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- Waszak, S. M., et al.
(författare)
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Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
- 2018
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Ingår i: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 19:6, s. 785-798
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Tidskriftsartikel (refereegranskat)abstract
- Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 4069) and 5-year overall survival was 65% (95% CI 5281); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.
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| 2. |
- Waszak, S. M., et al.
(författare)
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Germline Elongator mutations in Sonic Hedgehog medulloblastoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7803
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Tidskriftsartikel (refereegranskat)abstract
- Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
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| 4. |
- Farioli, A, et al.
(författare)
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Occupational exposure to asbestos and risk of cholangiocarcinoma: a population-based case-control study in four Nordic countries
- 2018
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Ingår i: Occupational and environmental medicine. - : BMJ. - 1470-7926 .- 1351-0711. ; 75:3, s. 191-198
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Tidskriftsartikel (refereegranskat)abstract
- To assess the association between occupational exposure to asbestos and the risk of cholangiocarcinoma (CC).MethodsWe conducted a case–control study nested in the Nordic Occupational Cancer (NOCCA) cohort. We studied 1458 intrahepatic CC (ICC) and 3972 extrahepatic CC (ECC) cases occurring among subjects born in 1920 or later in Finland, Iceland, Norway and Sweden. Each case was individually matched by birth year, gender and country to five population controls. The cumulative exposure to asbestos (measured in fibres (f)/ml × years) was assessed by applying the NOCCA job-exposure matrix to data on occupations collected during national population censuses (conducted in 1960, 1970, 1980/81 and 1990). Odds ratios (OR) and 95% CI were estimated using conditional logistic regression models adjusted by printing industry work.ResultsWe observed an increasing risk of ICC with cumulative exposure to asbestos: never exposed, OR 1.0 (reference category); 0.1–4.9 f/mL × years, OR 1.1 (95% CI 0.9 to 1.3); 5.0–9.9 f/mL × years, OR 1.3 (95% CI 0.9 to 2.1); 10.0–14.9 f/mL × years, OR 1.6 (95% CI 1.0 to 2.5); ≥15.0 f/mL × years, OR 1.7 (95% CI 1.1 to 2.6). We did not observe an association between cumulative asbestos exposure and ECC.ConclusionsOur study provides evidence that exposure to asbestos might be a risk factor for ICC. Our findings also suggest that the association between ECC and asbestos is null or weaker than that observed for ICC. Further studies based on large industrial cohorts of asbestos workers and possibly accounting for personal characteristics and clinical history are needed.
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- Hadkhale, K, et al.
(författare)
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Occupational variation in incidence of bladder cancer: a comparison of population-representative cohorts from Nordic countries and Canada
- 2017
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 7:8, s. e016538-
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to compare occupational variation of the risk of bladder cancer in the Nordic countries and Canada.MethodsIn the Nordic Occupational Cancer study (NOCCA), 73 653 bladder cancer cases were observed during follow-up of 141.6 million person-years. In the Canadian Census Health and Environment Cohort (CanCHEC), 8170 cases were observed during the follow-up of 36.7 million person-years. Standardised incidence ratios with 95% CI were estimated for 53 occupations in the NOCCA cohort and HR with 95% CIs were estimated for 42 occupations in the CanCHEC.ResultsElevated risks of bladder cancer were observed among hairdressers, printers, sales workers, plumbers, painters, miners and laundry workers. Teachers and agricultural workers had reduced risk of bladder cancer in both cohorts. Chimney-sweeps, tobacco workers and waiters had about 1.5-fold risk in the Nordic countries; no risk estimates for these categories were given from the CanCHEC cohort.ConclusionWe observed different occupational patterns in risk of bladder cancer in Nordic countries and Canada. The only occupation with similarly increased risk was observed among sales workers. Differences in smoking across occupational groups may explain some, but not all, of this variation.
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- McKay, James D., et al.
(författare)
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A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
- 2011
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
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| 12. |
- Pearce, Neil E, et al.
(författare)
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IARC Monographs : 40 Years of Evaluating Carcinogenic Hazards to Humans
- 2015
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 507-514
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also the approach used to perform these evaluations. Some critics have claimed that IARC Working Groups' failures to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.OBJECTIVES: The authors of this paper are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We have examined here criticisms of the IARC classification process to determine the validity of these concerns. We review the history of IARC evaluations and describe how the IARC evaluations are performed.DISCUSSION: We conclude that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various discipline and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
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| 13. |
- Reijula, J, et al.
(författare)
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Cancer incidence among waiters: 45 years of follow-up in five Nordic countries
- 2015
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Ingår i: Scandinavian journal of public health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 43:2, s. 204-211
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To study cancer risk patterns among waiters in the Nordic countries. Methods: We identified a cohort of 16,134 male and 81,838 female waiters from Denmark, Finland, Iceland, Norway and Sweden. During the follow-up period from 1961 to 2005, we found that 19,388 incident cancer cases were diagnosed. Standardised incidence ratio (SIR) was defined as the observed number of cancer cases divided by the expected number, based on national age, time period and gender-specific cancer incidence rates in the general population. Results: The SIR of all cancers in waiters, in the five countries combined, was 1.46 (95% CI 1.41–1.51) in men and 1.09 (1.07–1.11) in women. In male waiters, the SIR decreased from 1.79 (1.63–1.96) in 1961–1975, to 1.33 (1.26–1.40) in 1991–2005, but remained stable among women. The SIR among male waiters was highest for cancers in the pharynx (6.11; 95% CI 5.02–7.37), oral cavity (4.91; 95% CI 3.81–6.24) and tongue (4.36; 95% CI 3.13–5.92); and in female waiters, in the larynx (2.17; 95% CI 1.63–2.82), oral cavity (1.96; 95% CI 1.60–2.34) and lung (1.89; 95% CI 1.80–1.99). Conclusions: The risk of cancer among waiters was higher than in the general population. The elevated incidence in some cancer sites can likely be explained by higher alcohol consumption, the prevalence of smoking and occupational exposure to tobacco smoke. Hopefully, the incidence of cancer among waiters will decrease in the future, due to the banning of tobacco smoking in restaurants and bars in the Nordic countries.
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- Hung, Rayjean J, et al.
(författare)
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A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
- 2008
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 452:7187, s. 633-637
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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- Kjaerheim, K, et al.
(författare)
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Variation in Nordic Work-Related Cancer Risks after Adjustment for Alcohol and Tobacco
- 2018
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Ingår i: International journal of environmental research and public health. - : MDPI AG. - 1660-4601. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alcohol and tobacco strongly increases the risk of cancers of the tongue, mouth, pharynx, larynx, and oesophagus, and are also established risk factors for cancer of the liver, colon, and rectum. It is well documented that these habits are unequally distributed among occupational groups. Most occupational cohort studies lack information on these potentially important confounders, and may therefore be prone to bias. Aim: The aim of the study is to present Nordic standardized incidence ratios (SIRs) for alcohol and tobacco related cancer by occupation, after adjustment for alcohol and tobacco, and to compare to the unadjusted SIRs. Material and Methods: The study is based on the Nordic Occupational Cancer (NOCCA) database. We used confirmatory factor analysis models for simultaneous analysis of the cancer sites related to alcohol and tobacco, to obtain factors that allow for computation of adjusted expected numbers from the reference rates. We then calculated adjusted SIRs for the relevant cancer sites for each occupation. Results: For some occupations and cancers, the changes of risk estimates were striking, from significantly high to significantly low and vice versa. Among Nordic farmers, unadjusted SIRs for cancer of the mouth and oesophagus were 0.56 (95% confidence interval (CI) 0.51–0.61) and 0.67 (CI 0.63–0.70), respectively. After adjustment, estimates changed to 1.10 (CI 1.01–1.21) and 1.16 (CI 1.10–1.22). Unadjusted SIR for pharynx cancer among wood workers was 0.83 (CI 0.75–0.91), adjusted SIR was 1.14 (CI 1.03–1.25). For larynx cancer, results in the opposite direction were seen: unadjusted SIR for economically inactive was 1.38 (CI 1.31–1.46) while the adjusted SIR was 0.91 (CI 0.86–0.96). Conclusions: Adjustment for the latent indicators of alcohol and tobacco consumption changed risk estimates for several occupations, gave a less confounded description of risk, and may guide in the identification of true risk factors.
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