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- Figlioli, G, et al.
(author)
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The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases
- 2020
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In: Cancers. - : MDPI AG. - 2072-6694. ; 12:2
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Journal article (peer-reviewed)abstract
- Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.
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- Öfverholm, Anna, et al.
(author)
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Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer
- 2023
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In: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 23:1
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Journal article (peer-reviewed)abstract
- BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.
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- Pace, Ryan M., et al.
(author)
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Variation in human milk composition is related to differences in milk and infant fecal microbial communities
- 2021
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In: Microorganisms. - : MDPI AG. - 2076-2607. ; 9:6
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Journal article (peer-reviewed)abstract
- Previously published data from our group and others demonstrate that human milk oligosaccharide (HMOs), as well as milk and infant fecal microbial profiles, vary by geography. However, little is known about the geographical variation of other milk-borne factors, such as lactose and protein, as well as the associations among these factors and microbial community structures in milk and infant feces. Here, we characterized and contrasted concentrations of milk-borne lactose, protein, and HMOs, and examined their associations with milk and infant fecal microbiomes in samples collected in 11 geographically diverse sites. Although geographical site was strongly associated with milk and infant fecal microbiomes, both sample types assorted into a smaller number of community state types based on shared microbial profiles. Similar to HMOs, concentrations of lactose and protein also varied by geography. Concentrations of HMOs, lactose, and protein were associated with differences in the microbial community structures of milk and infant feces and in the abundance of specific taxa. Taken together, these data suggest that the composition of human milk, even when produced by relatively healthy women, differs based on geographical boundaries and that concentrations of HMOs, lactose, and protein in milk are related to variation in milk and infant fecal microbial communities.
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- Brofelth, Mattias, et al.
(author)
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Multiplex profiling of serum proteins in solution using barcoded antibody fragments and next generation sequencing
- 2020
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In: Communications Biology. - : NATURE PUBLISHING GROUP. - 2399-3642. ; 3:1
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Journal article (peer-reviewed)abstract
- The composition of serum proteins is reflecting the current health status and can, with the right tools, be used to detect early signs of disease, such as an emerging cancer. An earlier diagnosis of cancer would greatly increase the chance of an improved outcome for the patients. However, there is still an unmet need for proficient tools to decipher the information in the blood proteome, which calls for further technological development. Here, we present a proof-of-concept study that demonstrates an alternative approach for multiplexed protein profiling of serum samples in solution, using DNA barcoded scFv antibody fragments and next generation sequencing. The outcome shows high accuracy when discriminating samples derived from pancreatic cancer patients and healthy controls and represents a scalable alternative for serum analysis. Brofelth, Ekstrand et al use DNA barcoded scFv antibody fragments and next generation sequencing for multiplex profiling of proteins in serum from pancreatic cancer patients with high accuracy. This approach can potentially be used in high throughput precision diagnosis.
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- Djursby, Malene, et al.
(author)
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Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer
- 2022
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In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 141:12, s. 1925-1933
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Journal article (peer-reviewed)abstract
- The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.
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| 18. |
- Filbay, S., et al.
(author)
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Prognostic factors for tibiofemoral and patellofemoral osteoarthritis 32-37 years after anterior cruciate ligament injury managed with early surgical repair or rehabilitation alone
- 2021
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In: Osteoarthritis and Cartilage. - : Elsevier Science Ltd. - 1063-4584 .- 1522-9653. ; 29:12, s. 1682-1690
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Journal article (peer-reviewed)abstract
- Objective: Explore prognostic factors for tibiofemoral (TFJ) and patellofemoral (PFJ) radiographic osteoarthritis (ROA) and symptoms plus ROA (SOA), 32-37 years following anterior cruciate ligament (ACL) injury. Design: Exploratory analysis, longitudinal cohort. Methods: In 1980-1985, 251 patients aged 15-40 years with acute ACL rupture were allocated to early augmented or non-augmented repair (5 +/- 4 days post-injury) plus rehabilitation, or rehabilitation alone. 127 of 190 participants who completed follow-up questionnaires were eligible. We classified ROA as TFJ/ PFJ K&L Grade >2, and SOA as ROA plus pain and/or symptoms. Multivariable age-adjusted logistic regression investigated potential prognostic factors (assessed at 4 +/- 1 year follow-up: ACL treatment, isokinetic quadriceps/hamstrings strength, single-leg-hop for distance, knee flexion/extension deficit, knee laxity, Tegner Activity Scale, Lysholm Scale; sex, baseline meniscus status). Results: 127 patients were aged 58 +/- 6 years; BMI 27 +/- 4 kg/m2; 28% female; 59% had TFJ-ROA, 48% had TFJ-SOA (including n = 9 knee-arthroplasties), 36% had PFJ-ROA; 27% had PFJ-SOA. Baseline meniscus surgery was a prognostic factor for TFJ-ROA (multivariable age-adjusted odds ratio (95% CI): 3.0 (1.2, 7.8)). A single-leg-hop limb symmetry index (LSI) < 90% was a prognostic factor for PFJ-ROA (5.1 (1.4, 18.7)) and PFJ-SOA (4.9 (1.2, 19.7)). Hamstrings strength LSI <90% was a prognostic factor for PFJ-SOA (5.0 (1.3, 19.3)). ACL treatment with rehabilitation-alone was associated with an 80% reduction in the odds of PFJSOA (0.2 (0.1-0.7)), compared with early ACL-repair. Conclusions: These findings are hypothesis generating, research is needed to determine whether ACLinjured individuals with these characteristics benefit from interventions to prevent or delay the onset of osteoarthritis. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 19. |
- Jarvilehto, J., et al.
(author)
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Serum Creatine, Not Neurofilament Light, Is Elevated in CHCHD10-Linked Spinal Muscular Atrophy
- 2022
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 13
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Journal article (peer-reviewed)abstract
- ObjectiveTo characterize serum biomarkers in mitochondrial CHCHD10-linked spinal muscular atrophy Jokela (SMAJ) type for disease monitoring and for the understanding of pathogenic mechanisms. MethodsWe collected serum samples from a cohort of 49 patients with SMAJ, all carriers of the heterozygous c.197G>T p.G66V variant in CHCHD10. As controls, we used age- and sex-matched serum samples obtained from Helsinki Biobank. Creatine kinase and creatinine were measured by standard methods. Neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were measured with single molecule array (Simoa), fibroblast growth factor 21 (FGF-21), and growth differentiation factor 15 (GDF-15) with an enzyme-linked immunosorbent assay. For non-targeted plasma metabolite profiling, samples were analyzed with liquid chromatography high-resolution mass spectrometry. Disease severity was evaluated retrospectively by calculating a symptom-based score. ResultsAxon degeneration marker, NfL, was unexpectedly not altered in the serum of patients with SMAJ, whereas astrocytic activation marker, GFAP, was slightly decreased. Creatine kinase was elevated in most patients, particularly men. We identified six metabolites that were significantly altered in serum of patients with SMAJ in comparison to controls: increased creatine and pyruvate, and decreased creatinine, taurine, N-acetyl-carnosine, and succinate. Creatine correlated with disease severity. Altered pyruvate and succinate indicated a metabolic response to mitochondrial dysfunction; however, lactate or mitochondrial myopathy markers FGF-21 or GDF-15 was not changed. ConclusionsBiomarkers of muscle mass and damage are altered in SMAJ serum, indicating a role for skeletal muscle in disease pathogenesis in addition to neurogenic damage. Despite the minimal mitochondrial pathology in skeletal muscle, signs of a metabolic shift can be detected.
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| 22. |
- Kvist, Joanna, et al.
(author)
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Radiographic and Symptomatic Knee Osteoarthritis 32 to 37 Years After Acute Anterior Cruciate Ligament Rupture
- 2020
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In: American Journal of Sports Medicine. - : SAGE PUBLICATIONS INC. - 0363-5465 .- 1552-3365. ; 48:10, s. 2387-2394
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Journal article (peer-reviewed)abstract
- Background: The long-term prevalence of knee osteoarthritis (OA) after anterior cruciate ligament (ACL) injury is unknown, especially in patients without a history of ACL surgery. Purpose: To (1) describe the prevalence of radiographic OA, symptomatic OA, and knee replacement surgery 32 to 37 years after acute ACL injury and to (2) compare the prevalence of radiographic OA, symptomatic OA, and knee symptoms between patients allocated to early ACL surgery or no ACL surgery and patients who crossed over to ACL surgery. Study Design: Cohort study; Level of evidence, 2. Methods: Participants aged 15 to 40 years at the time of ACL injury were allocated to surgical (augmented or nonaugmented ACL repair) or nonsurgical ACL treatment within 14 days of injury. At 32 to 37 years after the initial injury, 153 participants were followed up with plain weightbearing radiographs and completed 4 subscales from the Knee injury and Osteoarthritis Outcome Score (KOOS). Radiographic OA was defined as Kellgren and Lawrence grade 2 or higher. Symptomatic OA was defined as radiographic OA plus knee symptoms measured with the KOOS. Results: Participants allocated to ACL surgery (n = 64) underwent surgery at a mean +/- SD of 5 +/- 4 days (range, 0-11 days) after injury. Of the 89 participants allocated to no ACL surgery, 53 remained nonsurgically treated, 27 had ACL surgery within 2 years, and 9 had ACL surgery between 3 and 21 years after injury. In the total sample, 95 participants (62%) had radiographic tibiofemoral OA, including 11 (7%) who had knee replacement. The prevalence of radiographic tibiofemoral OA was lower in the group allocated to ACL surgery compared with the group who never had ACL surgery (50% vs 75%;P= .005). The prevalence of symptomatic OA (50% in the total sample) and patellofemoral radiographic OA (35% in the total sample) was similar between groups. Conclusion: Patients allocated to early ACL surgery, performed a mean 5 days after injury, had a lower prevalence of tibiofemoral radiographic OA at 32 to 37 years after injury compared with patients who never had ACL surgery. The prevalences of symptomatic OA, radiographic patellofemoral OA, and knee symptoms were similar irrespective of ACL treatment. Overall, the prevalence of OA after ACL injury was high. Registration: NCT03182647 (ClinicalTrials.gov identifier)
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| 23. |
- Lansink, G. M. J., et al.
(author)
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Potential for increased connectivity between differentiated wolverine populations
- 2022
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In: Biological Conservation. - : Elsevier. - 0006-3207 .- 1873-2917. ; 272
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Journal article (peer-reviewed)abstract
- Information on genetic population structure provides important knowledge for species conservation. Yet, few studies combine extensive genetic data to evaluate the structure and population dynamics of transboundary populations. Here we used single nucleotide polymorphisms (SNPs), microsatellites and mitochondrial haplotypes to analyze the genetic population structure of wolverines (Gulo gulo) across Fennoscandia using a long-term monitoring dataset of 1708 individuals. Clear population subdivision was detected between the Scandinavian and the eastern Finnish population with a steep cline in the contact zone. While the Scandinavian population showed isolation by distance, large swaths of this population were characterized by high connectivity. Areas with high resistance to gene flow are likely explained by a combination of factors, such as historical isolation and founder effects. From a conservation perspective, promoting gene flow from the population in eastern Finland to the northwest of Scandinavia could augment the less variable Scandinavian population, and increase the demographic resilience of all subpopulations. Overall, the large areas of low resistance to gene flow suggest that transboundary cooperation with aligned actions of harvest and conflict mitigation could improve genetic connectivity across Finland, Sweden, and Norway.
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| 24. |
- Palm, Angelica A., et al.
(author)
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Intra-Patient Evolution of HIV-2 Molecular Properties
- 2022
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In: Viruses. - : MDPI AG. - 1999-4915. ; 14:11
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Journal article (peer-reviewed)abstract
- Limited data are available on the pathogenesis of HIV-2, and the evolution of Env molecular properties during disease progression is not fully elucidated. We investigated the intra-patient evolution of molecular properties of HIV-2 Env regions (V1–C3) during the asymptomatic, treatment-naïve phase of the infection in 16 study participants, stratified into faster or slower progressors. Most notably, the rate of change in the number of potential N-linked glycosylation sites (PNGS) within the Env (V1–C3) regions differed between progressor groups. With declining CD4+ T-cell levels, slower progressors showed, on average, a decrease in the number of PNGSs, while faster progressors showed no significant change. Furthermore, diversity increased significantly with time in faster progressors, whereas no such change was observed in slower progressors. No differences were identified between the progressor groups in the evolution of length or charge of the analyzed Env regions. Predicted virus CXCR4 use was rare and did not emerge as a dominating viral population during the studied disease course (median 7.9 years, interquartile range [IQR]: 5.2–14.0) in either progressor groups. Further work building on our observations may explain molecular hallmarks of HIV-2 disease progression and differences in pathogenesis between HIV-1 and HIV-2.
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