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Increased Risk of Cancer among Siblings of Long-term Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study

¹ University of Washington and ² Fred Hutchinson Cancer Research Center, Seattle, Washington; ³ Yale University, New Haven, Connecticut; ⁴ University of Minnesota, Minneapolis, Minnesota; ⁵ University of Alberta, Edmonton, Alberta, Canada; ⁶ University of Pennsylvania, Philadelphia, Pennsylvania; and ⁷ University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Debra L. Friedman, Fred Hutchinson Cancer Research Center, Suite D5-280, 1100 Fairview Avenue North, Seattle, WA 98109. Phone: 206-667-5935; Fax: 206-667-5899. E-mail: dfriedma{at}fhcrc.org

	Abstract

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We determined risk of cancer among first-degree relatives of 5-year survivors of childhood leukemia, lymphoma, central nervous system tumors, sarcomas, Wilms' tumor, and neuroblastoma. Subjects were 13,703 participants in the Childhood Cancer Survivor Study. Family history was collected on 56,759 first-degree relatives using a self-reported questionnaire. Incidence was compared with age- and sex-specific rates using the U.S. Surveillance, Epidemiology and End Results program. Siblings of the survivors had an increased risk of cancer [standardized incidence ratio (SIR), 1.5; 95% confidence interval (95% CI), 1.35-1.7]. Risk was elevated for siblings of probands of leukemia (SIR, 1.3; 95% CI, 1.0-1.6), Hodgkin's disease (SIR, 1.5; 95% CI, 1.2-1.9), non-Hodgkin's lymphoma (SIR, 1.8; 95% CI, 1.3-2.5), Wilms' tumor (SIR, 1.9; 95% CI, 1.2-3.2), soft tissue sarcoma (SIR, 1.5; 95% CI, 1.0-2.2), and bone tumors (SIR, 1.6; 95% CI, 1.2-2.2). Cancer risk was elevated in siblings (SIR, 2.4; 95% CI, 1.5-3.7) and offspring (SIR, 15.0; 95% CI, 5.3-42.9) of probands with second malignant neoplasms (SMN) compared with relatives of probands without SMNs. Siblings of probands with leukemia, Hodgkin's disease, neuroblastoma, and Wilms' tumor had elevated risks for the same malignancies. Parents had no increased risk (fathers' SIR, 0.7; 95% CI, 0.7-0.8; mothers' SIR, 0.9; 95% CI, 0.9-1.0). Seventy percent of siblings' cancers developed in adulthood. These findings suggest that familial cancer syndromes may be revealed as this cohort and family members age and with accrual of more offspring and subjects with SMNs.

	Introduction

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The etiology of the majority of childhood cancers remains elusive. A small fraction may be attributable to rare hereditary cancer syndromes, including familial Wilms' tumor, the genetic form of retinoblastoma, inherited colon cancer syndromes, Li-Fraumeni syndrome, familial adenomatous polyposis, neurofibromatosis type 1, and disorders of DNA repair (1-12).

Studies of cancer among siblings of childhood cancer patients show increased risk, but results differ greatly depending on the sample size, mechanism of ascertainment, inclusion of twin pairs, and specific childhood cancer diagnoses (13-24). Studies of cancer risk in offspring of childhood cancer survivors have suggested that the risk is low, outside of the known cancer predisposition syndromes (25-27). Appropriate anticipatory guidance to cancer survivors and their family members may depend on the knowledge of the cancer risk gained from such analyses. Furthermore, this information may lead to the discovery of new cancer predisposition syndromes, for which the responsible genes can then be studied.

The primary goal of this report is to describe the incidence and spectrum of cancers among first-degree relatives of the Childhood Cancer Survivor Study (CCSS) cohort and compare them to age- and sex-specific general population data. We seek to identify risk factors that may be associated with an excess of family cancers and to develop future initiatives to identify new cancer predisposition syndromes. Based in part on the paradigm of retinoblastoma (28, 29), we hypothesized that there would be an increased cancer risk in siblings and offspring overall and that relatives of probands with second malignant neoplasms (SMN) would also be at increased cancer risk.

	Materials and Methods

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The CCSS
The CCSS, a cohort study of 14,054 individuals, was established to address specific hypotheses related to long-term health-related outcomes in childhood cancer survivors (30). The cohort was constructed from rosters of all children treated at each of the participating institutions in the United States and Canada (Appendix 1). Inclusion criteria included (a) diagnosis of one of the following forms of childhood cancer before age 21 years: leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, neuroblastoma, soft tissue sarcoma, bone cancer, malignant central nervous system (CNS) tumor, or kidney tumor; (b) initial treatment at one of the collaborating institutions between January 1, 1970 and December 31, 1986; and (c) survival for at least 5 years following diagnosis. It is important to note that survivors of retinoblastoma were not included in this cohort.

The Human Subjects Committee at each participating institution reviewed and approved the CCSS protocol. Beginning August 1, 1994, all cohort members (or parents of patients ages <18 years) were asked to complete a baseline questionnaire that included information on family history of cancer, demographic and socioeconomic characteristics, health conditions and health-related behaviors, inherited conditions, congenital anomalies, and reproductive history. For those patients who survived for 5 years following the initial cancer diagnosis and subsequently died, a family member completed the baseline questionnaire. Full copies of the questionnaires used in the collection of the family history and other data can be viewed at http://www.cancer.umn.edu/ccss.

Of the 20,274 eligible survivors for the CCSS, 2,996 (15%) were lost to follow-up despite rigorous tracing methods. Of the remaining cases, 3,132 (15%) refused participation in the study and 94 were pending. At the time of the current analysis, family history data were available on 13,703 of the 14,054 cohort members.

Family History Data Analysis
Family history of cancer in parents, full siblings, and offspring of the CCSS participants was collected as part of the baseline questionnaire described above. Probands with at least one sibling, parent, or offspring with cancer were defined as having a positive "cancer history." The information collected was then reviewed by a panel of pediatric oncologists, cancer epidemiologists, and cancer geneticists. Nonmelanoma skin cancers, nonmalignant tumors, and cancers in situ were not included in the analysis. The classification scheme of the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program was used for classification of site of malignancy (31).

Conditions were determined to be ambiguous by the reviewing panel if (a) it was not clear whether the condition reported was malignant or benign, (b) the site of the cancer was unclear, or (c) multiple malignancies were reported for a single relative. Such conditions were then clarified by means of a probing telephone interview by trained interviewers (32). Of the 56,759 reported family members, cancers reported in 533 relatives of 500 CCSS probands were felt to be ambiguous for one or more of the above reasons. Clarification was obtained on 386 (77%) of these probands and resulted in an established malignancy status in 340 (88%) families. In the remaining 134 probands, the reported cancer condition could not be further clarified (32). In these probands, relatives' cancers were included in this analysis only if (a) they included the term "cancer," "carcinoma," or "malignant" or (b) the site-specific cancer diagnosis was provided. Examples are relatives reporting cancers using terms, such as "stomach cancer" or "brain cancer," but further details, such as histologic type, could not be clarified. Families who did not report a history of cancer did not have this history clarified. All analyses were based on the postclarification study.

To further characterize the self-reported family history data, we conducted a small reliability study, including 141 randomly selected families with a positive family history and 232 with a negative family history. We then successfully contacted original respondents in 279 (75%) of these families and completed a probing family history questionnaire. This identified 22 previously unreported cancers and invalidated 12 previously reported cancers. This study also identified 65 first-degree family members in 30 families who had not been listed in the original family history pedigree; none of these relatives had a cancer condition. Estimates of risk were not appreciably changed by this analysis.

Statistical Analysis
Person-years at risk for the cohort of relatives were determined from birth to the earlier time of development of cancer, death, or date of questionnaire completion. The person-years at risk were then stratified by age, sex, and calendar year and multiplied by year-, age-, and sex-specific rates of cancer types of interest from the SEER registry data to yield expected numbers of each type of cancer (31). For the calendar years outside of SEER coverage, we used the closest calendar year that is covered by the SEER program. We computed standardized incidence ratios (SIR), observed/expected ratios with 95% confidence limits, and Ps determined by a Poisson assumption for the observed counts (33), stratified by a factor of interest, such as relative type, development of SMNs, and age at diagnosis of the proband's cancer. The generalized estimating equations modification of the Poisson regression model (34) was used to account for the fact that relatives from the same family are not statistically independent, and their outcomes may be correlated. For relatives reported to have more than one cancer, all cancers that were clarified by a telephone interview and thus felt to be accurate were included in the analysis, consistent to the SEER registry's counting of multiple cancers.

SIRs for cancer incidence in relatives of probands with and without SMNs were computed as above. The Ps for the differences in incidence rates between the two groups were determined using a Poisson regression model (with generalized estimating equations modification), with SMN status as an explanatory variable.

	Results

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Among the 13,703 survivors, a family history of cancer was identified in 1,767, with 1,951 invasive cancers reported in 56,759 first-degree relatives with 2,083,757 person-years of follow-up. The characteristics of the survivor cohort and their first-degree relatives by cancer family history are provided in Table 1. Several differences were noted among families with and without cancer histories. Not surprisingly, families with cancer histories among first-degree relatives had significantly older first-degree relatives as well as a larger number of siblings and offspring. Older age at the time of the CCSS case diagnosis and increased time since the diagnosis were both associated with a higher frequency of a family history of cancer. Deceased CCSS cases were also more likely to have a family history of cancer than those who are alive. One hundred fifty-five (14%) of deceased cases died as a result of a SMN.

The incidence of cancer in all first-degree relatives was lower than expected [SIR, 0.9; 95% confidence interval (95% CI), 0.8-0.9]. No specific CCSS proband cancer diagnosis was associated with an increased incidence of cancer in all first-degree relatives (data not shown).

We examined the cancer incidence by relative type to determine whether there were specific groups at increased risk by age or relationship (Table 2). Siblings had an increased risk (SIR, 1.5; 95% CI, 1.3-1.7), with a mean and median age at cancer diagnosis of 24 and 25 years, respectively. Thirty percent of the cancers in the siblings were diagnosed before age 18 years. The offspring had an increased risk without statistical significance (SIR, 1.7; 95% CI, 0.8-3.5), which was based on a few offspring with cancer (n = 7). Ninety-seven percent of the offspring in the CCSS cohort are ages <18 years, with a mean and median age of the offspring of 6 and 5 years, respectively. Thus, it is not surprising that all the cancers in offspring occurred before age 18 years. Fathers had a lower than expected risk (SIR, 0.7; 95% CI, 0.7-0.8; P < 0.0001), whereas mothers' risk was closer to expected (SIR, 0.9; 95% CI, 0.9-1.0).

Risk was specifically elevated for siblings of probands of leukemia (SIR, 1.3; 95% CI, 1.0-1.7), Hodgkin's disease (SIR, 1.5; 95% CI, 1.2-1.9), non-Hodgkin's lymphoma (SIR, 1.8; 95% CI, 1.3-2.5), Wilms' tumor (SIR, 1.9; 95% CI, 1.2-3.2), soft tissue sarcoma (SIR, 1.5; 95% CI, 1.0-2.2), and bone tumors (SIR, 1.6; 95% CI, 1-2.2; Table 3).

We also examined patterns of malignancies among family members to evaluate the potential for additional family history syndromes that would require further investigation. There were 139 families reporting a first-degree relative with colon cancer. Thirteen (9%) of these families reported a sibling with cancer, and of those, 7 included siblings with colon cancer, suggesting a colon cancer predisposition syndrome. Similarly, there were 154 families among our leukemia and lymphoma probands reporting leukemia or lymphoma in a first-degree relative, of which 68 (44%) reported siblings with cancer. Of these 68 sibling cancers, 63 (93%) were leukemia or lymphoma.

We therefore examined the siblings' risk for the same cancer as the probands for all of the childhood cancer diagnostic groups and found it to be significantly elevated for leukemia (SIR, 2.6; 95% CI, 1.7-4.2), Hodgkin's disease (SIR, 5.9; 95% CI, 3.9-9.0), Wilms' tumor (SIR, 14.3; 95% CI, 4.3-47.3), and neuroblastoma (SIR, 9.2; 95% CI, 2.4-38.8). Risk for bone tumors in siblings of bone tumor probands was elevated (SIR, 4.0; 95% CI, 0.9-17.4), with borderline statistical significance (P = 0.06; Table 5). For Hodgkin's disease and leukemia, the excess risk among siblings was accounted for by siblings with the same cancer.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1. CCSS Institutions... References

 
The CCSS is a large multi-institutional resource for the study of late effects in survivors of childhood cancer (30). The cohort includes a heterogeneous group of 5-year survivors of the most common diagnoses of childhood cancer, many of whom have now reached young adulthood and for whom cancer family history is available. As such, the CCSS cohort provides an excellent opportunity to investigate risk of cancer among relatives of childhood cancer survivors and to investigate the genetic contribution to a variety of childhood cancers.

We identified an excess of cancers among siblings of 5-year childhood cancer survivors as well as risk for the same cancer among probands and siblings with leukemia, Hodgkin's lymphoma, Wilms' tumor, neuroblastoma, and bone tumor. Risk of cancer was also elevated in the cohort for siblings and offspring of probands with SMNs, although the offspring risk was based on a few offspring cancers. As in other studies (7, 9), no increased risk was found for parents.

As our study is limited to families of 5-year childhood cancer survivors, our results differ in important ways from other studies. It is a large, but selected, cohort study, not limited to a single institution or small group of families, specific diagnostic group, twin studies, or analyses of family cancers by death certificates, methodologies employed in other studies (13, 14, 16-19, 21-24). In this survivor cohort, highly lethal tumors, such as brain tumors, are not represented; thus, an increased risk of cancer among CNS tumor probands may not have been appreciated. Our results are somewhat similar to those of a population-based cohort of 25,602 childhood cancer patients in the Nordic countries, where Winther et al. found an increased cancer risk in 42,277 siblings (SIR, 1.2; 95% CI, 1.1-1.4). They attributed the excess to known hereditary syndromes but included clusterings of unknown etiology, such as "familial lymphoma" (20). As in other studies (13-15), we find an excess cancer risk in siblings, the majority of which has no defined genetic etiology. Families with known cancer predisposition syndromes (neurofibromatosis type 1, familial Wilms' tumor, Li-Fraumeni syndrome, and Li-Fraumeni–like syndrome) contributed to, but did not account for, the excess risk in this cohort. We acknowledge that the proportion of families with these syndromes may be underestimated due to the lack of second-degree family data, and there may exist familial leukemia/lymphoma, colon cancer, and similar family cancer syndromes that further contribute to the sibling risk. Planned collection of expanded first-degree and second-degree family history as the cohort ages together with the acquisition of biological specimens for molecular analyses will help to better define such syndromes.

As reported by Sankila et al. (27), we found no significant increased risk for cancer among offspring in this cohort (SIR, 1.7; 95% CI, 0.8-3.5). However, the CCSS cohort is young and our risk estimates are based on relatively few offspring. Further, the current mean ages of the offspring are less than the mean ages of the probands at cancer diagnosis. Hence, the offspring have not yet reached the ages of highest risk for the tumor type of their parent, and no conclusions regarding their risk should be made.

Few studies have examined the role of a family history of cancer and SMN risk. Bhatia et al. found no increased risk of cancer among relatives of Hodgkin's disease patients who developed breast cancer (37). In contrast, in a case control study of 25 childhood cancer survivors with SMN and 96 controls, Kony et al. reported that cancer among relatives ages <45 years increased the odds of SMN in probands (38). Strong et al., in their study of sarcoma survivors, noted that the relatives of SMN patients had an increased cancer risk and that the same tumor types occurring in excess in the relatives were also observed as SMNs in the patients (7). Further follow-up of the cohort, as they reach ages at which cancer becomes a common disease, will better identify any association between SMN risk in the proband and familial cancer risk.

Genetic studies of rare familial cancer aggregates have led to the identification or localization of many cancer susceptibility genes, including those for Wilms' tumor (39), neuroblastoma (40), and soft tissue and bone sarcoma (41, 42). However, less is known of the genetic susceptibility to childhood leukemia or Hodgkin's disease, the tumor types accounting for most of the excess of familial cancer in this survivor cohort. The high risk for the same tumor type in siblings is not explained by family histories that meet criteria for the LFS and further suggest that these cases are not likely due to a Li-Fraumeni syndrome–like gene with wide tissue specificity but likely due to a more tissue-specific effect. Our observations are consistent with those of Goldin et al. (43) regarding familial risk in Hodgkin's disease, an increased risk in siblings more so than in parents and offspring. Linkage analysis suggests there is some contribution from the HLA class II region (44) to familial Hodgkin's disease but that may not fully account for the familial aggregation. For childhood leukemia outside of the rare syndromes predisposing to acute myeloid leukemia and less likely represented in this survivor cohort, there are few leads.

As many studies have shown an increased cancer risk in siblings (13, 14, 20), we hypothesized an inherited predisposition to cancer in a limited proportion of the probands that would account for the excess risk observed in the siblings. In this model-free system, we found that if 5% of probands had an inherited predisposition that accounted for the observed sibling cancer excess, the relative risk to the siblings would be 10.8. The relative risks decreased to 5.9 and 3.0, if the "hereditary" subgroup increased to 10% or 20%, respectively. Ultimately, these hypotheses should be testable with expanded family histories combined with molecular diagnosis.

In conclusion, risks for siblings, albeit modest, are elevated above the general population and suggest a need for further investigation of focused surveillance and development of preventive strategies. Siblings and offspring of probands with SMNs are at higher risk and also may require such interventions. Survivors whose siblings have cancer may also require focused surveillance for SMN. Further follow-up is clearly required of this cohort to more definitively quantify risk, better define some of the potential family cancer syndromes, such as those in the families with siblings with hematopoietic cancers and colon cancers, pursue molecular genetic studies, provide targeted counseling and surveillance recommendations, and develop preventive strategies.

	Appendix 1. CCSS Institutions and Investigators

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1. CCSS Institutions... References

 

	Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/25/05; revised 5/20/05; accepted 6/ 6/05.

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