Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland.

Predisposing factors underlying familial aggregation of non-syndromic gliomas are still to be uncovered. Whole-exome sequencing was performed in four Finnish families with brain tumors to identify rare predisposing variants. A total of 417 detected exome variants and 102 previously reported glioma-related variants were further genotyped in 19 Finnish families with brain tumors using targeted sequencing. Rare damaging variants in GALNT13, MYO10 and AR were identified. Two families carried either c.553C>T (R185C) or c.1214T>A (L405Q) on GALNT13. Variant c.553C>T is located on the substrate-binding site of GALNT13. AR c.2180G>T (R727L), which is located on a ligand-binding domain of AR, was detected in two families, one of which also carried a GALNT13 variant. MYO10 c.4448A>G (N1483S) was detected in two families and c.1511C>T (A504V) variant was detected in one family. Both variants are located on functional domains related to MYO10 activity in filopodia formation. In addition, affected cases in six families carried a known glioma risk variant rs55705857 in CCDC26 and low-risk glioma variants. These novel findings indicate polygenic inheritance of familial glioma in Finland and increase our understanding of the genetic contribution to familial glioma susceptibility.

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation. To better understand their malignancy, we investigated how AT/RT-specific DNA hypermethylation was associated with gene expression and altered transcription factor binding and how it is linked to upstream regulation. Medulloblastomas, choroid plexus tumors, pluripotent stem cells, and fetal brain were used as references. A part of the genomic regions, which were hypermethylated in AT/RTs similarly as in pluripotent stem cells and demethylated in the fetal brain, were targeted by neural transcriptional regulators. AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 and linked to suppressed genes with a role in neural development and tumorigenesis. Activity of the several NEUROG/NEUROD pioneer factors, which are unable to bind to methylated DNA, was compromised via the suppressed expression or DNA hypermethylation of their target sites, which was also experimentally validated for NEUROD1 in medulloblastomas and AT/RT samples. These results highlight and characterize the role of DNA hypermethylation in AT/RT malignancy and halted neural cell differentiation.

Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.

As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.

Impact of Timing of Surgery and Adjuvant Treatment on Survival of Adult IDH-wild-type Glioblastoma: A Single-center Study of 392 Patients.

BACKGROUND: The purpose of our study was to analyze the impact of time interval from referral to surgery and from surgery to adjuvant treatment on survival of adult isocitrate dehydrogenase-wild-type (IDH-wt) glioblastomas. METHODS: Data on 392 IDH-wt glioblastomas diagnosed at the Tampere University Hospital in 2004-2016 were obtained from the electronic patient record system. Piecewise Cox regression was used to calculate hazard ratios for different time intervals between referral and surgery, as well as between surgery and adjuvant treatments. RESULTS: The median survival time from primary surgery was 9.5 months (interquartile range: 3.8-16.0). Survival among patients with an interval exceeding 4 weeks from referral to surgery was no worse compared to <2 weeks (hazard ratio: 0.78, 95% confidence interval: 0.54-1.14). We found indications of poorer outcome when the interval from surgery to radiotherapy exceeded 30 days (hazard ratio: 1.42, 95% confidence interval: 0.91-2.21 for 31-44 days; and 1.59, 0.94-2.67 for over 45 days). CONCLUSIONS: Interval from referral to surgery in the range of 4-10 weeks was not associated with decreased survivals in IDH-wt glioblastomas. In contrast, delay exceeding 30 days from surgery to adjuvant treatment may decrease long-term survival.

PTPRD and CNTNAP2 as markers of tumor aggressiveness in oligodendrogliomas.

Oligodendrogliomas are typically associated with the most favorable prognosis among diffuse gliomas. However, many of the tumors progress, eventually leading to patient death. To characterize the changes associated with oligodendroglioma recurrence and progression, we analyzed two recurrent oligodendroglioma tumors upon diagnosis and after tumor relapse based on whole-genome and RNA sequencing. Relapsed tumors were diagnosed as glioblastomas with an oligodendroglioma component before the World Health Organization classification update in 2016. Both patients died within 12 months after relapse. One patient carried an inactivating POLE mutation leading to a clearly hypermutated progressed tumor. Strikingly, both relapsed tumors carried focal chromosomal rearrangements in PTPRD and CNTNAP2 genes with associated decreased gene expression. TP53 mutation was also detected in both patients after tumor relapse. In The Cancer Genome Atlas (TCGA) diffuse glioma cohort, PTPRD and CNTNAP2 expression decreased by tumor grade in oligodendrogliomas and PTPRD expression also in IDH-mutant astrocytomas. Low expression of the genes was associated with poor overall survival. Our analysis provides information about aggressive oligodendrogliomas with worse prognosis and suggests that PTPRD and CNTNAP2 expression could represent an informative marker for their stratification.

Chronic subdural hematoma-incidence, complications, and financial impact.

OBJECTIVE: To examine the population-based incidence, complications, and total, direct hospital costs of chronic subdural hematoma (CSDH) treatment in a neurosurgical clinic during a 26-year period. The aim was also to estimate the necessity of planned postoperative follow-up computed tomography (CT). METHODS: A retrospective cohort (1990-2015) of adult patients living in Pirkanmaa, Finland, with a CSDH was identified using ICD codes and verified by medical records (n = 1148, median age = 76 years, men = 65%). Data collection was performed from medical records. To estimate the total, direct hospital costs, all costs from hospital admission until the last neurosurgical follow-up visit were calculated. All patients were followed until death or the end of 2017. The annual number of inhabitants in the Pirkanmaa Region was obtained from the Statistics Finland (Helsinki, Finland). RESULTS: The incidence of CSDH among the population 80 years or older has increased among both operatively (from 36.6 to 91/100,000/year) and non-operatively (from 4.7 to 36.9/100,000/year) treated cases. Eighty-five percent (n = 978) underwent surgery. Routine 4-6 weeks' postoperative follow-up CT increased the number of re-operations by 18% (n = 49). Most of the re-operations (92%) took place within 2 months from the primary operation. Patients undergoing re-operations suffered more often from seizures (10%, n = 28 vs 3.9%, n = 27; p < 0.001), empyema (4.3%, n = 12 vs 1.1%, n = 8; p = 0.002), and pneumonia (4.7%, n = 13 vs 1.4%, n = 12; p = 0.008) compared with patients with no recurrence. The treatment cost for recurrent CSDHs was 132% higher than the treatment cost of non-recurrent CSDHs, most likely because of longer hospital stay for re-admissions and more frequent outpatient follow-up with CT. The oldest group of patients, 80 years or older, was not more expensive than the others, nor did this group have more frequent complications, besides pneumonia. CONCLUSIONS: Based on our population-based study, the number of CSDH patients has increased markedly during the study period (1990-2015). Reducing recurrences is crucial for reducing both complications and costs. Greater age was not associated with greater hospital costs related to CSDH. A 2-month follow-up period after CSDH seems sufficient for most, and CT controls are advocated only for symptomatic patients.

Long-term excess mortality after chronic subdural hematoma.

OBJECTIVE: To assess possible long-term excess mortality and causes of death of patients with chronic subdural hematoma (CSDH). METHODS: A retrospective study (1990-2015) of adult patients (n = 1133, median age = 76 years old, men = 65%) with CSDH identified by ICD-codes and verified by medical records. All patients were followed until death or the end of 2017. Cumulative relative survival ratios and relative excess risks of death (RER) were estimated by comparing patients' mortality with that in the entire regional matched population. The causes of death were compared with a separate reference group formed by randomly choosing sex, age, and calendar time matched controls (4 controls per each CSDH patient). RESULTS: The median follow-up time was 4.8 years (range = 0-27 years), and 710 (63%) of the patients died (median age at death = 84 years old). The cumulative excess mortality was 1 year = 9%, 5 years = 18%, 10 years = 27%, 15 years = 37%, and 20 years = 48%. A subgroup of CSDH patients (n = 206) with no comorbidity had no excess mortality. Excess mortality was related to poor modified Rankin score at admission (RER = 4.93) and at discharge (RER = 8.31), alcohol abuse (RER = 4.47), warfarin (RER = 2.94), age ≥ 80 years old (RER = 1.83), non-operative treatment (RER = 1.56), and non-traumatic etiology (RER = 1.69). Hematoma characteristics or recurrence were unrelated to excess mortality. Dementia was the most common cause of death among the CSDH patients (21%) and the third most common cause in the reference group (15%, p < 0.001). CONCLUSIONS: Patients with CSDH have continuous excess mortality up to 20 years after diagnosis. Patient-related characteristics have a strong association with excess mortality, whereas specific CSDH-related findings do not. CSDH patients have an increased risk for dementia-related mortality.

The incidence of chronic subdural hematomas from 1990 to 2015 in a defined Finnish population.

OBJECTIVE: The aim of this study was to determine the population-based epidemiology of chronic subdural hematoma (CSDH) over a 26-year period. METHODS: A retrospective study was conducted of all adult patients (≥ 18 years and residents of Pirkanmaa [Finland]) with a diagnosis of CSDH between 1990 and 2015. The cases were identified using ICD codes. Detailed data collection was performed using medical records and death certificates. All patients were monitored until death or the end of year 2017. The annual number of inhabitants in the Pirkanmaa region was obtained from Statistics Finland (Helsinki, Finland). RESULTS: A total of 1168 patients with CSDH were identified from hospital records and death certificates; patients were considered as new-incidence cases if 2 years had elapsed following primary treatment and in cases involving a new contralateral CSDH. From 1990 to 2015, the overall incidence of CSDH doubled from 8.2 to 17.6/100,000/year. Among adults younger than 70 years, the incidence remained quite stable, whereas the incidence clearly increased among the ≥ 80-year-old population, from 46.9 to 129.5/100,000/year. The median age for a CSDH diagnosis increased from 73 to 79 years during the 26-year period. Head trauma was documented in 59% of cases. A ground-level fall was related to the CSDH in 31% of patients younger than 60 years and in 54% of those 80 years or older. The proportion of alcohol-related cases decreased toward the end of the study period (1990-1995: 16% and 2011-2015: 7%), because alcohol abuse was less frequent among the growing group of elderly patients. In contrast, the percentage of patients receiving anticoagulant or antiplatelet medication almost doubled toward 2015 (1990-1995, 27%; and 2011-2015, 49%). The patients' neurological condition on admission, based on both Glasgow Coma Scale score (score < 13: 1990-1995, 18%; and 2011-2015, 7%; p < 0.001) and the modified Rankin Scale score (score 0-2: 1990-1995, 8%; and 2011-2015, 19%; p < 0.001), was better in recent years than in the early 1990s. CONCLUSIONS: From 1990 to 2015, the incidence of CSDH has increased markedly. The incidence of CSDH among the population 80 years or older has nearly tripled since 1990. The use of anticoagulants has increased, but there has been no change regarding the ratio between a traumatic and a spontaneous CSDH etiology. As the world population becomes progressively older, the increasing incidence of CSDH will be a burden to patients and a future challenge for neurosurgical clinics.

Activation of Blood Coagulation After Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Trial of Rotational Thromboelastometry.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) has been reported to actuate blood coagulation. Rotational thromboelastometry (ROTEM) is a dynamic hemostatic test that can differentiate various coagulation abnormalities. For example, increased coagulation activity can be detected as a wider amplitude of tracing (maximal clot firmness [MCF]). ROTEM had not been used to evaluate coagulation changes after aSAH. We evaluated the on-going coagulation process in patients with aSAH in a prospective, observational study to compare their ROTEM assay results with the control values obtained from patients undergoing clipping of nonruptured aneurysms. METHODS: ROTEM analyses were performed at 12, 24, 48, and 72 hours after the onset of aSAH and compared with the preoperative analyses from the control group. A total of 17 patients with aSAH treated in the intensive care unit and 16 control patients were enrolled. RESULTS: At 72 hours, EXTEM-MCF was significantly greater in patients with aSAH compared with the baseline values of the control group (68.0 mm [interquartile range (IQR), 66.0-71.0] versus 64.5 mm [IQR, 59.5-66.8]; P = 0.024). This was mainly due to increased fibrin formation and fibrin polymerization. The same comparison in the FIBTEM-MCF analysis yielded similar results (aSAH group, 23.0 mm [IQR, 19.0-25.0] vs. control group, 15.4 mm [IQR, 12.5-17.8], respectively; P = 0.001). CONCLUSIONS: Blood coagulation is activated at 72 hours after aSAH onset, which can be detected by ROTEM EXTEM-MCF analysis. Also, the FIBTEM-MCF was elevated, implying that the relative contribution of fibrin formation and fibrin polymerization is essential.

Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma.

Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-neutral loss of heterozygosity (LOH) in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors. ATRX mutation was associated with the loss of ATRX protein expression. In the astrocytoma case, R132C missense mutation was found in the known hotspot site in isocitrate dehydrogenase 1 (IDH1) and LOH was detected in TP53 The mother carried few other somatic alterations, suggesting that the IDH1 mutation and LOH in TP53 were sufficient to drive tumor development. The genome in the AT/RT tumor was atypically aneuploid: Most chromosomes had experienced copy-neutral LOH or whole-chromosome gains. Only Chromosome 18 had normal diploid status. INI1/hSNF5/SMARCB1 was homozygously deleted in the AT/RT tumor. This report provides further information about tumor development in a predisposed genetic background and describes two special Li-Fraumeni cases with a familial brain tumor.

[Diagnosis and prognosis of gliomas--current prospects of molecular diagnostics]. / Glioomien diagnoosi ja ennuste--molekyylidiagnostiikan mahdollisuudet.

Gliomas are tumors of the support cells of the brain and the most common of the primary brain tumors. Treatment of diffuse gliomas is based on surgical excision of the tumor and on radiotherapy and chemotherapy. The diagnosis is made in histopathological examination of the tumor, which today can be complemented with examinations involving molecular diagnostics. The most important new methods predicting the prognosis of glioma patients include demonstrations of the IDH mutation and the 1p/19q co-deletion. Profiling of gliomas may in the future allow tailoring of therapy in a patient-specific manner.

[Childhood brain tumors]. / Lasten aivokasvaimet.

Brain tumors are the second most common pediatric neoplastic disease after leukemias. As causes of mortality and morbidity they add up to the most significant group of tumors. Treatment is based on thorough surgical excision of the tumor. Additional treatment with cytotoxic agents and radiotherapy is applied to malignant tumors. Treatment results have improved so that approximately three children out of four will make complete recovery from brain tumor. Long-term problems are, however, common and often significantly weakening the quality of life.

Complement activation in astrocytomas: deposition of C4d and patient outcome.

BACKGROUND: C4d is a cleavage product of complement component C4 and is considered to serve as a marker for the site of complement activation. In this study C4d staining of grade I-IV astrocytic tumors was studied to explore if there is an association between complement activation and the grade of tumor, or patient survival. METHODS: Tissue micro-array samples of 102 astrocytomas were stained immunohistochemically. The material consisted of 9 pilocytic astrocytomas and 93 grade II-IV astrocytomas, of which 67 were primary resections and 26 recurrent tumors. The intensity of C4d staining as well as extent of C4d and CD34 staining were evaluated. The intensity of C4d staining was scored semiquantitatively. The extent of the staining was counted morphometrically with a point counting grid yielding a percent of C4d and CD34 positive area of the sample. RESULTS: The intensity and extent of C4d staining increased in grade II-IV diffusely infiltrating astrocytoma tumors in line with the malignancy grade (p = 0.034 and p = 0.016, respectively, Kruskal-Wallis test). However, C4d positive tumor area percentages were higher in grade I pilocytic astrocytomas than in grade II-IV diffusely infiltrating astrocytomas (p = 0.041, Mann-Whitney test). There was a significant correlation between CD34 positive and C4d positive endothelial area fraction in diffusely infiltrating astrocytomas (p < 0.001, Pearson correlation). In these tumors, the increasing intensity of C4d staining was also associated with worsened patient outcome (p = 0.014, log-rank test). CONCLUSION: The worsening of patient outcome and malignant progression of tumor cells seem to be connected to microenvironmental changes evoked by chronically activated complement.

Carbonic anhydrases in meningiomas: association of endothelial carbonic anhydrase II with aggressive tumor features.

OBJECT: Carbonic anhydrase (CA) II and IX are enzymes involved in pH homeostasis and have been shown to be upregulated in several types of cancer. In this study, the authors evaluate the expression of CA II and IX in meningiomas and assess their relationship to patient age, tumor type and grade, tumor sex hormone receptor status, tumor cell proliferation, and tumor recurrence. METHODS: This study was conducted in consecutive patients who underwent meningioma surgeries at Tampere University Hospital between 1989 and 1999. The expression of CA II and IX was studied immunohistochemically using a tissue microarray technique and specific antibodies. RESULTS: Immunohistological staining with CA II and IX was assessed in 443 primary and 67 recurrent tumor specimens. Of these samples, 455 were benign (WHO Grade I), 49 atypical (Grade II), and 6 malignant (Grade III). Endothelial cells in 14.8% of the tumors stained positively for CA II. Tumor cells were positive for CA IX in 11.6% of the cases. Endothelial CA II expression correlated with increasing histological grade (p=0.002), and tumor proliferation rates were higher in CA II+ versus CA II- cases (p=0.002). Androgen receptor-negative tumors were found to be CA II+ significantly more often than androgen receptor-positive tumors (p=0.001). No associations were found with the CA IX enzyme. CONCLUSIONS: Carbonic anhydrase II positivity in the endothelium was associated with cell proliferation and malignancy grade. These results suggest that CA II expression is associated with malignant progression of meningiomas and could thus be a target molecule for anticancer therapy.

Decreased expression of antioxidant enzymes is associated with aggressive features in ependymomas.

The purpose of this study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in 67 ependymal tumors. We included into the analysis antioxidant enzymes (AOEs) and related proteins, such as, manganese superoxide dismutase (MnSOD), gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), thioredoxin (Trx) and thioredoxin reductase (TrxR). Their expression was studied in 46 primary (10 grade I, 30 grade II and 6 grade III) and 21 recurrent (3 grade I, 12 grade II and 6 grade III) tumors. Immunoreactivity for MnSOD was found in 87%, GLCL-C in 74%, GLCL-R in 89%, Trx in 72%, TrxR in 54%, of primary tumors. Lower GLCL-C and GLCL-R expression was associated with higher tumor grade (P = 0.047 and 0.049, respectively). MnSOD, GLCL-C and TrxR expressions were significantly higher in tumors located in the spinal cord compared to those in the brain (P = 0.044, 0.046 and 0.004, respectively). In the primary tumors Trx-positivity was found to correlate significantly with patient survival. In univariate survival analysis patients whose tumors did not express Trx had shorter survival (P = 0.045) and there was even more significant association (P = 0.011) when only adults were included in the analysis (in the total material median follow-up time of Trx-positive tumors was 9.7 years and of Trx-negative 5.4 years). The results indicate that AOEs have several biological functions in ependymal tumors. Trx had important prognostic value: all adults with Trx-positive tumors were alive at follow-up (median 7.8 years).

Desmoplastic infantile ganglioglioma: novel aspects in clinical presentation and genetics.

BACKGROUND: Desmoplastic infantile ganglioglioma is a rare tumor occurring mainly in infants and young children. Both radiological and histopathological appearances may resemble malignancy, although its clinical course is mainly benign. METHODS: Altogether, 5 cases of DIG have been operated on in our hospital since the first diagnosis of DIG in Finland in 1993. We evaluated their presenting symptoms, radiological and surgical findings, histologic characteristics, and follow-up. RESULTS: All patients were male. Three were less than 18 months old, and 2 were 35 and 79 months old. The most common presenting symptoms were epileptic seizures (4 cases). In 4 cases, there was a histopathologically verified single cystic tumor. In 1 case, DIG was operatively diagnosed in 2 separate locations. This patient, moreover, had 2 other lesions suspected of being DIG, including a mass originating from the ophthalmic nerve. None of the patients received adjuvant therapies. All our patients are alive after 7 to 120 months of follow-up. There were no recurrences in any of the patients after tumor resection. For the first time, we describe EGFR and MYCN amplifications in tumors which are, respectively, of their mixed glial and neuronal origin. CONCLUSION: The clinical presentation of DIG may be more often associated with epileptic seizures than previously thought. The radiological appearance of DIG may vary from cystic to solid and from contrast-enhancing to nonenhancing. Even multiple locations of DIG have been encountered. Increasing evidence supports surgery as the treatment of choice for DIG, although oncogene amplifications have been described.

Antioxidant enzymes in oligodendroglial brain tumors: association with proliferation, apoptotic activity and survival.

Purpose of the study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in oligodendroglial tumors. The expression of antioxidant enzymes and related proteins (AOEs), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR) and gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), was studied in 85 oligodendroglial tumors. The material included 71 primary (43 grade II and 28 grade III) and 14 recurrent (6 grade II and 8 grade III) tumors. Fifty-seven cases were pure oligodendrogliomas and 28 were mixed oligoastrocytomas. Immunoreactivity for MnSOD was found in 89%, Trx in 29%, TrxR in 76%, GLCL-C in 70% and GLCL-R in 68% of cases. Increased Trx expression was associated with higher tumor grade, cell proliferation and apoptosis (P=0.006, P=0.001 and P=0.003, Mann-Whitney test). Pure oligodendrogliomas showed more intense staining than oligoastrocytomas, especially for MnSOD (P=0.002, Mann-Whitney test). In the total series Trx was associated with poor prognosis in univariate survival analysis (P=0.0343, log-rank test) and furthermore in Cox multivariate analysis (P=0.009) along with age (P=0.002). The results suggest that the expression of Trx has a correlation to patient outcome and that there may be some association between AOEs, like MnSOD and Trx, and clinicopathological features of oligodendrogliomas.

A novel low-penetrance locus for familial glioma at 15q23-q26.3.

Epidemiological studies and case reports suggest that familial clustering of gliomas may occur in families that do not fit any known tumor syndromes. In the present study, 15 familial glioma pedigrees from a limited geographical area were hypothesized to carry the same low-penetrance susceptibility allele. We used a two-stage strategy for disease gene mapping. A genome scan in four glioma families revealed four interesting loci at chromosome arms 1q, 6q, 8p, and 15q. Additional markers in these regions provided evidence of significant linkage to 15q23-q26.3 with a maximum nonparametric linkage score of 3.35 with marker D15S130. Investigation of all 15 glioma families by association analysis (haplotype pattern mining) and through use of the transmission/disequilibrium test gave further evidence of significant association/transmission distortion at the same 15q locus (P = 0.02 and P = 0.03, respectively). No evidence of involvement of known tumor syndromes was obtained from the data provided by the linkage analysis or hospital records. Thus, the first genome-wide linkage analysis of familial glioma suggests a novel susceptibility locus at 15q23-q26.3.

Cancer incidence in families with multiple glioma patients.

Twenty-four Finnish families with 2 or more glioma patients were identified through questionnaires sent to 369 consecutive glioma patients receiving surgery at Tampere University Hospital during 1983-94. To explore whether unusual cancer susceptibility is involved, the cancer risk of 2,664 family members was estimated using population-based data from the Finnish Cancer Registry. Among the total cohort of relatives, 88 cancers were observed during 1953-97. The overall cancer risk among 12 families with juvenile onset gliomas was significantly decreased (standardized incidence ratio [SIR] 0.6, 95% confidence interval [CI]: 0.4-0.9). Among 12 families with adult onset gliomas, the overall cancer risk was equal to that of the reference population (SIR 1.1, 95% CI: 0.8-1.4) whereas the risk of skin melanoma (SIR 4.0, 95% CI: 1.5-8.8) and meningioma (SIR 5.5, 95% CI: 1.1-16) were significantly increased. Several other tumors, including those associated with neurofibromatosis 1 and 2, tuberous sclerosis and Li-Fraumeni and Turcot syndromes were surveyed, but no elevated risks were observed. In conclusion, the presence of meningiomas and skin melanomas in glioma families may indicate a novel association as a cancer susceptibility trait.