Genetic epidemiology of glioma

Abstract

SummaryThe present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second-and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model χ 2 (3) = 6.13, P < 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases. and pathology records. The complex segregation analysis was performed with the POINTER software (Morton et al, 1983). Since Pointer cannot accept pedigrees, the 297 families were divided into 504 nuclear families, one subset of nuclear families including siblings and parents of the proband and one subset of nuclear families including spouse and children of the proband. It was thus a mixture of complete and incomplete selection, since ascertainment through both parents and children was used. Data for the 257 wives or husbands could not be collected from the questionnaire and were coded as unaffected and having the same age as the proband. The segregation analysis was performed under the mixed model, which assumes the familial aggregation to be due to a major gene, a multifactorial component and a random environmental component, each acting independently. The estimated parameters are: H = multifactorial heritability; q = the estimated gene frequency of the major locus in the population; t = displacement between the homozygous means in standard deviations; d = degree of dominance, where d = 0 corresponds to an autosomal recessive gene and d = 1 corresponds to an autosomal dominant gene. Each person was assigned to one of nine liability classes since the risk of being affected varies with age ( Table 1). The risk of being affected was defined by Iselius et al (1991), as indicated by the formula:R j is the risk of being affected (morbid risk), I j is the cumulative incidence to the midpoint of the jth age interval and M j-i is the disease-specific mortality to the end of the preceding age interval. The incidence and mortality rates for glioma in each class (Ij) were calculated from the Regional Cancer Registry for Northern Sweden during the years 1958-1994. The age of each case was set...

Recent developments in brain tumor predisposing syndromes

“…The vast majority (83%) consisted of two glioma cases, and are likely due to multifactorial or random events rather than an actual disease causing gene [124]. This is well in line with earlier smaller family studies [125]. Linkage studies have suggested linkage on chromosome 17 [126], but there is yet to be determined if there is a clear disease causing mechanism in this area.…”

Cancer incidence in families with multiple glioma patients

“…Although a number of epidemiological studies on glioma families have been reported, association with other types of cancer has remained obscure because earlier results have been inconsistent. [5][6][7][8][9][10][11][12] Therefore, in the present study, the possibility that more than 1 tumour syndrome may involve pedigrees with multiple glioma patients was examined. Unlike most earlier epidemiological studies investigating families with 1 or more gliomas, [5][6][7][8][9][10][11] we focused on families affected with at least 2 verified gliomas.…”

Molecular Hallmarks of Gliomas

“…In large, carefully-designed epidemiological studies, familial glioma risks have been reported to be approximately two-fold, a magnitude that is similar to the familial association reported for other cancers for which susceptibility genes have been identified (e.g., breast cancer) (Malmer et al, 1999;Hemminki et al, 2000;Wrensch et al, 1997). The underlying causes of the pattern of familial brain tumor occurrence have been attributed to a variety of causes: one study implicates environmental factors only (Grossman et al, 1999), while others attribute multifactorial causes, polygenic causes, and autosomal recessive inheritance (de Andrade et al, 2001;Malmer et al, 2001). Two case-control studies have suggested that peripheral lymphocytes from glioma patients are more sensitive to gamma-radiation than lymphocytes from matched controls, suggesting that increased sensitivity to radiation is an independent risk factor for gliomas (Bondy et al, 1996;.…”