It is estimated that 20,500 new primary brain tumors were diagnosed in the United States in 2005.18
Half of these are gliomas (50% of which are high-grade or anaplastic). Approximately 5% of gliomas are thought to be hereditary. Recognized autosomal dominant syndromes in which brain tumors are seen with increased incidence include tuberous sclerosis, neurofibromatosis, and Li-Fraumeni syndrome. The genetic changes associated with these syndromes have been largely identified.19
The p53 tumor suppressor gene may have a role in tumor development in both familial and sporadic gliomas, but not of germline origin, as seen in Li-Fraumeni syndrome. Study of affected lineages revealed germ-line mutations in the APC
gene responsible for familial adenomatous polyposis, and likely for predisposition to brain tumors, including glioma, and possibly a separate variant which has increased incidence of medulloblastoma.20
Other familial neoplastic syndromes include Turcot’s,21
von Hippel–Lindau disease,22
and multiple endocrine neoplasia syndromes.24
There are numerous well-recognized hereditary syndromes that manifest with brain tumors as part of their phenotype. However, the incidence of brain tumors, specifically gliomas, which are hereditary in nature, but not associated with one of these well-described inherited syndromes, is less clear. The literature is mixed regarding support of a “non-syndromic” genetic component to familial brain tumors.
Thirty-eight of the 1,401 Utah astrocytoma/GBM cases analyzed have at least one first-degree relative also affected with a brain tumor. These 38 cases represent 19 different brain tumor pedigrees/clusters. These clusters might be considered more likely to represent syndromic pedigrees. A total of 101 high-risk brain cancer pedigrees were identified in the UPDB, each containing at least three cases of astrocytoma/GBM, and with a significant excess of cases observed.
Segregation studies have supported multifactorial and genetic heritability (4%) in childhood brain tumors.25
Studies of patients with glioma and segregation of cancer in their first- and second-degree relatives have supported multigenic Mendelian inheritance as well as environmental influences26
; even patterns suggestive of autosomal recessive inheritance have been noted.2
Following several case reports suggesting familiality in astrocytoma,27–29
the National Brain Tumor Registry was established to study the familiality in tumors involving first-degree relatives and spouses. Results of the study of 72 families demonstrated no significantly lower age at onset; clustering in time; and a significant number of occurrences in spouses. Given these findings, the authors concluded that environmental factors might be more responsible for these familial occurrences than hereditary causes.30
A study from a cohort of over 42,000 benign and malignant brain tumor cases from the Swedish Cancer Registry (1958–1997) found a significant increased risk (RR = 2.0–3.0) for brain tumors in first-degree relatives, but not in spouses, a finding which decreases the possibility of short-term shared environmental risk, but which cannot exclude the impact of environmental impact in formative years.31
Another descriptive study of 19 families with glial tumors in two or more related members failed to show any pattern of inheritance, but showed an almost 7% incidence of positive family history—higher than would be expected by chance occurrence.32
Some case-control studies have supported an increased risk of familiality, with ORs greater than 2.0, while others show ORs near 1.0.33,34
Several cohort studies show increased standardized incidence ratios (SIR) in first-degree relatives of patients with brain tumors.35,36
The largest of these studies, from the Swedish Cancer Registry, examined familial risk in first-degree relatives of low-grade (LGG) and high-grade (HGG) gliomas. The SIR for relatives of LGG individuals was significantly elevated at 3.65 and reached 7.0 in siblings. Risk for HGG in the LGG cohort and within the HGG cohort showed a less impressive twofold increase in risk.37
Studies limited to first-degree relatives are inherently unable to discern between possible environmental effects of childhood and shared genetic propensity. In a population-based retrospective study similar to ours, of 396 glioma cases from the Icelandic Cancer Registry, no excess risk for glioma was observed in the 25,546 first-, second-, and third-degree relatives of the probands.38
Our analysis of the familial nature of 1,401 primary astrocytomas and GBMs is unique in both its large sample size and the availability of data on cancer and genetic relationships from a homogeneous population. Because all cancers in Utah are reported by law, estimates of cancer risk in relatives from this resource avoid the common biases of ascertainment and recall.
Our results strongly suggest a heritable contribution to astrocytoma risk, while showing only nominal support for such a hypothesis for GBMs. The GIF results for GBM suggest that these cancer cases are related, on average, as any similar group of individuals would be in this population. While the absence of a significantly elevated GIF in GBM may suggest lack of a strong genetic component, and at first glance may seem counterintuitive, it could be argued that a larger group of de novo (“primary”) GBMs associated with environmental exposures of aging may mask a true genetic component in the (“secondary”) GBMs which result from transformation of astrocytoma to higher grade classification. The observed significantly increased RR for GBM among first-degree relatives of patients with GBM may suggest the presence of a minority subset of GBM that may indeed have a heritable component.
Incidence data from Sweden37
show a similar pattern of increased familial risk in lower grade vs higher grade cohorts, which correlates with our observation of stronger familiality in astrocytoma (low-grade) vs glioblastoma (high-grade). Prospective studies to identify de novo, vs transformed, GBM, both clinically and by molecular profile, are crucial to clarify this issue. Molecular discoveries show that these subsets of GBM have inherent genetic differences39
and may differ in their mode of acquisition as regards heritability.
A limitation of our study is that it is retrospective in nature, and may be subject to misclassification effects in coding of malignant categories of brain neoplasms. Diagnoses of glioma were based on mandatory reporting of pathology diagnoses to the Utah Cancer Registry. These diagnoses were retrospectively collected and not subject to central review after submission.
While association with a tumor predisposition syndrome could not be definitively excluded in this retrospective analysis, it is unlikely that the majority of our familial cases were “syndromic.” A closer degree of familial clustering would be expected for syndromic cases, as the inheritance patterns are more likely to be more highly penetrant.
We have previously reported an increased association of cancers of other sites in the first-degree relatives of patients with brain tumor.16
The relationship between primary brain tumors and other cancers, outside of recognized germline syndromes, needs to be further elucidated.
Our findings support the hypothesis of a genetic contribution to glioma predisposition. Prospective studies of families with higher than expected numbers of brain tumors among descendants (high-risk pedigrees) may identify brain tumor predisposition genes that are not known and not included in well-described syndromes. Brain tumors need to be categorized both histologically and molecularly for known glioma-associated chromosomal aberrations. We will prospectively study these pedigrees for phenotype, association with recognized neoplastic syndromes, and molecular genetic profile to further our understanding of the inherited contribution to risk for brain tumor. Further information from this unique and valuable resource may provide insight into the sporadic gliomas, and lead to intervention, and even prevention, of low-grade gliomas or preneoplastic brain tumor states. Study of the extended high-risk Utah brain tumor pedigrees could allow identification of predisposition genes for brain tumors and provide important information regarding variations in treatment response and prognosis, and a better understanding of interactions between genes and environmental risk factors.