Beatrice Malmer

Genome-wide association study identifies five susceptibility loci for glioma.

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 × 10−17), 8q24.21 (rs4295627, CCDC26; P = 2.34 × 10−18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 × 10−15), 20q13.33 (rs6010620, RTEL1; P = 2.52 × 10−12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 × 10−8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.

Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the groups consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address. Cancer 2008;113(7 suppl):1953–68.

Polymorphisms Associated with Asthma Are Inversely Related to Glioblastoma Multiforme

A reduced risk of primary malignant adult brain tumors is observed among people reporting asthma, hay fever, and other allergic conditions; however, findings may be attributed to prediagnostic effects of tumors or recall bias. To determine whether asthma and allergic condition polymorphisms are inversely related to glioblastoma multiforme (GBM) risk, we conducted a population-based case-control study of 111 GBM patients and 422 controls. We identified five single nucleotide polymorphisms on three genes previously associated with asthma [interleukin (IL)-4RA, IL-13, ADAM33] and one gene associated with inflammation (cyclooxygenase-2). Confirming previous literature, we found that self-reported asthma, eczema, and fever are inversely related to GBM [e.g., asthma odds ratio (OR), 0.64; 95% confidence interval (CI), 0.33-1.25]. In addition, IL-4RA Ser478Pro TC, CC, and IL-4RA Gln551Arg AG, AA are positively associated with GBM (OR, 1.64; 95% CI, 1.05-2.55; 1.61; 95% CI, 1.05-2.47), whereas IL-13 -1,112 CT, TT is negatively associated with GBM (0.56; 95% CI, 0.33-0.96). Each of these polymorphism-GBM associations is in the opposite direction of a corresponding polymorphism-asthma association, consistent with previous findings that self-reported asthmatics and people with allergic conditions are less likely to have GBM than are people who do not report these conditions. Because we used germ line polymorphisms as biomarkers of susceptibility to asthma and allergic conditions, our results cannot be attributed to recall bias or effects of GBM on the immune system. However, our findings are also consistent with associations between IL-4RA, IL-13, and GBM that are independent of their role in allergic conditions.

Epidermal growth factor receptor family (EGFR, ErbB2–4) in gliomas and meningiomas

Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2–4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P=0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P=0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P=0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.

Genetic epidemiology of glioma

The 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 χ2(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.

Familial aggregation of astrocytoma in northern Sweden: An epidemiological cohort study

This population‐based cohort study investigated the occurrence of familial astrocytoma among first‐degree relatives of patients with astrocytoma diagnosed between 1985 and 1993 in the northern region of Sweden. The 432 cases received a questionnaire. They were asked to provide names and cancer diagnoses of first‐degree relatives. Of the 297 answering, a cohort was constructed of their 1,890 first‐degree relatives (FDR). A significantly increased risk [standardized incidence ratio, SIR = 2.12, 95% confidence interval (CI) = 1.18–3.49] was shown for developing primary brain tumors (PBT). In 4.7% (14/297) of the families, a PBT was found. Interestingly, the increased risk was for astrocytoma only (SIR = 3.12, 95% CI 1.42–5.92), and not for other PBT (SIR 0.90, 95% CI 0.18–2.64). When the cohort was divided according to the median age of proband, most of the increased risk was restricted to the younger cohort (SIR = 4.71, 95% CI 1.52–10.99). Surprisingly, a significantly decreased risk for breast cancer and colon cancer was shown. The finding that the increased risk is restricted to astrocytoma only is a novel one. This study implies that familial aggregation of astrocytoma exists; the familial clustering occurs in a small fraction of astrocytoma, and might be explained by inherited factors. Int. J. Cancer 81:366–370, 1999.

GLIOGENE—an International Consortium to Understand Familial Glioma

Evidence for familial aggregation of glioma has been documented in both case-control and cohort studies and occurs apart from the well-described rare inherited genetic syndromes involving glioma: neurofibromatosis type 1 and 2, tuberous sclerosis, Turcots syndrome, and Li-Fraumeni syndrome. Nonsyndromic glioma families have been studied but no genes have been identified in the two published linkage studies of familial glioma probably due to the small number of families. Because glioma is a rare but devastating cancer, and a family history of glioma has been observed in ∼5% of the cases, we initiated an international consortium to identify glioma families not affected by syndromes to better understand the inherited factors related to this disease. The international consortium GLIOGENE is an acronym for “glioma gene” and includes 15 research groups in North America, Europe, and Israel to study familial glioma. The overarching goal is to characterize genes in glioma families using a genome-wide single-nucleotide polymorphism approach and conducting linkage analysis to identify new genomic regions or loci that could harbor genes important for gliomagenesis. Here, we review the rationale for studying familial glioma and our proposed strategy for the GLIOGENE study. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1730–4)

Familial brain tumours—genetics or environment? A nationwide cohort study of cancer risk in spouses and first‐degree relatives of brain tumour patients

Our study investigated whether the familial aggregation of glioma is due to environmental or genetic effects and it investigated and compared the risk to spouses and first‐degree relatives (FDR) of patients with primary brain tumours (PBT) for developing both PBT and the risk for other types of cancer. All PBT patients identified in Sweden from 1958–97 in The Swedish Cancer Registry (SCR) were linked to the nationwide Swedish Family Database, including persons in Sweden born from 1932–97. The cohorts of spouses and FDR were linked to the SCR to identify observed cases of PBT and other cancer. Standardised incidence ratios (SIR) were calculated using the incidence rates from SCR as the reference. We found that there were no increased risks for any specific type of PBT in the cohort of spouses. In the FDR cohort, generally the risk for a PBT was significantly increased by 2 to 3 times for the same histopathology as the probands. Spouses of PBT patients had an increased risk of skin cancer. We conclude that FDR, not spouses, have a significantly increased risk, which indicates a genetic origin of the familial aggregation of brain tumours.

An International Case-Control Study of Interleukin-4Rα, Interleukin-13, and Cyclooxygenase-2 Polymorphisms and Glioblastoma Risk

Previous studies found that allergies are inversely related to risk of glioma. In an earlier publication, using data from a Swedish case-control study, Schwartzbaum et al. report an inverse relation between risk of glioblastoma and four single nucleotide polymorphisms (SNP) on two genes [interleukin (IL)-4Rα, IL-13] that are associated with allergies. In addition, recent studies suggest that IL-4 and IL-13 induce cyclooxygenase-2 (COX-2) to resolve brain inflammation. To see whether previous Swedish results (110 cases, 430 controls) would be replicated, we estimated the association between glioblastoma and two IL-4Rα (rs1805015, rs1801275) and two IL-13 (rs20541, rs1800925) SNPs and their haplotypes and one COX-2 SNP (−765GC) using additional English, Danish, and Finnish data (217 cases, 1,171 controls). Among general population controls, we evaluated associations between these haplotypes, the COX-2 SNP, and self-reported allergies. Our data did not support our original observations relating individual IL-4Rα, IL-13, or COX-2 SNPs to glioblastoma risk. However, the T-G IL-4Rα haplotype was associated with glioblastoma risk (odds ratio, 2.26; 95% confidence interval, 1.13-4.52) and there was a suggestion of an inverse relation between this haplotype and hayfever prevalence among controls (odds ratio, 0.38; 95% confidence interval, 0.14-1.03). The lack of support for a link between four IL-4Rα and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma. Nonetheless, the association between the T-G IL-4Rα haplotype and glioblastoma risk may indicate a role of immune factors in glioblastoma development. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2448–54)

Anthropometric characteristics and non-Hodgkin’s lymphoma and multiple myeloma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

The incidences of non-Hodgkin’s lymphoma and multiple myeloma are increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. This European Prospective Investigation into Cancer and Nutrition (EPIC) study supports an association between height and overall non-Hodgkin’s lymphoma and multiple myeloma among women. Background The incidences of non-Hodgkin’s lymphoma and multiple myeloma are increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. It is biologically plausible that anthropometric characteristics can infuence the risk of non-Hodgkin’s lymphoma and multiple myeloma. Design and Methods In the context of the European Prospective Investigation into Cancer and Nutrition (EPIC), anthropometric characteristics were assessed in 371,983 cancer-free individuals at baseline. During the 8.5 years of follow-up, 1,219 histologically confirmed incident cases of non-Hodgkin’s lymphoma and multiple myeloma occurred in 609 men and 610 women. Gender-specific proportional hazards models were used to estimate relative risks and 95% confidence intervals (95% CI) of development of non-Hodgkin’s lymphoma and multiple myeloma in relation to the anthropometric characteristics. Results Height was associated with overall non-Hodgkin’s lymphoma and multiple myeloma in women (RR 1.50, 95% CI 1.14–1.98) for highest versus lowest quartile; p-trend < 0.01) but not in men. Neither obesity (weight and body mass index) nor abdominal fat (waist-to-hip ratio, waist or hip circumference) measures were positively associated with overall non-Hodgkin’s lymphoma and multiple myeloma. Relative risks for highest versus lowest body mass index quartile were 1.09 (95% CI 0.85–1.38) and 0.92 (95% CI 0.71–1.19) for men and women, respectively. Women in the upper body mass index quartile were at greater risk of diffuse large B-cell lymphoma (RR 2.18, 95% CI 1.05–4.53) and taller women had an elevated risk of follicular lymphoma (RR 1.25, 95% CI 0.59–2.62). Among men, height and body mass index were non-significantly, positively related to follicular lymphoma. Multiple myeloma risk alone was elevated for taller women (RR 2.34, 95% CI 1.29–4.21) and heavier men (RR 1.77, 95% CI 1.02–3.05). Conclusions The EPIC analyses support an association between height and overall non-Hodgkin’s lymphoma and multiple myeloma among women and suggest heterogeneous subtype associations. This is one of the first prospective studies focusing on central adiposity and non-Hodgkin’s lymphoma subtypes.