among 694 Patients with Huntington Disease and 695 Healthy At-Risk Relatives
|Site||HD patients||Healthy at-risk relatives|
|Obs.||Exp.||SIR (95% CI)||Obs.||Exp.||SIR (95% CI)|
|All malignant neoplasms||55||88.0||0.6 (0.5–0.8)||161||143.7||1.1 (0.9–1.3)|
|Digestive organs||14||23.1||0.6 (0.3–1.0)||35||40.3||0.9 (0.6–1.2)|
|Lung||6||10.2||0.6 (0.2–1.3)||29||20.6||1.4 (0.9–2.0)|
|Breast||7||10.4||0.7 (0.3–1.4)||15||13.3||1.1 (0.6–1.9)|
|Female genital organs||9||9.6||0.9 (0.4–1.8)||11||11.2||1.0 (0.5–1.8)|
|Male genital organs||3||4.1||0.7 (0.2–2.1)||19a||9.1||2.1 (1.3–3.3)|
|Urinary system||5||6.7||0.8 (0.2–1.7)||15||12.2||1.2 (0.7–2.0)|
|Skin||5||10.4||0.5 (0.2–1.1)||18||18.1||1.0 (0.6–1.6)|
|Lymphatic and hematopoetic tissue||3||4.7||0.6 (0.1–1.9)||8||8.0||1.0 (0.4–2.0)|
|Other specified sites||2||6.6||0.3 (0.0–1.1)||8||11.0||0.7 (0.3–1.4)|
|Secondary and unspecified||1||2.2||0.5 (0.0–2.6)||3||1.8||1.7 (0.4–5.0)|
The 695 at-risk relatives had accrued 11,121 person-years of follow-up (average, 16.0 years; range, 3 months to 42 years). In this group, which was assumed to include only a limited number of HD gene carriers, 161 cancers were observed and 143.7 expected, yielding a nonsignificantly increased SIR of 1.1 (Table 1). This slight increase in overall risk was due mainly to a marked excess of prostate carcinomas, with 18 cases versus 8.6 expected (SIR, 2.1; 95% CI, 1.3–3.3) and a more moderate excess of 24 observed lung carcinomas versus 18.2 expected (1.3; 95% CI, 0.8–2.0). The pattern of cancers at other sites was similar to that of the general population.
No cases of cancer were observed among the 64 healthy individuals who were found to be HD gene carriers; however, only 0.6 cancers were expected in this small, relatively young group (SIR, 0.0; 95% CI, 0.0–6.1). Among the 118 individuals without the mutation, we observed 7 cases of cancer, with 3.5 expected (SIR, 2.0; 95% CI, 0.8–4.1); none of these were prostate carcinoma.
As patients in the late stage of HD are completely deteriorated and cachectic, a cancer may go unnoticed or be incorrectly diagnosed, giving rise to some underestimation of the risk of cancer among HD patients. To evaluate this possibility, we examined documentation of the cancer diagnoses in the groups of HD patients and their healthy relatives (Table 2). Information was available for 93% of the HD patients and 94% of their relatives. The frequency with which different methods were used to verify the cancer diagnoses was almost identical in the two groups. In particular, the number of incidental cancer diagnoses at autopsy was no greater among the HD patients; however, the estimate would be false if autopsy were performed less often for HD patients than for other people. Performance of an autopsy has been noted on death certificates in Denmark since 1966. On the 311 death certificates available for the HD patients who died after 1966, autopsy was indicated in 84 cases, or 27%. This percentage was significantly lower than the autopsy rate (36%) noted on 192 death certificates for healthy at-risk individuals (Fisher exact test, P = 0.04), which corresponded to that of the general population.
Table 2. Methods of Verification of Cancer Diagnoses among Patients with Huntington Disease and Healthy At-Risk Relatives
|Method of verification||HD patients||Healthy at-risk relatives|
| Incidental at autopsy||1||2||6||4|
| Diagnostic examination||41||74||122||76|
|X-ray or clinical examination||2||4||4||2|
|All cancer cases||55||100||161||100|
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We found that the incidence of cancer among HD patients was significantly lower than that among their healthy relatives and in the general population. This finding supports our earlier observation.9 The same trend was found for the small samples of individuals who had been examined for the HD mutation. Our results contradict the hypothesis of Panzer et al.14 that trinucleotide expansions may increase cancer susceptibility.
We have no reason to believe that our finding of a reduced cancer risk among HD patients is due to biased selection of the study groups. All HD patients are reported to the national HD register in Copenhagen directly after diagnosis, and the identity of the patients' relatives was verified through population registers that are kept for administrative purposes. It cannot be ruled out, however, that the group of healthy relatives older than 55 years included individuals who were carriers of the HD gene but were still free of the disease at the time of death or until the end of the study period. The inclusion of gene carriers in the comparison group would, however, tend to bias the observed rate of cancer downward, i.e., below the rate of the general population, towards that of the HD patients, but this was not the case. In fact, the cancer rate in the comparison group was slightly greater than that of the general population.
A negative surveillance bias may have been generated in our study due to the relatively poor prognoses of HD patients. Some malignancies may not be diagnosed appropriately for such patients, leading to a reduced number of reports to the Cancer Registry. This is, however, unlikely to explain the low incidence, as we observed the same types of diagnostic confirmation of the cancers in the HD group as in the comparison group. The rates of autopsy were also similar in the two groups, and few cancers were identified by this procedure.
As the HD patients and their at-risk relatives have certain environmental exposures in common, the lower incidence of cancer among HD patients is probably not due to environmental factors. It is not likely that the medication of patients had an anticarcinogenic or cancer prevention effect, as we have studied patients over a period of 50 years, during which different drugs were administered. Nor can the diet of the patients be expected to have had a protective effect against cancer, as the patients had a common diet until they developed dysphagia in the late stage of the disease. The putative protective factor in HD patients, therefore, is most likely an intrinsic biologic one—probably the HD gene itself, as it is the most significant factor that these patients have in common and do not share with individuals in the general population who do not have HD.
Evidence has emerged that programmed cell death, apoptosis, is important in maintaining and controlling cell numbers in multicellular organisms, and that cancer may result if the balance between cell proliferation and apoptosis is disturbed.2 Further, it has recently been reported that huntingtin is a substrate for the protease apopain,8 which belongs to the CED-3/ICE family of cysteine proteases and plays a key role in the apoptotic pathway in mammalian cells.15 Green16 has suggested that the polyglutamine tract in huntingtin may activate transglutaminases to produce an insoluble shell of cross-linked protein, a phenomenon that has been observed in apoptotic cells.17 On the basis of these findings, we put forward the hypothesis that growth and proliferation of cancer cells in individuals carrying an expanded CAG sequence are arrested because the expanded polyglutamine tract in huntingtin accelerates or induces physiologic cell death.
The rate of hydrolysis of huntingtin by apopain increases with an increase in the length of the polyglutamine tract.8 A possible reason why some HD patients develop malignancies could be that this occurs preferentially in patients with small CAG extensions. We were unable to investigate this hypothesis, owing to the small number of patients alive with cancer.
Huntingtin is expressed in all cells and tissues.18 Thus, our model of the protective effect of huntingtin against cancer may be universal and not limited to the central nervous system, in accordance with our finding of a lower number of cancers at all major sites.
If the polyglutamine sequence has a preventive effect against cancer in HD patients, a similar effect could be expected in patients with other neurodegenerative disorders caused by an expanded polyglutamine tract. Recently, Wellington et al.19 presented evidence that the polyglutamine-containing proteins atrophin-1, ataxin-3, and the androgen receptor, like huntingtin, are cleaved by caspases. Polyglutamine expansions in these proteins all result in neurodegenerative diseases, and it may well be that the effect of the cleavage of the proteins by caspases results in the truncation of proteins, leading to cell death. In fact, Ikeda et al.20 have shown that ataxin-3 can induce cell death in cultured cells and in transgenic mice. Various studies21–24 have shown that there is an inverse relation between the number of CAG repeats in the androgen receptor gene and the risk for prostate carcinoma. It has been suggested, however, that the increased risk of prostate carcinoma in individuals with short alleles is caused by higher transactivity on the androgen receptor by short alleles than by longer ones, as higher transactivation activity may result in increased proliferative activity in cancer cells.
We are aware of only one other disease—namely, schizophrenia—that has been associated with a lower incidence of cancer, as reported in various large, independent studies (for a review, see Mortensen25). No explanation has been found for this reduced incidence, but it is noteworthy that expanded trinucleotide repeats have been reported to occur in patients with schizophrenia.26–28 If so, our hypothesis that apoptosis has the effect of lowering the incidence of cancer in HD patients may apply to schizophrenia as well.