Publications by authors named "Beatrice Melin"

131 Publications

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the and genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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http://dx.doi.org/10.1016/j.xhgg.2021.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336922PMC
July 2021

A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients.

Sci Rep 2021 Jul 20;11(1):14763. Epub 2021 Jul 20.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden.

The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.
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http://dx.doi.org/10.1038/s41598-021-93926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292481PMC
July 2021

High risk of cardiovascular side effects after treatment of Hodgkin's lymphoma - is there a need for intervention in long-term survivors?

Ups J Med Sci 2021 15;126. Epub 2021 Feb 15.

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

Background: Hodgkin lymphoma (HL) patients have a good prognosis after adequate treatment. Previous treatment with mantle field irradiation has been accompanied by an increased long-term risk of cardiovascular disease (CVD). This study identified co-morbidity factors for the development of cardiovascular side effects and initiated an intervention study aimed to decrease morbidity and mortality of CVD in HL survivors.

Design: Hodgkin lymphoma patients aged ≤45 years diagnosed between 1965 and 1995 were invited to participate. In total, 453 patients completed a questionnaire that addressed co-morbidity factors and clinical symptoms. Of these, 319 accepted to participate in a structured clinical visit. The statistical analyses compared individuals with CVD with those with no CVD.

Results: Cardiovascular disease was reported by 27.9%. Radiotherapy (odds ratio [OR]: 3.27), hypertension and hypercholesterolemia were shown to be independent risk factors for the development of CVD. The OR for CVD and valve disease in patients who received radiotherapy towards mediastinum was 4.48 and 6.07, respectively. At clinical visits, 42% of the patients were referred for further investigation and 24% of these had a cardiac ultrasound performed due to previously unknown heart murmurs.

Conclusion: Radiotherapy towards mediastinum was an independent risk factor for CVD as well as hypercholesterolemia and hypertension. A reasonable approach as intervention for this cohort of patients is regular monitoring of hypertension and hypercholesterolemia and referral to adequate investigation when cardiac symptoms appear. Broad knowledge about the side effects from radiotherapy in the medical community and well-structured information regarding late side effects to the patients are all reasonable approaches as late effects can occur even 40 years after cancer treatment.
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http://dx.doi.org/10.48101/ujms.v126.6117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043572PMC
February 2021

Partitioned glioma heritability shows subtype-specific enrichment in immune cells.

Neuro Oncol 2021 08;23(8):1304-1314

Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

Background: Epidemiological studies of adult glioma have identified genetic syndromes and 25 heritable risk loci that modify individual risk for glioma, as well increased risk in association with exposure to ionizing radiation and decreased risk in association with allergies. In this analysis, we assess whether there is a shared genome-wide genetic architecture between glioma and atopic/autoimmune diseases.

Methods: Using summary statistics from a glioma genome-wide association studies (GWAS) meta-analysis, we identified significant enrichment for risk variants associated with gene expression changes in immune cell populations. We also estimated genetic correlations between glioma and autoimmune, atopic, and hematologic traits using linkage disequilibrium score regression (LDSC), which leverages genome-wide single-nucleotide polymorphism (SNP) associations and patterns of linkage disequilibrium.

Results: Nominally significant negative correlations were observed for glioblastoma (GB) and primary biliary cirrhosis (rg = -0.26, P = .0228), and for non-GB gliomas and celiac disease (rg = -0.32, P = .0109). Our analyses implicate dendritic cells (GB pHM = 0.0306 and non-GB pHM = 0.0186) in mediating both GB and non-GB genetic predisposition, with GB-specific associations identified in natural killer (NK) cells (pHM = 0.0201) and stem cells (pHM = 0.0265).

Conclusions: This analysis identifies putative new associations between glioma and autoimmune conditions with genomic architecture that is inversely correlated with that of glioma and that T cells, NK cells, and myeloid cells are involved in mediating glioma predisposition. This provides further evidence that increased activation of the acquired immune system may modify individual susceptibility to glioma.
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http://dx.doi.org/10.1093/neuonc/noab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328033PMC
August 2021

Identification of Pre-Diagnostic Metabolic Patterns for Glioma Using Subset Analysis of Matched Repeated Time Points.

Cancers (Basel) 2020 Nov 12;12(11). Epub 2020 Nov 12.

Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.

Here, we present a strategy for early molecular marker pattern detection-Subset analysis of Matched Repeated Time points (SMART)-used in a mass-spectrometry-based metabolomics study of repeated blood samples from future glioma patients and their matched controls. The outcome from SMART is a predictive time span when disease-related changes are detectable, defined by time to diagnosis and time between longitudinal sampling, and visualization of molecular marker patterns related to future disease. For glioma, we detect significant changes in metabolite levels as early as eight years before diagnosis, with longitudinal follow up within seven years. Elevated blood plasma levels of myo-inositol, cysteine, N-acetylglucosamine, creatinine, glycine, proline, erythronic-, 4-hydroxyphenylacetic-, uric-, and aceturic acid were particularly evident in glioma cases. We use data simulation to ensure non-random events and a separate data set for biomarker validation. The latent biomarker, consisting of 15 interlinked and significantly altered metabolites, shows a strong correlation to oxidative metabolism, glutathione biosynthesis and monosaccharide metabolism, linked to known early events in tumor development. This study highlights the benefits of progression pattern analysis and provide a tool for the discovery of early markers of disease.
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http://dx.doi.org/10.3390/cancers12113349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696703PMC
November 2020

Public support for healthcare-mediated disclosure of hereditary cancer risk information: Results from a population-based survey in Sweden.

Hered Cancer Clin Pract 2020 15;18:18. Epub 2020 Sep 15.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Background: Targeted surveillance of at-risk individuals in families with increased risk of hereditary cancer is an effective prevention strategy if relatives are identified, informed and enrolled in screening programs. Despite the potential benefits, many eligible at-risk relatives remain uninformed of their cancer risk. This study describes the general public's opinion on disclosure of hereditary colorectal cancer (CRC) risk information, as well as preferences on the source and the mode of information.

Methods: A random sample of the general public was assessed through a Swedish citizen web-panel. Respondents were presented with scenarios of being an at-risk relative in a family that had an estimated increased hereditary risk of CRC; either 10% (moderate) or 70% (high) lifetime risk. A colonoscopy was presented as a preventive measure. Results were analysed to identify significant differences between groups using the Pearson's chi-square (χ) test.

Results: Of 1800 invited participants, 977 completed the survey (54%). In the moderate and high-risk scenarios, 89.2 and 90.6% respectively, would like to receive information about a potential hereditary risk of CRC (χ2,  = .755). The desire to be informed was higher among women (91.5%) than men (87.0%, χ2,  = .044). No significant differences were found when comparing different age groups, educational levels, place of residence and having children or not. The preferred source of risk information was a healthcare professional in both moderate and high-risk scenarios (80.1 and 75.5%). However, 18.1 and 20.1% respectively would prefer to be informed by a family member. Assuming that healthcare professionals disclosed the information, the favoured mode of information was letter and phone (38.4 and 33.2%).

Conclusions: In this study a majority of respondents wanted to be informed about a potential hereditary risk of CRC and preferred healthcare professionals to communicate this information. The two presented levels of CRC lifetime risk did not significantly affect the interest in being informed. Our data offer insights into the needs and preferences of the Swedish population, providing a rationale for developing complementary healthcare-assisted communication pathways to realise the full potential of targeted prevention of hereditary CRC.
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http://dx.doi.org/10.1186/s13053-020-00151-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493346PMC
September 2020

A whole-genome sequenced control population in northern Sweden reveals subregional genetic differences.

PLoS One 2020 11;15(9):e0237721. Epub 2020 Sep 11.

Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.

The number of national reference populations that are whole-genome sequenced are rapidly increasing. Partly driving this development is the fact that genetic disease studies benefit from knowing the genetic variation typical for the geographical area of interest. A whole-genome sequenced Swedish national reference population (n = 1000) has been recently published but with few samples from northern Sweden. In the present study we have whole-genome sequenced a control population (n = 300) (ACpop) from Västerbotten County, a sparsely populated region in northern Sweden previously shown to be genetically different from southern Sweden. The aggregated variant frequencies within ACpop are publicly available (DOI 10.17044/NBIS/G000005) to function as a basic resource in clinical genetics and for genetic studies. Our analysis of ACpop, representing approximately 0.11% of the population in Västerbotten, indicates the presence of a genetic substructure within the county. Furthermore, a demographic analysis showed that the population from which samples were drawn was to a large extent geographically stationary, a finding that was corroborated in the genetic analysis down to the level of municipalities. Including ACpop in the reference population when imputing unknown variants in a Västerbotten cohort resulted in a strong increase in the number of high-confidence imputed variants (up to 81% for variants with minor allele frequency < 5%). ACpop was initially designed for cancer disease studies, but the genetic structure within the cohort will be of general interest for all genetic disease studies in northern Sweden.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237721PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485808PMC
October 2020

Travel time to care does not affect survival for patients with colorectal cancer in northern Sweden: A data linkage study from the Risk North database.

PLoS One 2020 5;15(8):e0236799. Epub 2020 Aug 5.

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

Introduction: Numerous prior studies, even from countries with free access to care, have associated long travel time to care with poor survival in patients with colorectal cancer.

Methods: This is a data-linkage study of all 3718 patients with colorectal cancer, diagnosed between 2007 and 2013 in Northern Sweden, one of the most sparsely populated areas in Europe. Travel time to nearest hospital was calculated based on GPS coordinates and multivariable Cox regression was used to analyse possible associations between travel time and cause-specific survival.

Results: No association between travel time and survival was observed, either in univariable analysis (colon HR 1.00 [95% CI 0.998-1.003]; rectal HR 0.998; [95% CI 0.995-1.002]) or in multivariable Cox regression analysis (colon HR 0.999 [95% CI 0.997-1.002]; rectal HR 0.997 [95% CI 0.992-1.002]).

Conclusions: In contrast to most other studies, no association between travel time and colorectal cancer survival was found; despite that longer travel time was associated with known risk factors for poorer outcome. In the Swedish health care setting, travel time does not appear to represent a barrier to care or to negatively influence outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236799PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406033PMC
October 2020

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Nat Commun 2020 07 3;11(1):3353. Epub 2020 Jul 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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http://dx.doi.org/10.1038/s41467-020-16483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335068PMC
July 2020

A genome-wide association study on medulloblastoma.

J Neurooncol 2020 Apr 13;147(2):309-315. Epub 2020 Feb 13.

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

Introduction: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.

Methods: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.

Results: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10), but none were statistically significant after adjusting for multiple testing (p < 5 × 10). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (OR = 1.59, p = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, OR = 3.76, p = 3.2 × 10) and rs79036813 (PTCH1, OR = 0.42, p = 2.6 × 10).

Conclusion: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.
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http://dx.doi.org/10.1007/s11060-020-03424-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136185PMC
April 2020

The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes.

Cancers (Basel) 2019 Dec 12;11(12). Epub 2019 Dec 12.

Department of Radiation Sciences, Oncology, Umeå University, 901 87 Umeå, Sweden.

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including -mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in and were associated with increased risk of all glioma subtypes. Second, variants in , , and were associated with -wildtype glioma. Third, variants in (the 8q24 locus), (close to ), , , , and were associated with -mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.
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http://dx.doi.org/10.3390/cancers11122001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966482PMC
December 2019

Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

Neuro Oncol 2020 02;22(2):207-215

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Background: The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian randomization (MR) framework to examine if lifestyle, cardiometabolic, and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation.

Methods: We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12 488 glioma patients and 18 169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures:Lifestyle and dietary factors-height, plasma insulin-like growth factor 1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamins (A1, B12, B6, E, and 25-hydroxyvitamin D), fatty acid levels (monounsaturated, omega-3, and omega-6) and circulating fetuin-A;Cardiometabolic factors-birth weight, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, glycated hemoglobin levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio; andInflammatory factors- C-reactive protein, plasma interleukin-6 receptor subunit alpha and serum immunoglobulin E.

Results: After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism, no significant association with glioma risk was observed (ie, PCorrected > 0.05).

Conclusions: This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.
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http://dx.doi.org/10.1093/neuonc/noz209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442418PMC
February 2020

Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study.

J Neurooncol 2019 Nov 25;145(2):287-294. Epub 2019 Sep 25.

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

Background: The Mono-amine oxidase-A (MAO-A) enzyme is involved in the degradation and regulation of catecholamines such as serotonin, dopamine, epinephrine and nor-epinephrine. Preclinical studies suggest that this enzyme may contribute to an environment favorable for growth of malignant glioma. The MAO-A gene is located on the X-chromosome and has at least one functional genetic polymorphism. The aim of the present study was to explore possible effects of MAO-A genotype on development of glioblastoma in males.

Methods: Genotypes for 437 glioma cases and 876 population-based controls from the Swedish Glioma International Case-Control study (GICC) were compared. We analyzed the germline DNA using the Illumina Oncoarray. We selected seven single nucleotide polymorphisms (SNPs) located in the MAO-A gene, and imputed genotypes based on data from the 1000 genomes project. We used 1579 male glioblastoma cases and 1875 controls comprising the whole GICC cohort for subsequent validation of findings.

Results: The rs144551722 SNP was a significant predictor of development of glioblastoma in males (p-value = 0.0056) but not in females even after correction for multiple testing. We conducted haplotype analysis to confirm an association between MAO-A gene and risk of glioblastoma (p-value = 0.016). We found similar results in the validation sample.

Conclusions: These results suggest the possibility of a role for the MAO-A enzyme and the MAO-A gene in the development of glioblastoma in males.
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http://dx.doi.org/10.1007/s11060-019-03294-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856259PMC
November 2019

Soft-tissue sarcoma in adolescents and young adults compared with older adults: A report among 5000 patients from the Scandinavian Sarcoma Group Central Register.

Cancer 2019 10 9;125(20):3595-3602. Epub 2019 Jul 9.

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

Background: In recent years, there has been growing awareness of the distinct characteristics of adolescents and young adults (AYA) diagnosed with cancer. Soft-tissue sarcoma (STS) accounts for approximately 1% of all cancers diagnosed in adults and 8% of cancers diagnosed in AYA. To the best of our knowledge, only a few sarcoma registers include data regarding histological subtype, age at diagnosis, and detailed clinical information. Therefore, little is known regarding clinical presentation and outcomes in AYA diagnosed with STS.

Methods: Using the Scandinavian Sarcoma Group Central Register, data were obtained regarding 4977 patients who were diagnosed with STS for the period between 1986 and 2011. AYA (those aged 18-39 years) were compared with older adults (OA; those aged 40-80 years) with respect to clinical presentation, treatment, and outcome.

Results: There were 868 AYA and 4109 OA. Overall and by STS subtype, there were significant differences noted between AYA and OA with regard to presentation, treatment, and survival. The distribution of STS subtypes was different between OA and AYA (eg, OA were more likely to be diagnosed with malignant fibrous histiocytoma compared with AYA [34% vs 16%; P < .001]). OA also were more likely to have tumors measuring ≥5 cm (68% vs 56%; P < .001) and a higher malignancy grade (75% vs 67%; P < .001). In the majority of STS subtypes AYA had significantly better overall survival and less disease recurrence compared with OA, but this finding was not true for those with malignant peripheral nerve sheath tumors.

Conclusions: There are several differences between AYA and OA with STS with regard to presentation, treatment, and survival, and such differences must be taken into consideration when designing clinical trials. Additional work also is needed to characterize the potential biological mechanisms underlying these differences.
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http://dx.doi.org/10.1002/cncr.32367DOI Listing
October 2019

Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults: A Case-Control Study.

Cancer Epidemiol Biomarkers Prev 2019 07 30;28(7):1252-1258. Epub 2019 Apr 30.

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

Background: Genome-wide association studies have identified germline genetic variants in 25 genetic loci that increase the risk of developing glioma in adulthood. It is not known if these variants increase the risk of developing glioma in children and adolescents and young adults (AYA). To date, no studies have performed genome-wide analyses to find novel genetic variants associated with glioma risk in children and AYA.

Methods: We investigated the association between 8,831,628 genetic variants and risk of glioma in 854 patients diagnosed up to the age of 29 years and 3,689 controls from Sweden and Denmark. Recruitment of patients and controls was population based. Genotyping was performed using Illumina BeadChips, and untyped variants were imputed with IMPUTE2. We selected 41 established adult glioma risk variants for detailed investigation.

Results: Three adult glioma risk variants, rs634537, rs2157719, and rs145929329, all mapping to the 9p21.3 () locus, were associated with glioma risk in children and AYA. The strongest association was seen for rs634537 (odds ratio = 1.21; 95% confidence interval = 1.09-1.35; = 5.8 × 10). In genome-wide analysis, an association with risk was suggested for 129 genetic variants ( <1 × 10).

Conclusions: Carriers of risk alleles in the 9p21.3 locus have an increased risk of glioma throughout life. The results from genome-wide association analyses require validation in independent cohorts.

Impact: Our findings line up with existing evidence that some, although not all, established adult glioma risk variants are associated with risk of glioma in children and AYA. Validation of results from genome-wide analyses may reveal novel susceptibility loci for glioma in children and AYA.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1026DOI Listing
July 2019

Perinatal and familial risk factors for soft tissue sarcomas in childhood through young adulthood: A population-based assessment in 4 million live births.

Int J Cancer 2020 02 2;146(3):791-802. Epub 2019 May 2.

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

Perinatal factors have been associated with soft tissue sarcomas (STS) in case-control studies. However, (i) the contributions of factors including fetal growth remain unknown, ( ii) these factors have not been examined in cohort studies and (iii) few assessments have evaluated risk in specific STS subtypes. We sought to identify the role of perinatal and familial factors on the risk of STS in a large population-based birth cohort. We identified 4,023,436 individuals in the Swedish Birth Registry born during 1973-2012. Subjects were linked to the Swedish Cancer Registry, where incident STS cases were identified. We evaluated perinatal and familial factors obtained from Statistics Sweden, including fetal growth, gestational age, and presence of a congenital malformation. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for associations between perinatal factors and STS overall, as well as by common subtypes. There were 673 individuals diagnosed with STS in 77.5 million person-years of follow-up. Having a congenital malformation was associated with STS (IRR = 1.70, 95% CI: 1.23-2.35). This association was stronger (IRR = 2.90, 95% CI: 1.25-6.71) in recent years (2000-2012). Low fetal growth was also associated with STS during the same time period (IRR = 1.86, 95% CI: 1.05-3.29). Being born preterm was associated with rhabdomyosarcoma (IRR = 1.74, 95% CI: 1.08-2.79). In our cohort study, those with congenital malformations and other adverse birth outcomes were more likely to develop a STS compared to their unaffected contemporaries. These associations may point to disrupted developmental pathways and genetic factors influencing the risk of STS.
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http://dx.doi.org/10.1002/ijc.32335DOI Listing
February 2020

Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics.

Int J Cancer 2020 02 22;146(3):739-748. Epub 2019 Apr 22.

Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ), and ≥15% NAA (AMR ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 ; 11p11.12, p = 7.0 × 10 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR . In addition, we identified a peak at rs1620291 (p = 4.36 × 10 ) in 7q21.3. Among AMR , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.
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http://dx.doi.org/10.1002/ijc.32318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785354PMC
February 2020

Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated pre-diagnostic blood samples.

Haematologica 2019 12 4;104(12):2456-2464. Epub 2019 Apr 4.

Department of Radiation Sciences, Oncology, Umeå University, Sweden.

Biomarkers reliably predicting progression to multiple myeloma (MM) are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor-alpha (TGF-α). In this study, we aimed to replicate these findings and study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases and 65 matched cancer-free controls each with two donated blood samples within the Northern Sweden Health and Disease Study. The first and repeated samples from myeloma cases were donated at a median 13 and 4 years, respectively, before the myeloma was diagnosed. Known risk factors for progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of MCP-3, VEGF, FGF-2, and TGF-α in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were noted for TGF-α (=2.5 × 10) indicating progression to MM. Investigating this, we found that low levels of TGF-α assessed at the time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; =0.003). TGF-α can potentially improve early detection of MM.
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http://dx.doi.org/10.3324/haematol.2019.216895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959165PMC
December 2019

A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis.

PLoS One 2019 27;14(3):e0213350. Epub 2019 Mar 27.

Department of Medical Biochemistry and Biophysics, Umeå University, SE Umeå, Sweden.

Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e.g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213350PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436687PMC
December 2019

Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma.

Cancer Res 2019 04 1;79(8):2065-2071. Epub 2019 Feb 1.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.

Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict -predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of < 5.69 × 10, we identified 31 genes, including at 12q13.33, as a candidate novel risk locus for GBM (mean = 4.43; = 5.68 × 10). resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus ( at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522343PMC
April 2019

Using germline variants to estimate glioma and subtype risks.

Neuro Oncol 2019 03;21(4):451-461

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes.

Methods: Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray.

Results: Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85.

Conclusions: These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.
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http://dx.doi.org/10.1093/neuonc/noz009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422428PMC
March 2019

The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking.

Cancer Causes Control 2019 Feb 17;30(2):177-185. Epub 2018 Dec 17.

Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden.

Purpose: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown.

Methods: rLTL was measured by qPCR in a Swedish population-based glioma case-control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification.

Results: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02-1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex.

Conclusions: In this Swedish glioma case-control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.
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http://dx.doi.org/10.1007/s10552-018-1120-2DOI Listing
February 2019

Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-analysis.

Cancer Epidemiol Biomarkers Prev 2019 03 27;28(3):555-562. Epub 2018 Nov 27.

Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.

Background: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis.

Methods: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies.

Results: A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54-0.70]. There was a significant duration-response trend ( = 1.67 × 10), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70-1.02), but no association for NSAID use.

Conclusions: Our study suggests that aspirin may be associated with a reduced risk of glioma.

Impact: These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401283PMC
March 2019

Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition.

Am J Epidemiol 2019 02;188(2):274-281

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.
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http://dx.doi.org/10.1093/aje/kwy259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357796PMC
February 2019

Survival of glioma patients in relation to mobile phone use in Denmark, Finland and Sweden.

J Neurooncol 2019 Jan 12;141(1):139-149. Epub 2018 Nov 12.

Section of Environment and Radiation, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372, Lyon CEDEX 08, France.

Purpose: Gliomas are the most common cancer of the brain, with a poor prognosis in particular for glioblastoma. In 2014, a study suggested reduced survival in relation to latency of mobile phone use among glioblastoma patients. A joint epidemiological/experimental project to study effects of RF-EMF on tumor development and progression was established. The current analysis relates to the epidemiological part and addresses whether pre-diagnostic mobile phone use was associated with survival among glioma patients.

Methods: Glioma cases (n = 806) previously enrolled in a collaborative population-based case-control study in Denmark, Finland and Sweden were followed up for survival. Vital status, date of death, date of emigration, or date last known to be alive was obtained based on registry linkages with a unique personal ID in each country. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) stratified by country. Covariates investigated were sex, age, education, histology, treatment, anatomic location and marital status.

Results: No indication of reduced survival among glioblastoma patients was observed for various measures of mobile phone use (ever regular use, time since start of regular use, cumulative call time overall or in the last 12 months) relative to no or non-regular use. All significant associations suggested better survival for mobile phone users. Results were similar for high-grade and low-grade gliomas.

Conclusions: We found no evidence of reduced survival among glioma patients in relation to previous mobile phone use.
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http://dx.doi.org/10.1007/s11060-018-03019-5DOI Listing
January 2019

Disparities in colorectal cancer between Northern and SouthernSweden - a report from the new RISK North database.

Acta Oncol 2018 Dec 3;57(12):1622-1630. Epub 2018 Oct 3.

a Department of Radiation Sciences, Oncology , Umeå University , Umeå , Sweden.

Background: Geographic cancer health disparities have been reported in Sweden. The disparities are not fully understood, but may be attributed to differences in exposure to risk factors as well as differences in health care, socioeconomics and demography. The aim of this study was to describe the new nationwide population based RISK North database and its potential by analysing health disparities in colorectal cancer between Northern and Southern Sweden.

Methods: Cancer-specific data from the National Cancer Quality Registers for colorectal, gastric and oesophageal cancer and brain tumours were linked to several nationwide registers hereby creating a new database - RISK North. To exemplify the potential of RISK North, we analyzed differences in colorectal cancer incidence, mortality and survival in relation to gender, age, cohabitation and education between Northern and Southern Sweden 2007-2013.

Results: In colon cancer, the age-adjusted incidence per 100.000 was lower in Northern than Southern Sweden, 35.9 in the North vs. 41.1 in the South (p < .01); mortality rates were 11.0 vs. 12.2 (p < .01). For rectal cancer, incidence rates were 17.6 vs. 19.7 (p < .01) and mortality rates 5.33 vs. 5.89 (p = .07), respectively. The largest difference in incidence was demonstrated for colon cancer among individuals >79 years old (190. vs. 237, i.e., ∼20%). Survival in colon cancer was higher in Southern Sweden, HR 0.92 (0.87-0.98) adjusted for age, gender, co-habiting, education and m-stage at diagnosis. No difference in survival was seen for rectal cancer.

Conclusions: The new RISK North database enabled analysis of cancer disparities between Northern and Southern Sweden. The incidence of colorectal cancer were lower in the North of Sweden whereas colon cancer survival was higher in the South. These differences can be further analysed utilising the RISK North database.
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http://dx.doi.org/10.1080/0284186X.2018.1497300DOI Listing
December 2018

Prognostic factors and primary treatment for Waldenström macroglobulinemia - a Swedish Lymphoma Registry study.

Br J Haematol 2018 11 10;183(4):564-577. Epub 2018 Sep 10.

Department of Haematology, Karolinska Institute, Stockholm, Sweden.

We present a nationwide prospective Swedish registry-based study of Waldenström macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11·5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86·1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin ≤115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin ≤115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival.
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http://dx.doi.org/10.1111/bjh.15558DOI Listing
November 2018

Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age.

Int J Cancer 2018 11 19;143(10):2359-2366. Epub 2018 Sep 19.

Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p = 1.50x10 , OR = 1.28, 95%CI = 1.18-1.39; p = 2.14x10 , OR = 1.32, 95%CI = 1.21-1.43] and rs11979158 [p = 6.13x10 , OR = 1.35, 95%CI = 1.21-1.50; p = 2.18x10 , OR = 1.42, 95%CI = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p = 9.30 × 10 , OR = 1.76, 95%CI = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'
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http://dx.doi.org/10.1002/ijc.31759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205887PMC
November 2018

The BRCA1 exon 13 duplication: clinical characteristics of 22 families in Northern Sweden.

Fam Cancer 2019 01;18(1):37-42

Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

The clinical management of BRCA1/2 mutation carriers requires accurate cancer risk estimates. Cancer risks vary according to type and location of the mutation and since there is limited information about mutation-specific cancer risks, genotype-phenotype correlation studies are needed. This is a report of 22 families with the same mutation, BRCA1 duplication exon 13, a mutation that is found world-wide, with the objective to describe the cancer history found in these families. We studied 69 confirmed carriers, 53 women and 16 men, and additionally 29 women who were clinically expected carriers. Among the confirmed carriers, 27 women (51%) were diagnosed with breast cancer, 10 (19%) with ovarian cancer, 5 (9%) with breast and ovarian cancer and 17 (32%) without cancer. Nine women (17%) with breast cancer were 35 years or younger at diagnose. Also, two cases of early onset colon cancer were found, and 37,5% of the male carriers were diagnosed with prostate cancer. These data may have implications for risk assessment and cancer prevention decision making for carriers of the BRCA1 duplication exon 13 mutation.
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http://dx.doi.org/10.1007/s10689-018-0098-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323134PMC
January 2019
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