Publications by authors named "Eivind Hovig"

161 Publications

The CRCbiome study: a large prospective cohort study examining the role of lifestyle and the gut microbiome in colorectal cancer screening participants.

BMC Cancer 2021 Aug 18;21(1):930. Epub 2021 Aug 18.

Department of Research, Cancer Registry of Norway, Oslo, Norway.

Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions.

Methods: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50-74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period.

Discussion: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.

Trial Registration: ClinicalTrials.gov Identifier: NCT01538550 .
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http://dx.doi.org/10.1186/s12885-021-08640-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371800PMC
August 2021

The ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.

F1000Res 2020 13;9. Epub 2020 Oct 13.

Centre for Skin Sciences, University of Bradford, Bradford, UK.

Copy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While "High-Throughput" sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR's recently established with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context.
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http://dx.doi.org/10.12688/f1000research.24887.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311797PMC
August 2021

Cancer Predisposition Sequencing Reporter (CPSR): A flexible variant report engine for high-throughput germline screening in cancer.

Int J Cancer 2021 Dec 4;149(11):1955-1960. Epub 2021 Aug 4.

Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

The value of high-throughput germline genetic testing is increasingly recognized in clinical cancer care. Disease-associated germline variants in cancer patients are important for risk management and surveillance, surgical decisions and can also have major implications for treatment strategies since many are in DNA repair genes. With the increasing availability of high-throughput DNA sequencing in cancer clinics and research, there is thus a need to provide clinically oriented sequencing reports for germline variants and their potential therapeutic relevance on a per-patient basis. To meet this need, we have developed the Cancer Predisposition Sequencing Reporter (CPSR), an open-source computational workflow that generates a structured report of germline variants identified in known cancer predisposition genes, highlighting markers of therapeutic, prognostic and diagnostic relevance. A fully automated variant classification procedure based on more than 30 refined American College of Medical Genetics and Genomics (ACMG) criteria represents an integral part of the workflow. Importantly, the set of cancer predisposition genes profiled in the report can be flexibly chosen from more than 40 virtual gene panels established by scientific experts, enabling customization of the report for different screening purposes and clinical contexts. The report can be configured to also list actionable secondary variant findings, as recommended by ACMG. CPSR demonstrates comparable sensitivity and specificity for the detection of pathogenic variants when compared to other algorithms in the field. Technically, the tool is implemented in Python/R, and is freely available through Docker technology. Source code, documentation, example reports and installation instructions are accessible via the project GitHub page: https://github.com/sigven/cpsr.
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http://dx.doi.org/10.1002/ijc.33749DOI Listing
December 2021

Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential.

Front Immunol 2021 5;12:682492. Epub 2021 Jul 5.

Research and Development, Ultimovacs ASA, Oslo, Norway.

Telomerase-based therapeutic cancer vaccines (TCVs) have been under clinical investigation for the past two decades. Despite past failures, TCVs have gained renewed enthusiasm for their potential to improve the efficacy of checkpoint inhibition. Telomerase stands as an attractive target for TCVs due to its almost universal presence in cancer and its essential function promoting tumor growth. Herein, we review tumor telomerase biology that may affect the efficacy of therapeutic vaccination and provide insights on optimal vaccine design and treatment combinations. Tumor types possessing mechanisms of increased telomerase expression combined with an immune permissive tumor microenvironment are expected to increase the therapeutic potential of telomerase-targeting cancer vaccines. Regardless, rational treatment combinations, such as checkpoint inhibitors, are likely necessary to bring out the true clinical potential of TCVs.
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http://dx.doi.org/10.3389/fimmu.2021.682492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288190PMC
July 2021

Recommendations for the FAIRification of genomic track metadata.

F1000Res 2021 1;10. Epub 2021 Apr 1.

Center for Bioinformatics, University of Oslo (UiO), Oslo, Norway.

Many types of data from genomic analyses can be represented as genomic tracks, features linked to the genomic coordinates of a reference genome. Examples of such data are epigenetic DNA methylation data, ChIP-seq peaks, germline or somatic DNA variants, as well as RNA-seq expression levels. Researchers often face difficulties in locating, accessing and combining relevant tracks from external sources, as well as locating the raw data, reducing the value of the generated information. We propose to advance the application of FAIR data principles (Findable, Accessible, Interoperable, and Reusable) to produce searchable metadata for genomic tracks. Findability and Accessibility of metadata can then be ensured by a track search service that integrates globally identifiable metadata from various track hubs in the Track Hub Registry and other relevant repositories. Interoperability and Reusability need to be ensured by the specification and implementation of a basic set of recommendations for metadata. We have tested this concept by developing such a specification in a JSON Schema, called FAIRtracks, and have integrated it into a novel track search service, called TrackFind. We demonstrate practical usage by importing datasets through TrackFind into existing examples of relevant analytical tools for genomic tracks: EPICO and the GSuite HyperBrowser. We here provide a first iteration of a draft standard for genomic track metadata, as well as the accompanying software ecosystem. It can easily be adapted or extended to future needs of the research community regarding data, methods and tools, balancing the requirements of both data submitters and analytical end-users.
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http://dx.doi.org/10.12688/f1000research.28449.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226415PMC
July 2021

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in and : A Prospective Lynch Syndrome Database Study.

J Clin Med 2021 Jun 28;10(13). Epub 2021 Jun 28.

Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland.

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown.

Objective: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the and genes.

Methods: Carriers of pathogenic variants of () and () genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity.

Results: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately.

Conclusion: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of and .
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http://dx.doi.org/10.3390/jcm10132856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121PMC
June 2021

Combining a Universal Telomerase Based Cancer Vaccine With Ipilimumab in Patients With Metastatic Melanoma - Five-Year Follow Up of a Phase I/IIa Trial.

Front Immunol 2021 11;12:663865. Epub 2021 May 11.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

Background: Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma.

Patients And Methods: In this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production.

Results: Twelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years.

Conclusion: Treatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.
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http://dx.doi.org/10.3389/fimmu.2021.663865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147687PMC
October 2021

The genetic structure of Norway.

Eur J Hum Genet 2021 May 17. Epub 2021 May 17.

Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.

The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity, and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway's long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been an isolated region in Norway, highlighting the open sea as a barrier to gene flow into Norway.
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http://dx.doi.org/10.1038/s41431-021-00899-6DOI Listing
May 2021

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology.

J Pers Med 2021 Apr 22;11(5). Epub 2021 Apr 22.

Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital-Radium Hospital, 0424 Oslo, Norway.

Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants. We identify multiple somatic aberrations that are known to be enriched in prostate cancer, including a deletion of PTEN and a fusion transcript involving BRCA2. The gene expression patterns in the tumor biopsy were also strikingly similar to prostate tumor samples from TCGA. Furthermore, we detected multiple lines of evidence for homologous recombination repair deficiency (HRD), including a dominant contribution by mutational signature SBS3, which is specifically attributed to HRD. On the basis of the genomic and transcriptomic findings, and in light of the clinical case presentation, we discussed the personalized treatment options that exist for this patient and the various challenges that one faces in the process of translating high-throughput sequencing data towards treatment regimens.
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http://dx.doi.org/10.3390/jpm11050330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143497PMC
April 2021

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Eur J Cancer 2021 05 17;148:124-133. Epub 2021 Mar 17.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
May 2021

Editorial: Genomic Colocalization and Enrichment Analyses.

Front Genet 2020 26;11:617876. Epub 2021 Jan 26.

Computer Science Department, University of Colorado, Boulder, CO, United States.

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http://dx.doi.org/10.3389/fgene.2020.617876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870795PMC
January 2021

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Genet Med 2021 04 1;23(4):705-712. Epub 2020 Dec 1.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.

Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively.

Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.
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http://dx.doi.org/10.1038/s41436-020-01029-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026395PMC
April 2021

Accuracy and efficiency of germline variant calling pipelines for human genome data.

Sci Rep 2020 11 19;10(1):20222. Epub 2020 Nov 19.

Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0310, Oslo, Norway.

Advances in next-generation sequencing technology have enabled whole genome sequencing (WGS) to be widely used for identification of causal variants in a spectrum of genetic-related disorders, and provided new insight into how genetic polymorphisms affect disease phenotypes. The development of different bioinformatics pipelines has continuously improved the variant analysis of WGS data. However, there is a necessity for a systematic performance comparison of these pipelines to provide guidance on the application of WGS-based scientific and clinical genomics. In this study, we evaluated the performance of three variant calling pipelines (GATK, DRAGEN and DeepVariant) using the Genome in a Bottle Consortium, "synthetic-diploid" and simulated WGS datasets. DRAGEN and DeepVariant show better accuracy in SNP and indel calling, with no significant differences in their F1-score. DRAGEN platform offers accuracy, flexibility and a highly-efficient execution speed, and therefore superior performance in the analysis of WGS data on a large scale. The combination of DRAGEN and DeepVariant also suggests a good balance of accuracy and efficiency as an alternative solution for germline variant detection in further applications. Our results facilitate the standardization of benchmarking analysis of bioinformatics pipelines for reliable variant detection, which is critical in genetics-based medical research and clinical applications.
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http://dx.doi.org/10.1038/s41598-020-77218-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678823PMC
November 2020

Breast cancer survival in Nordic BRCA2 mutation carriers-unconventional association with oestrogen receptor status.

Br J Cancer 2020 11 17;123(11):1608-1615. Epub 2020 Sep 17.

Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland.

Background: The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers.

Methods: We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression.

Results: About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26-0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07-3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26-4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11-3.59, P = 0.02).

Conclusions: The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.
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http://dx.doi.org/10.1038/s41416-020-01056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686356PMC
November 2020

Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database.

J Clin Med 2020 Jul 18;9(7). Epub 2020 Jul 18.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, 80336 Munich, Germany.

Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome.

Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT.

Results: Risk-reducing hysterectomy and BSO are offered to _ and carriers in 20/21 (95%) contributing centers, to carriers in 19/21 (91%) and to carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years).

Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of , and variants but less so for carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.
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http://dx.doi.org/10.3390/jcm9072290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408942PMC
July 2020

Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes.

Cancers (Basel) 2020 Jun 28;12(7). Epub 2020 Jun 28.

Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.

The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C. The transformed HA-tagged MITF-M transduced Hermes 4C cells form colonies in soft agar and tumors in mice. Further, Hermes 4C cells display increased MITF chromatin binding, and transcriptional reprogramming consistent with an invasive melanoma phenotype. Mechanistically, forced expression of MITF-M drives the upregulation of the AXL tyrosine receptor kinase (AXL), with concomitant downregulation of phosphatase and tensin homolog (PTEN), leading to increased activation of the PI3K/AKT pathway. Treatment with AXL inhibitors reduces growth of the transformed cells by reverting AKT activation. In conclusion, we present a model system of melanoma development, driven by MITF-M in the context of MC1R loss of function, and independent of UV exposure. This model provides a basis for further studies of critical changes in the melanocyte transformation process.
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http://dx.doi.org/10.3390/cancers12071719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408466PMC
June 2020

Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Genetics and Epigenetics of Behaviour Laboratory, Istituto Italiano di Tecnologia, via Morego 30, Italy.

Imprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chromosome 15q11-q13, is characterized by hypothalamic insufficiency. Here, we investigate the role of the paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a significant role of this imprinted gene in the function and organization of the 2 main neuromodulatory systems of the lateral hypothalamus (LH) - namely, the orexin (OX) and melanin concentrating hormone (MCH) - systems. We observed that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScrm+/p-) are compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutant mice. Therefore, we propose that an imbalance between OX- and MCH-expressing neurons in the LH of mutant mice reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake, and temperature control.
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http://dx.doi.org/10.1172/jci.insight.137495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406246PMC
June 2020

Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models.

Commun Biol 2020 04 24;3(1):196. Epub 2020 Apr 24.

Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.

The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, a substantial number of patients fail to respond to checkpoint pathway blockade. Evidence for WNT/β-catenin signaling-mediated immune evasion is found in a subset of cancers including melanoma. Currently, there are no therapeutic strategies available for targeting WNT/β-catenin signaling. Here we show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/β-catenin and YAP signaling in the syngeneic murine B16-F10 and Clone M-3 melanoma models and sensitizes the tumors to anti-PD-1 immune checkpoint therapy. Mechanistically, we demonstrate that the synergistic effect of tankyrase and checkpoint inhibitor treatment is dependent on loss of β-catenin in the tumor cells, anti-PD-1-stimulated infiltration of T cells into the tumor and induction of an IFNγ- and CD8 T cell-mediated anti-tumor immune response. Our study uncovers a combinatorial therapeutical strategy using tankyrase inhibition to overcome β-catenin-mediated resistance to immune checkpoint blockade in melanoma.
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http://dx.doi.org/10.1038/s42003-020-0916-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181813PMC
April 2020

Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer - the MetAction study.

Acta Oncol 2020 Jul 25;59(7):733-740. Epub 2020 Mar 25.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014-2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016-2019). Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints. Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2-3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment. The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies. NCT02142036.
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http://dx.doi.org/10.1080/0284186X.2020.1742377DOI Listing
July 2020

Correction: Møller, P.; et al. Causes for Frequent Pathogenic Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift. 2019, , 132.

Cancers (Basel) 2020 Feb 10;12(2). Epub 2020 Feb 10.

Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, 0424 Oslo, Norway.

The authors wish to make the following corrections to this paper [1]: The authors would like to replace Table 3 in [1]. The corrections are correcting typographical errors when translating our database in BIC format to HGVS nomenclature, and removing four carriers which had zero follow-up time. [...].
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http://dx.doi.org/10.3390/cancers12020410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072602PMC
February 2020

Diagnostic Profiling of the Human Public IgM Repertoire With Scalable Mimotope Libraries.

Front Immunol 2019 3;10:2796. Epub 2019 Dec 3.

Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Specific antibody reactivities are routinely used as biomarkers, but the antibody repertoire reactivity (igome) profiles are still neglected. Here, we propose rationally designed peptide arrays as efficient probes for these system level biomarkers. Most IgM antibodies are characterized by few somatic mutations, polyspecificity, and physiological autoreactivity with housekeeping function. Previously, probing this repertoire with a set of immunodominant self-proteins provided a coarse analysis of the respective repertoire profiles. In contrast, here, we describe the generation of a peptide mimotope library that reflects the common IgM repertoire of 10,000 healthy donors. In addition, an appropriately sized subset of this quasi-complete mimotope library was further designed as a potential diagnostic tool. A 7-mer random peptide phage display library was panned on pooled human IgM. Next-generation sequencing of the selected phage yielded 224,087 sequences, which clustered in 790 sequence clusters. A set of 594 mimotopes, representative of the most significant sequence clusters, was shown to probe symmetrically the space of IgM reactivities in patients' sera. This set of mimotopes can be easily scaled including a greater proportion of the mimotope library. The trade-off between the array size and the resolution can be explored while preserving the symmetric sampling of the mimotope sequence and reactivity spaces. BLAST search of the non-redundant protein database with the mimotopes sequences yielded significantly more immunoglobulin J region hits than random peptides, indicating a considerable idiotypic connectivity of the targeted igome. The proof of principle predictors for random diagnoses was represented by profiles of mimotopes. The number of potential reactivity profiles that can be extracted from this library is estimated at more than 10. Thus, a quasi-complete IgM mimotope library and a scalable representative subset thereof are found to address very efficiently the dynamic diversity of the human public IgM repertoire, providing informationally dense and structurally interpretable IgM reactivity profiles.
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http://dx.doi.org/10.3389/fimmu.2019.02796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901697PMC
November 2020

Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.

Sci Rep 2019 12 6;9(1):18555. Epub 2019 Dec 6.

Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.
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http://dx.doi.org/10.1038/s41598-019-54517-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898579PMC
December 2019

PathTracer: High-sensitivity detection of differential pathway activity in tumours.

Sci Rep 2019 11 8;9(1):16332. Epub 2019 Nov 8.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Gene expression profiling of tumours is an important source of information for cancer patient stratification. Detecting subtle alterations of gene expression remains a challenge, however. Here, we propose a novel tool for high-sensitivity detection of differential pathway activity in tumours. For a pathway defined by a collection of genes, the samples are projected onto a low-dimensional manifold in the subspace spanned by those genes. For each sample, a score is next found by calculating the distance between each projected sample and the projection of a subgroup of reference samples. Depending on the aim of the analysis and the available data, the reference samples may represent e.g. normal tissue or tumour samples with a particular genotype or phenotype. The proposed tool, PathTracer, is demonstrated on gene expression data from 1952 invasive breast cancer samples, 10 DCIS, 9 benign samples and 144 tumour adjacent normal breast tissue samples. PathTracer scores are shown to predict survival, clinical subtypes, cellular proliferation and genomic instability. Furthermore, predictions are shown to outperform those obtained with other comparable methods.
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http://dx.doi.org/10.1038/s41598-019-52529-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841931PMC
November 2019

Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report.

Hered Cancer Clin Pract 2019 14;17:28. Epub 2019 Oct 14.

23High Risk and GI Cancer prevention Clinic, Gatro-Oncology Unit, The Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel.

Background: We previously reported that in pathogenic mismatch repair () variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated.

Methods: The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis.

Results: Ninety-nine carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 , 17 and 2 carriers. The number of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5-3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively ( < 0.001). Ten-year crude survival when the last colonoscopy had been < 1.5, 1.5-2.5, 2.5-3.5 or > 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively ( = 0.91).

Conclusions: In and carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.
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http://dx.doi.org/10.1186/s13053-019-0127-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792227PMC
October 2019

MirGeneDB 2.0: the metazoan microRNA complement.

Nucleic Acids Res 2020 01;48(D1):D132-D141

Department of Biological Sciences, Dartmouth College, Hanover, NH, USA.

Small non-coding RNAs have gained substantial attention due to their roles in animal development and human disorders. Among them, microRNAs are special because individual gene sequences are conserved across the animal kingdom. In addition, unique and mechanistically well understood features can clearly distinguish bona fide miRNAs from the myriad other small RNAs generated by cells. However, making this distinction is not a common practice and, thus, not surprisingly, the heterogeneous quality of available miRNA complements has become a major concern in microRNA research. We addressed this by extensively expanding our curated microRNA gene database - MirGeneDB - to 45 organisms, encompassing a wide phylogenetic swath of animal evolution. By consistently annotating and naming 10,899 microRNA genes in these organisms, we show that previous microRNA annotations contained not only many false positives, but surprisingly lacked >2000 bona fide microRNAs. Indeed, curated microRNA complements of closely related organisms are very similar and can be used to reconstruct ancestral miRNA repertoires. MirGeneDB represents a robust platform for microRNA-based research, providing deeper and more significant insights into the biology and evolution of miRNAs as well as biomedical and biomarker research. MirGeneDB is publicly and freely available at http://mirgenedb.org/.
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http://dx.doi.org/10.1093/nar/gkz885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943042PMC
January 2020

A snapshot of current genetic testing practice in Lynch syndrome: The results of a representative survey of 33 Latin American existing centres/registries.

Eur J Cancer 2019 09 20;119:112-121. Epub 2019 Aug 20.

Hospital de Especialidades Eugenio Espejo, Subproceso de Anatomía Patológica, Área de Genética Clínica, Quito, Ecuador.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p < 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.
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http://dx.doi.org/10.1016/j.ejca.2019.07.017DOI Listing
September 2019

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Genet Med 2020 01 24;22(1):15-25. Epub 2019 Jul 24.

Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.

Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.

Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
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http://dx.doi.org/10.1038/s41436-019-0596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371626PMC
January 2020
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