Affiliations of authors: Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (OF, JP); Cancer Research UK Genetic Epidemiology Unit, Department of Public Health, University of Cambridge, Cambridge, UK (DE); Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN (KA); Cancer Research UK Epidemiology and Genetics Unit, The Institute of Cancer Research, Surrey, UK (CG, JP); Institute of Ophthalmology, London (MJ).
Correspondence to: Professor Julian Peto, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St., London, WC13 7HT, UK (e-mail: julian.peto{at}icr.ac.uk)
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ABSTRACT |
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INTRODUCTION |
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The protein encoded by RB1, p105 Rb, functions in multiple cellular processes, including proliferation, DNA replication, DNA repair, and cell-cycle checkpoint control (2). The mouse homolog of human RB1 is highly expressed during embryogenesis in the lens of the eye, the developing nervous system, blood cells, and skeletal muscle (3,4), and is ubiquitously expressed in adult animals. During the cell cycle, p105 Rb is phosphorylated by the cyclin D-cyclin-dependent kinase (CDK)4 and cyclin D-CDK6 complexes, whose activities are themselves regulated by a family of polypeptide inhibitors, which includes p16INK4a (5).
p105 Rb and the proteins that interact with it appear to play roles in many other cancers. Mutations in RB1 or altered expression of p105 Rb have been found in many sarcomas (68), small-cell lung and bladder cancer cell lines (9), primary breast tumors (10), glioblastomas (11) and, less frequently, in various other cancers. Overexpression of cyclin D1 or CDK4 and loss of function of p16INK4a have been found in a range of human tumors (1214), and truncating mutations in RB1CC1, the gene encoding a putative transcription factor that induces expression of RB1, have been reported in breast cancer (15). The transforming proteins adenovirus E1A, simian virus 40 (SV40) T antigen, and human papillomavirus (HPV) E7 all bind to and inactivate p105 Rb (2).
The combined results of previous cohort studies suggest that hereditary retinoblastoma survivors have increased risks of various soft-tissue sarcomas, osteosarcoma, melanoma, and brain cancer (16) and, possibly, an excess of lung cancers (1719), compared with the general population. However, there have been no reports of a general excess of epithelial cancers among hereditary retinoblastoma survivors, leading Ponten (20) to suggest that most stem cells use alternative mechanisms to compensate for the loss of p105 Rb function. However, there is little information available about the overall cancer rates among RB1 carriers who are older than 50 years because of limited follow-up in the existing cohorts of hereditary retinoblastoma survivors beyond this age. We have followed a cohort of British retinoblastoma survivors who were born between 1873 and 1950, a period when few British patients received high-dose radiotherapy, to determine their lifelong cancer incidence and mortality.
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METHODS |
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The cohort was flagged for continuing notification of mortality, cancer incidence, and emigration through the National Health Service Central Register (NHSCR). The NHSCR is a register of everyone in England and Wales who has ever been registered with an NHS general practitioner and includes virtually all residents. The NHSCR routinely traces and records all cancer registrations and deaths among flagged individuals (including those who have moved to Scotland) as well as permanent emigration. Follow-up for mortality in the NHSCR began on January 1, 1940, after the establishment of the national register on which the NHSCR was based. We calculated the expected numbers of deaths from cancer and from other causes by using the quinquennial age and calendar-specific rates for England and Wales, which are published annually by the Office for National Statistics (http://www.statistics.gov.uk). Follow-up for cancer incidence began on January 1, 1971, when national cancer registration was linked to the NHSCR. We used the date of death as the date of diagnosis for nine cancer deaths in 1971 or later that had no corresponding cancer registration. The earliest of these deaths was in 1981; it is unlikely that any of these individuals had been diagnosed with a second cancer before 1971. All individuals were censored at age 85, at emigration, or on December 31, 1999, whichever came first. Subjects who developed two primary cancers were censored after their first cancer registration. Subjects with in situ carcinomas and benign tumors, including one bladder tumor of uncertain behavior and one of unspecified nature, were excluded from the analysis. Mortality and cancer incidence were analyzed only from age 25. Most of the subjects in our cohort were born before 1946 and, hence, had no systematic follow-up for cancer registration before age 25.
Statistical Analysis
We used Poisson regression to model the dependence of cancer rates on age. Standardized mortality ratios (SMRs) are given with exact Poisson 95% confidence intervals (CIs). Cumulative risks for cancer incidence and mortality in the absence of other causes of death were calculated by the Kaplan-Meier method (22) with confidence intervals that were based on the modification of Greenwood's formula described by Kalbfleisch and Prentice (23). All statistical significance tests were two-sided. All analyses were carried out using Stata statistical software (version 7.0; Stata Corporation, College Station, TX).
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RESULTS |
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DISCUSSION |
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The radiotherapy methods and doses used to treat retinoblastoma patients have differed widely between the United Kingdom and the United States. Although individual treatment details were not available for our cohort, most retinoblastoma patients in the United Kingdom did not receive radiotherapy during the 1930s and 1940s (28), and those who did were usually treated with implanted radon seeds or, after 1948, with radioactive scleral plaques that were placed next to the tumor (29). The short- and long-term side effects of external irradiation, including case reports of sarcomas of irradiated bone or muscle, led Stallard (29) to conclude in 1952 that radioactive scleral plaques were the best treatment for tumors covering less than one-third of the retina, and this treatment has remained the primary treatment for most localized retinoblastomas (30). By contrast, almost 90% of retinoblastoma patients in the large U.S. cohort studied by Wong et al. (26) were treated with external radiotherapy, and many of those patients received very high doses of radiation, particularly between 1937 and 1965, when the mean orbital dose among patients who later developed osteosarcoma was 111 Gy (26).
There appears to be a striking difference in the contribution of epithelial cancers at nonirradiated sites between our cohort and those from centers or countries where external beam irradiation was widely used, although the age-specific incidence rates may be similar. Only seven (4%) of the 190 incident tumors diagnosed among hereditary retinoblastoma survivors in the large U.S. study reported by Wong et al. (26) were carcinomas not originating in the head (two each of breast, colon, and uterine cancer and one bladder cancer), whereas 26 (60%) of the 43 incident tumors (excluding skin cancers) diagnosed among our cohort since 1971 were carcinomas that did not originate in the head. This difference is due largely to the much higher incidence of radiogenic cancers, particularly sarcomas, in the U.S. cohort, but it also reflects the older age range spanned by the follow-up of our cohort. Our cancer incidence data for hereditary retinoblastoma survivors younger than 25 years were too incomplete for useful analysis. However, the 94 hereditary retinoblastoma survivors born in 1940 or later were all followed up for mortality from birth, and there was only one cancer death in an individual younger than 25 years that was not due to retinoblastoma (a peritoneal cancer in an 18-year-old). In our cohort, only three sarcomas were diagnosed among the hereditary retinoblastoma survivors between the ages of 25 and 44 years (including one sarcoma diagnosed 2 years after an ovarian cancer diagnosis), corresponding to a cumulative risk of sarcoma by age 45 of only 4%. By contrast, the cumulative second cancer incidence among hereditary retinoblastoma survivors in the U.S. cohort was 20% by age 25 and 44% by age 45, and 115 (61%) of the 190 second cancers were sarcomas (26).
The high incidence of cancers at nonirradiated sites that we observed in the older hereditary retinoblastoma survivors in our cohort seems unlikely to be an effect of treatment. They had a low incidence of radiogenic tumors, and they were treated before the introduction of chemotherapy. It was recognized many years ago that retinoblastoma patients who did not receive radiotherapy have increased risks for melanoma and osteogenic sarcoma and that retinoblastoma patients who did receive radiotherapy have increased risks for these cancers at nonirradiated sites (21). Apart from sarcomas, melanoma was the most common type of second primary tumor diagnosed among retinoblastoma survivors in the studies reviewed by Moll et al. (16). Various authors (20,26,31) have commented that the virtual absence of lung and bladder cancers among previous cohorts of retinoblastoma survivors seems surprising, considering the high rate of somatic RB1 inactivation in these tumor types. However, Wong et al. (26) cautioned that few members of their cohort had yet been followed to age 50, and Kleinerman et al. (19) subsequently reported five lung cancer deaths among that cohort after a further 7 years of follow-up. The youngest survivors in our cohort were at least 49 years old by the end of follow-up, and 19 (33%) of the 58 incident cancers in the hereditary retinoblastoma survivors originated in the lung (14 cases) or bladder (five cases). We observed a statistically significant increase in mortality from lung cancer (SMR = 7.01), bladder cancer (SMR = 26.31), all other major epithelial cancers combined (SMR = 3.29), and melanoma (SMR = 23.29). The epithelial cancer category included three breast cancer deaths (SMR = 3.65; P = .10). In addition, there were four nonfatal breast cancers, including one that had not been registered in the NHSCR but was mentioned on a death certificate that noted lung cancer as the cause of death and one that was diagnosed 6 years after the diagnosis of a nasal cavity tumor. Horowitz et al. (9) found aberrant p105 Rb1 expression in 31 of 32 small-cell lung cancer cell lines, in six of 16 bladder cancer cell lines, and in two of 10 breast cancer cell lines. Thus, in the general population, somatic RB1 mutation is common in the same types of epithelial cancer that show the largest excesses among survivors of hereditary retinoblastoma.
A germline genetic defect that reduces the number of rate-limiting steps in multistage carcinogenesis was proposed by Ashley (32) to explain why the incidence of colon cancer increases as the fifth power of age in the general population but only as the third or fourth power of age in polyposis coli patients. Likewise, germline loss or inactivation of one copy of RB1 bypasses one of the critical somatic events in carcinogenesis, so the standardized mortality ratio for cancer among hereditary retinoblastoma survivors might be expected to be inversely proportional to age. Our observation of an approximately quadratic decline in the standardized mortality ratio for epithelial cancers with increasing age may be due, at least in part, to heterogeneity of risk among RB1 mutation carriers resulting in the progressive elimination of those at highest risk from the surviving population. Heterogeneity of risk is likely to arise from differences in the functional consequences of different RB1 mutations as well as from nongenetic influences, particularly cigarette smoking. This apparently quadratic decline in the standardized mortality ratio with increasing age could, however, also be due to chance, because the exponent of age we estimated (i.e., -2.1, 95% CI = -3.6 to -0.7) is statistically consistent with a linear decline in the standardized mortality ratio.
We observed a small excess in overall cancer mortality among unilateral sporadic retinoblastoma survivors younger than age 45 (six deaths observed versus 1.90 deaths expected; three sarcomas and three lung cancers), which presumably reflects the inclusion of some unilaterally affected RB1 mutation carriers among the survivors of apparently sporadic retinoblastoma. Eng et al. (33) reported a similar excess in overall cancer mortality among survivors of unilateral retinoblastoma, although this excess mortality was reduced when familial cases were excluded from their cohort (26). Unilateral RB1 carriers with no known family history may also account for the unexpected excess of testicular cancer (two deaths observed versus 0.07 deaths expected) in our unilateral sporadic patients, although this could be a chance finding. Testicular cancer was also diagnosed in a 55-year-old patient with hereditary retinoblastoma.
The spectrum of early-onset cancers that are associated with germline p53 mutation, which includes osteosarcoma, soft tissue sarcomas, breast cancer, and brain cancer (34), is similar to that seen in RB1 mutation carriers. The only tumor clearly associated with p53 germline mutations that is not also seen among hereditary retinoblastoma survivors is adrenocortical carcinoma. The widely reported association between germline p53 mutation and childhood leukemia is due at least partly to ascertainment bias (34), and the relative excess of pancreatic cancer recently reported by Birch et al. (35) was not seen in the larger series of Li-Fraumeni families reviewed by Nichols et al. (34).
Our results suggest that carriers of mutant or deleted RB1 who did not receive high-dose radiotherapy have a much higher lifetime risk of common epithelial cancers, particularly cancers of the lung, bladder and, probably, breast, than of sarcomas and other early-onset cancers. However, the number of cancers in our cohort is still relatively small, and data from several cohorts with longer follow-up will need to be combined to estimate more precisely the risks for specific cancers. Although ascertainment of mortality in cohorts flagged through the NHSCR is virtually complete, British cancer registration is known to be incomplete, particularly for nonfatal cases (36). The adult cancer risk among RB1 mutation carriers may thus be even higher than the cumulative incidence of 68.8% from age 25 to 84 shown in Fig. 1. Their excess risk is concentrated in cancers normally associated with exposure to ionizing radiation or other DNA-damaging agents (i.e., sarcomas, tobacco-related lung and bladder cancers, and UV-related skin melanomas). Most of these cancers could probably have been prevented. The sarcoma risk can be greatly reduced by limiting the use of radiotherapy (26), and the very high lung and bladder cancer risk in middle and older age among RB1 mutation carriers could presumably be reduced by avoiding tobacco. No smoking data were available for our cohort. However, four of the five lung cancer deaths reported by Kleinerman et al. (19) occurred in smokers. That only 17% of the hereditary retinoblastoma survivors in their cohort were current smokers suggests that smoking increases the lung cancer risk approximately 20-fold among RB1 mutation carriers, similar to the relative risk of lung cancer associated with smoking in the general population. The standardized mortality ratios for lung cancer and bladder cancer (SMRs of 7.01 and 26.31, respectively) that we observed among hereditary retinoblastoma survivors would constitute a virtually penetrant lifetime risk among heavy smokers but a risk of less than one in 10 among nonsmokers. Finally, avoiding sunburn would presumably reduce their melanoma hazard.
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NOTES |
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Manuscript received July 16, 2003; revised December 22, 2003; accepted January 5, 2004.
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