| 1. |
- Strausz, Satu, et al.
(author)
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Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health
- 2021
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In: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 57:5, s. 1-17
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Journal article (peer-reviewed)abstract
- There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background. We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries. We estimated 0.08 (95% CI 0.06.0.11) heritability and identified five loci associated with OSA (p<5.0×10-8): rs4837016 near GAPVD1 (GTPase activating protein and VPS9 domains 1), rs10928560 near CXCR4 (C-X-C motif chemokine receptor type 4), rs185932673 near CAMK1D (calcium/calmodulindependent protein kinase ID) and rs9937053 near FTO (fat mass and obesity-associated protein; a variant previously associated with body mass index (BMI)). In a BMI-adjusted analysis, an association was observed for rs10507084 near RMST/NEDD1 (rhabdomyosarcoma 2 associated transcript/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (rg=0.72 (95% CI 0.62-0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (rg>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA. Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.
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| 2. |
- Behboudi, Afrouz, 1967, et al.
(author)
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Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene.
- 2006
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In: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 45:5, s. 470-81
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Journal article (peer-reviewed)abstract
- Mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation resulting in a MECT1-MAML2 fusion in which the CREB-binding domain of the CREB coactivator MECT1 (also known as CRTC1, TORC1 or WAMTP1) is fused to the transactivation domain of the Notch coactivator MAML2. To gain further insights into the molecular pathogenesis of MECs, we cytogenetically and molecularly characterized a series of 29 MECs. A t(11;19) and/or an MECT1-MAML2 fusion was detected in more than 55% of the tumors. Several cases with cryptic rearrangements that resulted in gene fusions were detected. In fusion-negative MECs, the most common aberration was a single or multiple trisomies. Western blot and immunohistochemical studies demonstrated that the MECT1-MAML2 fusion protein was expressed in all MEC-specific cell types. In addition, cotransfection experiments showed that the fusion protein colocalized with CREB in homogeneously distributed nuclear granules. Analyses of potential downstream targets of the fusion revealed differential expression of the cAMP/CREB (FLT1 and NR4A2) and Notch (HES1 and HES5) target genes in fusion-positive and fusion-negative MECs. Moreover, clinical follow-up studies revealed that fusion-positive patients had a significantly lower risk of local recurrence, metastases, or tumor-related death compared to fusion-negative patients (P = 0.0012). When considering tumor-related deaths only, the estimated median survival for fusion-positive patients was greater than 10 years compared to 1.6 years for fusion-negative patients. These findings suggest that molecularly classifying MECs on the basis of an MECT1-MAML2 fusion is histopathologically and clinically relevant and that the fusion is a useful marker in predicting the biological behavior of MECs.
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| 3. |
- Boéthius, Helena, et al.
(author)
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A Nordic survey of the management of palliative care in patients with head and neck cancer
- 2021
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In: European Archives of Oto-Rhino-Laryngology. - : Springer. - 0937-4477 .- 1434-4726. ; 278, s. 2027-2032
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Journal article (peer-reviewed)abstract
- Background: The five Nordic countries with a population of 27M people form a rather homogenous region in terms of health care. The management of Head and Neck Cancer (HNC) is centralized to the 21 university hospitals in these countries. Our aim was to survey the current status of organization of palliative care for patients with HNC in the Nordic countries as the field is rapidly developing.Materials and methods: A structured web-based questionnaire was sent to all the Departments of Otorhinolaryngology-Head and Neck Surgery and Oncology managing HNC in the Nordic countries.Results: All 21 (100%) Nordic university hospitals responded to the survey. A majority (over 90%) of the patients are discussed at diagnosis in a multidisciplinary tumor board (MDT), but the presence of a palliative care specialist is lacking in 95% of these MDT's. The patients have access to specialized palliative care units (n = 14, 67%), teams (n = 10, 48%), and consultants (n = 4, 19%) in the majority of the hospitals.Conclusion: The present results show that specialized palliative care services are available at the Nordic university hospitals. A major finding was that the collaboration between head and neck surgeons, oncologists and palliative care specialists is not well structured and the palliative care pathway of patients with HNC is not systematically organized. We suggest that early integrated palliative care needs to be included as an addition to the already existing HNC care pathways in the Nordic countries.
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| 4. |
- Farnebo, Lovisa
(author)
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Predictive markers : for treatment sensitivity in head and neck squamous cell carcinoma
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Head and neck cancer is the sixth most common cancer world wide. In Sweden approximately 850 new cases are diagnosed each year, and two thirds are men. The past decades of improved treatment strategies have unfortunately not significantly improved the five-year survival rates for this group of patients. Therefore, it is important to rapidly find combinations of new and strong predictive markers for treatment response. Different predictive markers have been investigated for decades, without succeeding in finding means to securely predict response to treatment. Models to combine markers are called for.The aim of this thesis was to test multiple predictive markers on both gene and protein level to evaluate their predictive value for radiotherapy and cisplatin response. Furthermore, to combine, and correlate them to treatment response in order to extract the panel of markers that strongest correlated to the investigated treatment. Cell lines derived from 42 patients with head and neck squamous cell carcinoma (HNSCC) were used for protein quantification with Western blot and ELISA of the proteins survivin, Epidermal Growth Factor Receptor, Bcl-2, Bcl-XL, Bax, Bad, Bak, PUMA, Heat shock protein 70, MDM2, p53, SMAD4, Cyclooxygenase-2, and Cyclin D1. The expression of the selected proteins was related to the mean expression of normal oral keratinocytes (NOK) from healthy individuals. Furthermore, mutations in the p53 gene, along with single nucleotide polymorphisms in the genes of p53, MDM2, FGFR4, XRCC1, XRCC3, XPD, and XPC were analysed. To allow a large number of predictive markers on both protein and gene level to be combined and correlated to treatment response, the number of negative points (NNP) model was introduced. Both correlations of sensitivity to radiotherapy and to cisplatin treatment was analysed among the cell lines. In the first paper, including nine cell lines, the panel of EGFR, survivin, and splice site/missense p53 mutations correlated strongest to radioresponse. In paper II, 42 cell lines were used and the combination of survivin, Bcl-2, Bcl-XL, Bax, COX-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse. In paper IV, the panel correlating strongest with cisplatin sensitivity consisted of EGFR, Hsp70, Bax, and Bcl-2 in combination with SNPs in the DNA-repair genes XRCC3 and XPD.The predisposition of the FGFR4 Gly388Arg polymorphism for the development of HNSCC was investigated in paper III. DNA was isolated from 110 tumour biopsies, and restriction fragment length polymorphism analysis showed that 58% of the individuals in the control group carried the FGFR4 Arg388 allele, whereas the frequency in the tumour group was 45%. The Gly388 allele gave a significantly higher risk of developing HNSCC, suggesting Gly388 to be the risk allele for cancer development. Furthermore, a novel mutation was found in the FGFR4 gene. The influence of this new mutation is however unknown.In conclusion, predictive markers for treatment sensitivity need to be combined to receive an accurate prediction of treatment response.
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| 5. |
- Jee, Kowan Ja, et al.
(author)
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Genomic profiles and CRTC1-MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma.
- 2013
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In: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 26:2, s. 213-222
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Journal article (peer-reviewed)abstract
- Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1-MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion-positive whereas only 3 of 13 high-grade tumors were fusion-positive. High-resolution array-based comparative genomic hybridization revealed that fusion-positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P=0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusion-negative tumors lacked copy number alterations. The profiles of fusion-positive and fusion-negative tumors were very similar to those of low- and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; P<0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients.Modern Pathology advance online publication, 28 September 2012; doi:10.1038/modpathol.2012.154.
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| 6. |
- Mäkitie, Antti A., et al.
(author)
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Transoral Robotic Surgery in the Nordic Countries : Current Status and Perspectives
- 2018
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In: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 8
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Journal article (peer-reviewed)abstract
- Background: The five Nordic countries with a population of 27 M people form a rather homogenous region in terms of health care. The management of head and neck cancer is centralized to the 21 university hospitals in these countries. Our aim was to gain an overview of the volume and role of transoral robotic surgery (TORS) and to evaluate the need to centralize it in this area as the field is rapidly developing.Materials and Methods: A structured questionnaire was sent to all 10 Departments of Otorhinolaryngology-Head and Neck Surgery in the Nordic countries having an active programme for TORS in December 2017.Results: The total cumulative number of performed robotic surgeries at these 10 Nordic centers was 528 and varied between 5 and 240 per center. The median annual number of robotic surgeries was 38 (range, 5-60). The observed number of annually operated cases remained fairly low (<25) at most of the centers.Conclusions: The present results showing a limited volume of performed surgeries call for considerations to further centralize TORS in the Nordic countries.
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| 7. |
- Nethander, Maria, 1980, et al.
(author)
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An atlas of genetic determinants of forearm fracture.
- 2023
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In: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
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Journal article (peer-reviewed)abstract
- Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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| 8. |
- Ottosson, Sandra, 1981-
(author)
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Impact of disease and treatment on body weight and eating in patients with head and neck cancer : experiences from a multicenter study
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Background Nutritional deterioration in patients with head and neck cancer (HNC) has a multifactorial etiology mainly associated with tumor and treatment related factors. The objective of the present thesis was to investigate the impact of the disease and treatment on body weight and eating in patients with HNC treated with radiation therapy (RT) as the single modality treatment or as preoperative RT by analyzing body weight and body mass index (BMI) over time, predictive factors for weight loss and BMI, weight loss and BMI as prognostic factors for survival, and by studying the patients’ own experience of food and eating.Methods ARTSCAN is a randomized prospective multicenter trial conducted between the years of 1998 - 2006. Data were collected during and after RT with a total follow-up time of five years. Nutritional data from the whole study cohort (n = 712), from patients with oropharyngeal cancer (n = 232) and from two of the participating treatment centers (n = 101) were retrospectively analyzed in the present thesis. In addition, interviews (n = 13) were conducted nine months after the termination of RT as part of a care development project.Results On a group level, the patients lost weight during and after RT with a nadir at five months after the termination of RT. Factors related to a higher weight loss were oropharyngeal cancer, a high BMI at the start of RT, post-treatment aspiration, no tube feeding at the start of RT, and larger treated volumes. Furthermore, a high BMI at the start of RT was shown to be significantly related to a better five-year overall survival in patients with oropharyngeal cancer, whereas weight loss was not. The patients’ own narratives showed that all aspects of food, eating and meals were affected by the remaining sequelae, and that the patients found ways to accept and cope with the changes that had to be done to facilitate eating.Conclusions and clinical implications The disease and treatment gave persistent effects on the HNC patients’ weight and BMI which calls for a prolonged nutritional follow-up. The predictive factors found for weight loss can be used during patient history to find patients at risk for nutritional deterioration. In oropharyngeal cancer, patients with a high BMI at the start of RT had the best survival. This finding indicates that patients with a low BMI should be encouraged to gain weight before RT start. All aspects of food, eating and meals were affected during and after RT, and therefore the nutritional treatment should be given with a holistic approach to meet the multifaceted need patients with HNC experience.
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| 9. |
- Strausz, Satu, et al.
(author)
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Obstructive sleep apnoea and the risk for coronary heart disease and type 2 diabetes : A longitudinal population-based study in Finland
- 2018
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In: BMJ Open. - : BMJ. - 2044-6055. ; 8:10
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Journal article (peer-reviewed)abstract
- Objective To evaluate if obstructive sleep apnoea (OSA) modifies the risk of coronary heart disease, type 2 diabetes (T2D) and diabetic complications in a gender-specific fashion. Design and setting A longitudinal population-based study with up to 25-year follow-up data on 36 963 individuals (>500 000 person years) from three population-based cohorts: the FINRISK study, the Health 2000 Cohort Study and the Botnia Study. Main outcome measures Incident coronary heart disease, diabetic kidney disease, T2D and all-cause mortality from the Finnish National Hospital Discharge Register and the Finnish National Causes-of-Death Register. Results After adjustments for age, sex, region, high-density lipoprotein (HDL) and total cholesterol, current cigarette smoking, body mass index, hypertension, T2D baseline and family history of stroke or myocardial infarction, OSA increased the risk for coronary heart disease (HR=1.36, p=0.0014, 95% CI 1.12 to 1.64), particularly in women (HR=2.01, 95% CI 1.31 to 3.07, p=0.0012). T2D clustered with OSA independently of obesity (HR=1.48, 95% CI 1.26 to 1.73, p=9.11× 10 7). The risk of diabetic kidney disease increased 1.75-fold in patients with OSA (95% CI 1.13 to 2.71, p=0.013). OSA increased the risk for coronary heart disease similarly among patients with T2D and in general population (HR=1.36). All-cause mortality was increased by OSA in diabetic individuals (HR=1.35, 95% CI 1.06 to 1.71, p=0.016). Conclusion OSA is an independent risk factor for coronary heart disease, T2D and diabetic kidney disease. This effect is more pronounced even in women, who until now have received less attention in diagnosis and treatment of OSA than men.
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