Publications by authors named "Hildur Helgadottir"

33 Publications

The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma.

Authors:
Lars Ny Henrik Jespersen Joakim Karlsson Samuel Alsén Stefan Filges Charlotta All-Eriksson Bengt Andersson Ana Carneiro Hildur Helgadottir Max Levin Ingrid Ljuslinder Roger Olofsson Bagge Vasu R Sah Ulrika Stierner Anders Ståhlberg Gustav Ullenhag Lisa M Nilsson Jonas A Nilsson

Nat Commun 2021 08 27;12(1):5155. Epub 2021 Aug 27.

Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.

Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016-002114-50.
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http://dx.doi.org/10.1038/s41467-021-25332-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397717PMC
August 2021

Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants.

Authors:
Francesco Spagnolo Bruna Dalmasso Enrica Tanda Miriam Potrony Susana Puig Remco van Doorn Ellen Kapiteijn Paola Queirolo Hildur Helgadottir Paola Ghiorzo

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy.

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/-MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/-MEKi with an expected rate derived from phase III trials and "real-world" studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (-value = 0.143; 95% CI = 0.60-0.97); the difference was statistically significant (-value = 0.019; 95% CI = 0.62-0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/-MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.
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http://dx.doi.org/10.3390/cancers13102440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157545PMC
May 2021

genetic testing in melanoma-prone families in Sweden in the years 2015-2020: implications for novel national recommendations.

Authors:
Maria Pissa Teo Helkkula Frida Appelqvist Gustav Silander Åke Borg Jenny Pettersson Jan Lapins Kari Nielsen Veronica Höiom Hildur Helgadottir

Acta Oncol 2021 Jul 4;60(7):888-896. Epub 2021 May 4.

Department of Oncology and Pathology, Karolinska Institutet and Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.

Inherited pathogenic variants (PVs) in the gene are among the strongest known risk factors for cutaneous melanoma. Carriers are at high risks to develop multiple primary melanomas and other cancers, in particular pancreatic cancer. In this study, the testing, carried out in Sweden in the years 2015-2020, was evaluated. Included families had (1) three or more cases of melanoma and/or pancreatic cancer, (2) two melanomas in first-degree relatives, the youngest case <55 years or (3) individuals with three or more multiple primary melanomas, the first before the age of 55 years, and no other affected family members. The included families had at least one affected member that had been tested for PVs. In total, 403 families were included, whereof 913 family members had been diagnosed with cutaneous melanoma and 129 with pancreatic cancer, 33 (8.2%) were found to have PVs in . Frequencies ranged from 0.9% in families with only two melanomas to 43.2% in families with three or more melanoma cases and pancreatic cancer ( < 0.001). The frequency of PVs ranged from 2.1% to 16.5% in families where the youngest case was ≥55 years or <35 years ( = 0.040). In families with or without PVs, 37.6% and 10.0% had melanoma cases that had died from melanoma, respectively ( < 0.001). Significant differences were seen in the frequencies of PVs, dependent on numbers or age at diagnosis of melanomas and diagnoses of pancreatic cancers in the family. Further, melanoma cases belonging to families that tested positive for PVs had a significantly higher mortality. To summarize, the current evaluation shows that, with adequately selected criteria to guide genetic testing, PVs are identified at significant frequencies. Identification of carrier families is of importance to ensure that members are enrolled in a preventive surveillance program.
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http://dx.doi.org/10.1080/0284186X.2021.1914346DOI Listing
July 2021

TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma.

Authors:
Ylva Naeser Hildur Helgadottir Yvonne Brandberg Johan Hansson Roger Olofsson Bagge Nils O Elander Christian Ingvar Karolin Isaksson Petra Flygare Cecilia Nilsson Frida Jakobsson Olga Del Val Munoz Antonis Valachis Malin Jansson Charlotte Sparring Lars Ohlsson Ulf Dyrke Dimitrios Papantoniou Anders Sundin Gustav J Ullenhag

BMC Cancer 2020 Dec 7;20(1):1197. Epub 2020 Dec 7.

Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck laboratory, 75185, Uppsala, Sweden.

Background: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only.

Methods: The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group.

Discussion: This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM.

Results: The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden.

Trial Registration: ClinicalTrials.gov , NCT03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412.
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http://dx.doi.org/10.1186/s12885-020-07632-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720485PMC
December 2020

Surgery of metastatic melanoma after systemic therapy - the SUMMIST trial: study protocol for a randomized controlled trial.

Authors:
Carl Jacob Holmberg Dimitrios Katsarelias Henrik Jespersen Ana Carneiro Nils O Elander Hildur Helgadottir Karolin Isaksson Malin Jansson Sara Wirén Gustav J Ullenhag Lars Ny Roger Olofsson Bagge

Acta Oncol 2021 Jan 30;60(1):52-55. Epub 2020 Nov 30.

Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

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http://dx.doi.org/10.1080/0284186X.2020.1846213DOI Listing
January 2021

Sentinel node biopsy in cutaneous melanoma patients with germline CDKN2A mutations.

Authors:
Norbertus A Ipenburg Jos A van der Hage Julia A Newton-Bishop Mark Harland Nicole A Kukutsch Hildur Helgadottir Maarten H Vermeer Omgo E Nieweg Remco van Doorn

Melanoma Res 2020 12;30(6):630-631

Department of Dermatology.

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http://dx.doi.org/10.1097/CMR.0000000000000676DOI Listing
December 2020

Multiple Primary Melanoma Incidence Trends Over Five Decades: A Nationwide Population-Based Study.

Authors:
Hildur Helgadottir Karolin Isaksson Ildiko Fritz Christian Ingvar Jan Lapins Veronica Höiom Julia Newton-Bishop Håkan Olsson

J Natl Cancer Inst 2021 03;113(3):318-328

Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.

Background: Over the past decades, many regions have experienced a steady increase in the incidence of cutaneous melanoma. Here, we report on incidence trends for subsequent primary melanoma.

Methods: In this nationwide population-based study, patients diagnosed with a first primary cutaneous melanoma reported to the Swedish Cancer Registry were followed for up to 10 years for a diagnosis of subsequent primary melanoma. Patients were grouped with patients diagnosed with first melanoma in the same decade (1960s, 1970s, 1980s, 1990s, and 2000s, respectively). Frequencies, incidence rates (IRs), standardized incidence ratios (SIRs), and 95% confidence intervals (CIs) for second melanomas were calculated. All tests of statistical significance were 2-sided.

Results: Of patients with melanoma, 54 884 were included and 2469 were diagnosed, within 10 years, with subsequent melanomas. Over the 5 decades, there was a statistically significant steady increase in the frequency, IR, and SIR for second primary melanoma. For example, in the 1960s cohort, less than 1% (IR = 1.0, 95% CI = 0.5 to 1.7, and IR = 1.1, 95% CI = 0.5 to 1.9 per 1000 person-years in women and men, respectively) had second primary melanoma, and this rose to 6.4% (IR = 7.5, 95% CI = 6.8 to 8.3, per 1000 person-years) in the women and 7.9% (IR = 10.3, 95% CI = 9.3 to 11.2, per 1000 person-years) in the men in the 2000s cohort. This rise was seen independent of age, sex, invasiveness, or site of the melanoma. Further, in patients diagnosed with a second melanoma, the frequency of those having more than 2 melanomas increased statistically significantly and was 0.0% in the 1960s and rose to 18.0% in the 2000s (P < .001).

Conclusions: This is the first study to evaluate and report on a rising trend for subsequent primary melanoma. Additional primary melanomas worsen the patients' survival, and precautions are needed to turn this steep upgoing trend.
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http://dx.doi.org/10.1093/jnci/djaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936055PMC
March 2021

Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study): protocol for a multicenter phase II open label study.

Authors:
Henrik Jespersen Roger Olofsson Bagge Gustav Ullenhag Ana Carneiro Hildur Helgadottir Ingrid Ljuslinder Max Levin Charlotta All-Eriksson Bengt Andersson Ulrika Stierner Lisa M Nilsson Jonas A Nilsson Lars Ny

BMC Cancer 2019 05 2;19(1):415. Epub 2019 May 2.

Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 2, 413 45, Gothenburg, Sweden.

Background: While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.

Methods: The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months.

Discussion: The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.

Trial Registration: ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.
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http://dx.doi.org/10.1186/s12885-019-5623-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498539PMC
May 2019

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

Authors:
Sebastian Walpole Antonia L Pritchard Colleen M Cebulla Robert Pilarski Meredith Stautberg Frederick H Davidorf Arnaud de la Fouchardière Odile Cabaret Lisa Golmard Dominique Stoppa-Lyonnet Erin Garfield Ching-Ni Njauw Mitchell Cheung Joni A Turunen Pauliina Repo Reetta-Stiina Järvinen Remco van Doorn Martine J Jager Gregorius P M Luyten Marina Marinkovic Cindy Chau Miriam Potrony Veronica Höiom Hildur Helgadottir Lorenza Pastorino William Bruno Virginia Andreotti Bruna Dalmasso Giulia Ciccarese Paola Queirolo

J Natl Cancer Inst 2018 12;110(12):1328-1341

Medical Oncology Unit, Ospedale Policlinico San Martino, Genoa, Italy.

Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors.

Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided.

Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001).

Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.
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http://dx.doi.org/10.1093/jnci/djy171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292796PMC
December 2018

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline mutations.

Authors:
Hildur Helgadottir Paola Ghiorzo Remco van Doorn Susana Puig Max Levin Richard Kefford Martin Lauss Paola Queirolo Lorenza Pastorino Ellen Kapiteijn Miriam Potrony Cristina Carrera Håkan Olsson Veronica Höiom Göran Jönsson

J Med Genet 2020 05 5;57(5):316-321. Epub 2018 Oct 5.

Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.

Background: Inherited mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in mutation carriers with metastatic melanoma were evaluated.

Methods: mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic mutation were analysed for association with tumour mutational load.

Results: Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without mutation (Wilcoxon test, p<0.001).

Conclusion: Patients with mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.
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http://dx.doi.org/10.1136/jmedgenet-2018-105610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231460PMC
May 2020

Personalized Medicine in Malignant Melanoma: Towards Patient Tailored Treatment.

Authors:
Hildur Helgadottir Iara Rocha Trocoli Drakensjö Ada Girnita

Front Oncol 2018 12;8:202. Epub 2018 Jun 12.

Skin Tumor Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.

Despite enormous international efforts, skin melanoma is still a major clinical challenge. Melanoma takes a top place among the most common cancer types and it has one of the most rapidly increasing incidences in many countries around the world. Until recent years, there have been limited options for effective systemic treatment of disseminated melanoma. However, lately, we have experienced a rapid advancement in the understanding of the biology and molecular background of the disease. This has led to new molecular classifications and the development of more effective targeted therapies adapted to distinct melanoma subtypes. Not only are these treatments more effective but they can be rationally prescribed to the patients standing to benefit. As such, melanoma management has now become one of the most developed for personalized medicine. The aim of the present paper is to summarize the current knowledge on melanoma molecular classification, predictive markers, combination therapies, as well as emerging new treatments.
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http://dx.doi.org/10.3389/fonc.2018.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006716PMC
June 2018

CM-Score: a validated scoring system to predict germline mutations in melanoma families from Northern Europe.

Authors:
Thomas P Potjer Hildur Helgadottir Mirjam Leenheer Nienke van der Stoep Nelleke A Gruis Veronica Höiom Håkan Olsson Remco van Doorn Hans F A Vasen Christi J van Asperen Olaf M Dekkers Frederik J Hes

J Med Genet 2018 10 16;55(10):661-668. Epub 2018 Apr 16.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Several factors have been reported that influence the probability of a germline mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family.

Methods: Five clinical features and their association with mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (()) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with mutation).

Results: All five features were significantly associated (p<0.05) with a mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to >90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98).

Conclusion: We developed a practical scoring system to predict mutation status among melanoma-prone families. We suggest that analysis should be recommended to families with a CM-Score of ≥16 points.
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http://dx.doi.org/10.1136/jmedgenet-2017-105205DOI Listing
October 2018

Phenocopies in melanoma-prone families with germ-line CDKN2A mutations.

Authors:
Hildur Helgadottir Håkan Olsson Margaret A Tucker Xiaohong R Yang Veronica Höiom Alisa M Goldstein

Genet Med 2018 09 7;20(9):1087-1090. Epub 2017 Dec 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: Carriers of CDKN2A mutations have high risks of melanoma and certain other cancers. In this study we examined the occurrence of tumors among CDKN2A wild type (wt) members of melanoma-prone families with CDKN2A mutations.

Methods: Swedish and US melanoma-prone families with CDKN2A mutations were included. Data was collected on tumors diagnosed among family members. Among the CDKN2A mutated families, members with CDKN2A wt status who were diagnosed with melanoma were designated phenocopies.

Results: Of patients with melanoma in the CDKN2A mutated families (n = 266), 7.1%, were seen among members with CDKN2A wt status (phenocopy rate). Among the CDKN2A wt family members of the CDKN2A mutated families (n = 256), 7.4% were diagnosed with melanoma. The prospective relative risk for melanomas was significantly higher among the CDKN2A wt subjects compared with population-based controls (7.4 (95% confidence interval 1.7-33.2)), while no elevated risks of nonmelanoma cancers were seen and their offspring did not have significantly elevated risks of melanoma or other cancers.

Conclusion: Members of CDKN2A mutation carrying families who test negative for their family's mutation have moderately increased risk for melanoma and should, in addition to being considered for continuing dermatologic surveillance, be encouraged to follow sun safety recommendations and practice skin self-exams.
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http://dx.doi.org/10.1038/gim.2017.216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916246PMC
September 2018

Cancer risks and survival in patients with multiple primary melanomas: Association with family history of melanoma and germline CDKN2A mutation status.

Authors:
Hildur Helgadottir Rainer Tuominen Håkan Olsson Johan Hansson Veronica Höiom

J Am Acad Dermatol 2017 Nov 14;77(5):893-901. Epub 2017 Aug 14.

Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Background: Worse outcomes have been noted in patients with multiple primary melanomas (MPMs) than in patients with single primary melanomas.

Objective: We investigated how family history of melanoma and germline CDKN2A mutation status of MPM patients affects risks of developing subsequent melanomas and other cancers and survival outcomes.

Methods: Comprehensive data on cancer diagnoses and deaths of MPM patients, their first-degree relatives, and matched controls were obtained through Swedish national health care and population registries.

Results: Familial MPM cases with germline CDKN2A mutations were youngest at the diagnosis of their second melanoma (median age 42 years) and had among the MPM cohorts the highest relative risks (RR) compared to controls of developing >2 melanomas (RR 238.4, 95% CI 74.8-759.9). CDKN2A mutated MPM cases and their first-degree relatives were the only cohorts with increased risks of nonskin cancers compared to controls (RR 3.6, 95% CI 1.9-147.1 and RR 3.2, 95% CI 1.9-5.6, respectively). In addition, CDKN2A mutated MPM cases had worse survival compared with both cases with familial (HR 3.0, 95% CI 1.3-8.1) and sporadic wild-type MPM (HR 2.63, 95% CI 1.3-5.4).

Limitations: Our study examined outcomes in subgroups of MPM patients, which affected the sample size of the study groups.

Conclusion: This study demonstrates that CDKN2A mutation status and family history of melanoma significantly affects outcomes of MPM patients.
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http://dx.doi.org/10.1016/j.jaad.2017.05.050DOI Listing
November 2017

[The melanoma incidence continues to rise].

Authors:
Hildur Helgadottir Ulrika Stierner

Lakartidningen 2017 05 9;114. Epub 2017 May 9.

Sahlgrenska universitetssjukhuset - Goteborg, Sweden Sahlgrenska universitetssjukhuset - Goteborg, Sweden.

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May 2017

[Increased knowledge on familial melanoma and the underlying genetics].

Authors:
Hildur Helgadottir Kari Nielsen Veronica Höiom

Lakartidningen 2017 05 9;114. Epub 2017 May 9.

Karolinska Institutet - Stockholm, Sweden Karolinska Institutet - Stockholm, Sweden.

Increased knowledge on familial melanoma and the underlying genetics Approximately 5-10 % of all melanoma patients have close relatives with melanoma. 5-20% of melanoma families have germline mutations in the CDKN2A gene. Swedish CDKN2A mutation carriers have a young median age of onset of melanoma, increased risks of multiple primary melanoma and of tobacco-associated cancers in respiratory and upper digestive tissues, and also worse survival compared to non-carriers. In up to 80% of melanoma families no high risk melanoma associated germline mutations are found. In a few (non-Swedish) melanoma families, mutations in other genes have been found, including CDK4, TERT, POT1, ACD and TERF2IP. In some families with multiple cases of uveal and cutaneous melanoma (including a few Swedish families), mutations in the BAP1 gene have been found. In genes that regulate cellular pigmentation pathways, including MC1R, ASIP, IRF4, TYR, TYRP1 and OCA, there are different common variants that determine complexion traits, and those variants are also associated with different risks of melanoma. Members belonging to identified melanoma families require close follow-up with dermatologic exams. Individuals with known mutations in tumor suppressor genes such as CDKN2A and BAP1 require, in addition, follow up for other cancers.
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May 2017

Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation.

Authors:
Elizabeth M Kass Pei Xin Lim Hildur R Helgadottir Mary Ellen Moynahan Maria Jasin

Nat Commun 2016 10 25;7:13241. Epub 2016 Oct 25.

Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.

The mammary gland undergoes significant proliferative stages after birth, but little is known about how the developmental changes impact DNA double-strand break (DSB) repair. Mutations in multiple genes involved in homology-directed repair (HDR), considered a particularly accurate pathway for repairing DSBs, are linked to breast cancer susceptibility, including BRCA2. Using reporter mice that express an inducible endonuclease, we find that HDR is particularly robust in mammary tissue during puberty and pregnancy, accounting for 34-40% of detected repair events, more than in other tissues examined. Brca2 hypomorphic mutation leads to HDR defects in mammary epithelium during puberty and pregnancy, including in different epithelial lineages. Notably, a similar dependence on Brca2 is observed in other proliferative tissues, including small intestine epithelium. Our results suggest that the greater reliance on HDR in the proliferating mammary gland, rather than a specific dependence on BRCA2, may increase its susceptibility to tumorigenesis incurred by BRCA2 mutation.
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http://dx.doi.org/10.1038/ncomms13241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093336PMC
October 2016

The genetics of uveal melanoma: current insights.

Authors:
Hildur Helgadottir Veronica Höiom

Appl Clin Genet 2016 6;9:147-55. Epub 2016 Sep 6.

Department of Oncology and Pathology, Karolinska institutet.

Uveal melanoma (UM) is the most common malignant eye tumor in adults affecting ~7,000 individuals per year worldwide. UM is a rare subtype of melanoma with distinct clinical and molecular features as compared to other melanoma subtypes. UMs lack the most typical cutaneous melanoma-associated mutations (BRAF, NRAS, and NF1) and are instead characterized by a different set of genes with oncogenic or loss-of-function mutations. By next-generation sequencing efforts on UM tumors, several driver genes have been detected. The most frequent ones are BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. In many cases, mutations in these genes appear in a mutually exclusive manner, have different risk of metastasis, and are consequently of prognostic importance. The majority of UM cases are sporadic but a few percentage of the cases occurs in families with an inherited predisposition for this malignancy. In recent years, germline mutations in the BAP1 gene have been found to segregate in an autosomal dominant pattern with numerous different cancer types including UM in cancer-prone families. This cancer syndrome has been denoted as the tumor predisposition syndrome.
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http://dx.doi.org/10.2147/TACG.S69210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019476PMC
September 2016

Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations.

Authors:
Xiaohong R Yang Melissa Rotunno Yanzi Xiao Christian Ingvar Hildur Helgadottir Lorenza Pastorino Remco van Doorn Hunter Bennett Cole Graham Joshua N Sampson Michael Malasky Aurelie Vogt Bin Zhu Giovanna Bianchi-Scarra William Bruno Paola Queirolo Giuseppe Fornarini Johan Hansson Rainer Tuominen Laurie Burdett Belynda Hicks Amy Hutchinson Kristine Jones Meredith Yeager Stephen J Chanock Maria Teresa Landi Veronica Höiom Håkan Olsson Nelleke Gruis Paola Ghiorzo

Hum Genet 2016 Nov 23;135(11):1241-1249. Epub 2016 Jul 23.

Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.

The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A- cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A- PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A- PC patients. Further, nine CDKN2A+ and four CDKN2A- PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A- PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A- PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.
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http://dx.doi.org/10.1007/s00439-016-1715-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152573PMC
November 2016

Germline CDKN2A Mutation Status and Survival in Familial Melanoma Cases.

Authors:
Hildur Helgadottir Veronica Höiom Rainer Tuominen Kari Nielsen Göran Jönsson Håkan Olsson Johan Hansson

J Natl Cancer Inst 2016 11 10;108(11). Epub 2016 Jun 10.

Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).

Background: Germline mutations in CDKN2A have been associated with increased risk of melanoma and tobacco-related cancers in respiratory and upper digestive tissues. In CDKN2A wild-type (wt) melanoma families, other known high-risk, melanoma-predisposing mutations are rare, and no increased risk has been observed for nonskin cancers in this group. This study is the first to compare survival in germline CDKN2A mutated (mut) and nonmutated melanoma cases.

Methods: Melanoma-prone families participating in this study were identified through a nationwide predictive program starting in 1987. Information on cancer diagnoses (types, stages, and dates) and deaths (causes and dates) were obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan Meier and Cox proportional hazards regression models were used to assess survival in CDKN2A(mut) (n = 96) and CDKN2A(wt) (n = 377) familial melanoma cases and in matched sporadic melanoma cases (n = 1042). All statistical tests were two-sided.

Results: When comparing CDKN2A(mut) and CDKN2A(wt) melanoma cases, after adjusting for age, sex, and T classification, CDKN2A(mut) had worse survival than melanoma (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.49 to 4.21) and than nonmelanoma cancers (HR = 7.77, 95% CI = 3.65 to 16.51). Compared with matched sporadic cases, CDKN2A(mut) cases had statistically significantly worse survival from both melanoma and nonmelanoma cancers while no differences in survival were seen in CDKN2A(wt) compared with sporadic cases.

Conclusions: CDKN2A(mut) cases had statistically significantly worse survival than nonmelanoma cancers and, intriguingly, also from melanoma, compared with melanoma cases with no CDKN2A mutations. Further studies are required to elucidate possible mechanisms behind increased carcinogen susceptibility and the more aggressive melanoma phenotype in CDKN2A mutation carriers.
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http://dx.doi.org/10.1093/jnci/djw135DOI Listing
November 2016

The role of germline alterations in the DNA damage response genes BRIP1 and BRCA2 in melanoma susceptibility.

Authors:
Rainer Tuominen Pär G Engström Hildur Helgadottir Hanna Eriksson Per Unneberg Sanela Kjellqvist Muyi Yang Diana Lindén Daniel Edsgärd Johan Hansson Veronica Höiom

Genes Chromosomes Cancer 2016 07 2;55(7):601-11. Epub 2016 May 2.

Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety-two high-risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell-cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22363DOI Listing
July 2016

CDKN2a mutation-negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies.

Authors:
Hildur Helgadottir Veronica Höiom Rainer Tuominen Göran Jönsson Eva Månsson-Brahme Håkan Olsson Johan Hansson

Int J Cancer 2015 Nov 21;137(9):2220-6. Epub 2015 May 21.

Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.

Germline CDKN2A mutations are found in 5-20% of melanoma families. Numerous studies have shown that carriers of CDKN2A mutations have increased risks of non-melanoma cancers, but so far there have been no studies investigating cancer risks in CDKN2A wild type (wt) melanoma families. In this prospective cohort study, index melanoma cases (n = 224) and their first-degree relatives (n = 944) were identified from 154 confirmed CDKN2A wt melanoma families. Cancer diagnoses in family members and matched controls were obtained from the Swedish Cancer Registry. Relative risks (RR), odds ratios (OR) and two-sided 95% confidence intervals (95% CI) were calculated. In index cases and first-degree relatives, the prospective RR for melanoma was 56.9 (95% CI 31.4-102.1) and 7.0 (95% CI 4.2-11.4), respectively, and for squamous cell skin cancers 9.1 (95% CI 6.0-13.7) and 3.4 (95% CI 2.2-5.2), respectively. In neither group, elevated risks were seen for non-skin cancers. In a subgroup analysis, CDKN2A wt melanoma families with young (<40 years) melanoma cases were found to have increased risk of non-skin cancers (RR 1.5, 95% CI 1.0-1.5). Further, MC1R gene variants were increased in familial melanoma cases compared to controls (OR 2.4, 95% CI 1.6-3.4). Our findings suggest that in the majority of CDKN2A wt melanoma families, a segregation of variants in low-risk melanoma genes such as MC1R causes increased skin cancer susceptibility, rather than mutations in high-risk cancer predisposing genes, such mutations are more probable to be found in melanoma families with young melanoma cases. This study further supports an implication of CDKN2A mutation screening as a clinical test that determines counseling and follows up routines of melanoma families.
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http://dx.doi.org/10.1002/ijc.29595DOI Listing
November 2015

High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families.

Authors:
Hildur Helgadottir Veronica Höiom Göran Jönsson Rainer Tuominen Christian Ingvar Ake Borg Håkan Olsson Johan Hansson

J Med Genet 2014 Aug 16;51(8):545-52. Epub 2014 Jun 16.

Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Background: Germline mutations in the tumour suppressor gene CDKN2A occur in 5-20% of familial melanoma cases. A single founder mutation, p.Arg112dup, accounts for the majority of CDKN2A mutations in Swedish carriers. In a national program, carriers of p.Arg112dup mutation have been identified. The aim of this study was to assess cancer risks in p.Arg112dup carriers and their first degree relatives (FDRs) and second degree relatives (SDRs).

Methods: In this prospective cohort study, cancer diagnoses in carriers (n=120), non-carriers (n=111), carriers' FDRs (n=275) and SDRs (n=321) and controls (n=3976) were obtained from the Swedish Cancer Registry. Relative risks (RRs) for cancers were calculated (number of cancers/person years). Two-sided 95% CIs were calculated for all RRs.

Results: In carriers prospective RR for non-melanoma cancers was 5.0 (95% CI 3.7 to 7.3), for pancreatic cancer 43.8 (95% CI 13.8 to 139.0), for cancers in upper digestive tissues 17.1 (95% CI 6.3 to 46.5), and in respiratory tissues 15.6 (5.4 to 46.0). In FDRs and SDRs RRs were significantly elevated for cancers in pancreas, respiratory and upper digestive tissues. In ever-smoking carriers compared with never-smoking carriers, the odds ratio (OR) of cancers in pancreas, respiratory or upper digestive tissues was 9.3 (95% CI 1.9 to 44.7).

Conclusions: CDKN2A p.Arg112dup mutation carriers from melanoma-prone families and their FDRs and SDRs have elevated risk for pancreatic, lung, head and neck and gastro-oesophageal carcinomas. These cancers were mainly seen in ever-smoking carriers. Germline CDKN2A mutations may confer an increased sensitivity to carcinogens in tobacco smoke. CDKN2A mutation carriers should be counselled to abstain from smoking.
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http://dx.doi.org/10.1136/jmedgenet-2014-102320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112445PMC
August 2014

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase.

Authors:
Elizabeth M Kass Hildur R Helgadottir Chun-Chin Chen Maria Barbera Raymond Wang Ulrica K Westermark Thomas Ludwig Mary Ellen Moynahan Maria Jasin

Proc Natl Acad Sci U S A 2013 Apr 18;110(14):5564-9. Epub 2013 Mar 18.

Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.

Homology-directed repair (HDR) is a critical pathway for the repair of DNA double-strand breaks (DSBs) in mammalian cells. Efficient HDR is thought to be crucial for maintenance of genomic integrity during organismal development and tumor suppression. However, most mammalian HDR studies have focused on transformed and immortalized cell lines. We report here the generation of a Direct Repeat (DR)-GFP reporter-based mouse model to study HDR in primary cell types derived from diverse lineages. Embryonic and adult fibroblasts from these mice as well as cells derived from mammary epithelium, ovary, and neonatal brain were observed to undergo HDR at I-SceI endonuclease-induced DSBs at similar frequencies. When the DR-GFP reporter was crossed into mice carrying a hypomorphic mutation in the breast cancer susceptibility gene Brca1, a significant reduction in HDR was detected, showing that BRCA1 is critical for HDR in somatic cell types. Consistent with an HDR defect, Brca1 mutant mice are highly sensitive to the cross-linking agent mitomycin C. By contrast, loss of the DSB signaling ataxia telangiectasia-mutated (ATM) kinase did not significantly alter HDR levels, indicating that ATM is dispensable for HDR. Notably, chemical inhibition of ATM interfered with HDR. The DR-GFP mouse provides a powerful tool for dissecting the genetic requirements of HDR in a diverse array of somatic cell types in a normal, nontransformed cellular milieu.
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http://dx.doi.org/10.1073/pnas.1216824110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619303PMC
April 2013

Hereditary uveal melanoma: a report of a germline mutation in BAP1.

Authors:
Veronica Höiom Daniel Edsgärd Hildur Helgadottir Hanna Eriksson Charlotta All-Ericsson Rainer Tuominen Ivayla Ivanova Joakim Lundeberg Olof Emanuelsson Johan Hansson

Genes Chromosomes Cancer 2013 Apr 23;52(4):378-84. Epub 2013 Jan 23.

Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.

Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome-wide analysis identified a novel loss-of-function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild-type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis.
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http://dx.doi.org/10.1002/gcc.22035DOI Listing
April 2013

Early vascular deficits are correlated with delayed mammary tumorigenesis in the MMTV-PyMT transgenic mouse following genetic ablation of the NG2 proteoglycan.

Authors:
Krissa Gibby Weon-Kyoo You Kuniko Kadoya Hildur Helgadottir Lawrence Jt Young Lesley G Ellies Yunchao Chang Robert D Cardiff William B Stallcup

Breast Cancer Res 2012 Apr 24;14(2):R67. Epub 2012 Apr 24.

Cancer Center, Tumor Microenvironment Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 USA.

Introduction: The neuron-glial antigen 2 (NG2) proteoglycan promotes pericyte recruitment and mediates pericyte interaction with endothelial cells. In the absence of NG2, blood vessel development is negatively impacted in several pathological models. Our goal in this study was to determine the effect of NG2 ablation on the early development and function of blood vessels in mammary tumors in the mammary tumor virus-driven polyoma middle T (MMTV-PyMT) transgenic mouse, and to correlate these vascular changes with alterations in mammary tumor growth.

Methods: Three different tumor paradigms (spontaneous tumors, transplanted tumors, and orthotopic allografts of tumor cell lines) were used to investigate the effects of NG2 ablation on breast cancer progression in the MMTV-PyMT transgenic mouse. In addition to examining effects of NG2 ablation on mammary tumor growth, we also investigated effects on the structure and function of tumor vasculature.

Results: Ablation of NG2 led to reduced early progression of spontaneous, transplanted, and orthotopic allograft mammary tumors. NG2 was not expressed by the mammary tumor cells themselves, but instead was found on three components of the tumor stroma. Microvascular pericytes, myeloid cells, and adipocytes were NG2-positive in both mouse and human mammary tumor stroma. The effect of NG2 on tumor progression therefore must be stromal in nature. Ablation of NG2 had several negative effects on early development of the mammary tumor vasculature. In the absence of NG2, pericyte ensheathment of endothelial cells was reduced, along with reduced pericyte maturation, reduced sprouting of endothelial cells, reduced assembly of the vascular basal lamina, and reduced tumor vessel diameter. These early deficits in vessel structure are accompanied by increased vessel leakiness, increased tumor hypoxia, and decreased tumor growth. NG2 ablation also diminishes the number of tumor-associated and TEK tyrosine kinase endothelial (Tie2) expressing macrophages in mammary tumors, providing another possible mechanism for reducing tumor vascularization and growth.

Conclusions: These results emphasize the importance of NG2 in mediating pericyte/endothelial cell communication that is required for proper vessel maturation and function. In the absence of normal pericyte/endothelial cell interaction, poor vascular function results in diminished early progression of mammary tumors.
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http://dx.doi.org/10.1186/bcr3174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446402PMC
April 2012

RAD51 can inhibit PDGF-B-induced gliomagenesis and genomic instability.

Authors:
Ulrica K Westermark Nanna Lindberg Pernilla Roswall Daniel Bråsäter Hildur R Helgadottir Sanna-Maria Hede Anders Zetterberg Maria Jasin Monica Nistér Lene Uhrbom

Neuro Oncol 2011 Dec 16;13(12):1277-87. Epub 2011 Sep 16.

Karolinska Institutet, Department of Oncology-Pathology, Stockholm, Sweden.

Faithful replication and DNA repair are vital for maintenance of genome integrity. RAD51 is a central protein in homologous recombination repair and during replication, when it protects and restarts stalled replication forks. Aberrant RAD51 expression occurs in glioma, and high expression has been shown to correlate with prolonged survival. Furthermore, genes involved in DNA damage response (DDR) are mutated or deleted in human glioblastomas, corroborating the importance of proper DNA repair to suppress gliomagenesis. We have analyzed DDR and genomic instability in PDGF-B-induced gliomas and investigated the role of RAD51 in glioma development. We show that PDGF-B-induced gliomas display genomic instability and that co-expression of RAD51 can suppress PDGF-B-induced tumorigenesis and prolong survival. Expression of RAD51 inhibited proliferation and genomic instability of tumor cells independent of Arf status. Our results demonstrate that the RAD51 pathway can prevent glioma initiation and maintain genome integrity of induced tumors, suggesting reactivation of the RAD51 pathway as a potential therapeutic avenue.
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http://dx.doi.org/10.1093/neuonc/nor131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223091PMC
December 2011

The common Scandinavian human leucocyte antigen ancestral haplotype 62.1 as prognostic factor in patients with advanced malignant melanoma.

Authors:
Hildur Helgadottir Emilia Andersson Lisa Villabona Lena Kanter Henk van der Zanden Geert W Haasnoot Barbara Seliger Kjell Bergfeldt Johan Hansson Boel Ragnarsson-Olding Rolf Kiessling Giuseppe Valentino Masucci

Cancer Immunol Immunother 2009 Oct 13;58(10):1599-608. Epub 2009 Feb 13.

Department of Oncology-Pathology, Karolinska Institute, Radiumhemmet, Karolinska University Hospital, 171 76, Stockholm, Sweden.

Purpose: We have previously demonstrated an association of the human leukocyte antigen (HLA), HLA-A2 allele with ovarian and prostate cancer mortality as well as a segregation of the ancestral HLA haplotype (AHH) 62.1 [(A2) B15 Cw3 DRB1*04] in patients with stage III-IV serous ovarian cancer. The objective of the present study was to determine the role of the HLA phenotype on the prognosis in stage III-IV malignant melanoma patients.

Patients And Methods: A cohort of metastatic malignant melanoma patients (n = 91), in stage III (n = 26) or IV (n = 65) were analysed for HLA-A, -B, -Cw and -DRB1 types by PCR/sequence-specific primer method. The frequencies of HLA alleles in the patients were compared to that of healthy Swedish bone marrow donors. The effect of HLA types on prognosis was defined by Kaplan-Meier and Cox analysis.

Results: The presence of the AHH 62.1 in clinical stage IV patients was significantly and independently associated with the worst survival rate recorded from the appearance of metastasis (HR = 2.14; CI = 1.02-4.4; P = 0.04). In contrast, the period from the primary diagnosis to metastasis was the longest in patients with this haplotype (HR = 0.40; CI = 0.17-0.90; P = 0.02).

Conclusions: Melanoma patients in our cohort with 62.1 AHH which is associated with autoimmune diseases have an initial strong anti-tumour control with longer metastasis-free period. These patients have rapid progression after the appearance of metastasis, responding poorly to chemo- or/and immunotherapy. This apparently paradoxical clinical process could be due to the interplay between tumour clones escape and immune surveillance ending up with a rapid disease progression.
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http://dx.doi.org/10.1007/s00262-009-0669-8DOI Listing
October 2009

Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis.

Authors:
Christos Gekas Katrin E Rhodes Laurraine M Gereige Hildur Helgadottir Roberto Ferrari Siavash K Kurdistani Encarnación Montecino-Rodriguez Rhonda Bassel-Duby Eric Olson Andrei V Krivtsov Scott Armstrong Stuart H Orkin Matteo Pellegrini Hanna K A Mikkola

Blood 2009 Apr 11;113(15):3461-71. Epub 2009 Feb 11.

Department of Molecular, Cell and Developmental Biology, University of California-Los Angeles, Los Angeles, CA 90095, USA.

The basic helix-loop-helix transcription factor stem cell leukemia gene (Scl) is a master regulator for hematopoiesis essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. Here, we identified a novel Scl target gene, transcription factor myocyte enhancer factor 2 C (Mef2C) from Scl(fl/fl) fetal liver progenitor cell lines. Analysis of Mef2C(-/-) embryos showed that Mef2C, in contrast to Scl, is not essential for specification into primitive or definitive hematopoietic lineages. However, adult VavCre(+)Mef2C(fl/fl) mice exhibited platelet defects similar to those observed in Scl-deficient mice. The platelet counts were reduced, whereas platelet size was increased and the platelet shape and granularity were altered. Furthermore, megakaryopoiesis was severely impaired in vitro. Chromatin immunoprecipitation microarray hybridization analysis revealed that Mef2C is directly regulated by Scl in megakaryocytic cells, but not in erythroid cells. In addition, an Scl-independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice, characterized as severe age-dependent reduction of specific B-cell progenitor populations reminiscent of premature aging. In summary, this work identifies Mef2C as an integral member of hematopoietic transcription factors with distinct upstream regulatory mechanisms and functional requirements in megakaryocyte and B-lymphoid lineages.
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http://dx.doi.org/10.1182/blood-2008-07-167577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945827PMC
April 2009

Assaying double-strand break repair pathway choice in mammalian cells using a targeted endonuclease or the RAG recombinase.

Authors:
David M Weinstock Koji Nakanishi Hildur R Helgadottir Maria Jasin

Methods Enzymol 2006 ;409:524-40

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

DNA damage repair is essential for the maintenance of genetic integrity in all organisms. Unrepaired or imprecisely repaired DNA can lead to mutagenesis, cell death, or malignant transformation. DNA damage in the form of double-strand breaks (DSBs) can occur as a result of both exogenous insults, such as ionizing radiation and drug therapies, and normal metabolic processes including V(D)J recombination. Mammalian cells have multiple pathways for repairing DSBs, including nonhomologous end-joining (NHEJ), homologous recombination (HR), and single-strand annealing (SSA). This chapter describes the use of reporter substrates for assaying the contributions of these pathways to DSB repair in mammalian cells, in particular murine embryonic stem cells. The individual contributions of NHEJ, HR, and SSA can be quantified using fluorescence and PCR-based assays after the precise introduction of DSBs either by the I-SceI endonuclease or by the RAG recombinase. These reporters can be used to assess the effects of genetic background, dominant-negative constructs, or physiological conditions on DSB repair in a wide variety of mammalian cells.
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http://dx.doi.org/10.1016/S0076-6879(05)09031-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036680PMC
August 2006
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