Mervi Aavikko1, Eevi Kaasinen1, Janne K Nieminen2, Minji Byun3, Iikki Donner1, Roberta Mancuso4, Pasquale Ferrante5, Mario Clerici6, Lucia Brambilla7, Athanasia Tourlaki7, Ronit Sarid8, Emma Guttman-Yassky9, Minna Taipale10, Ekaterina Morgunova11, Pirita Pekkonen12, Päivi M Ojala13, Eero Pukkala14, Jean-Laurent Casanova15, Outi Vaarala2, Pia Vahteristo1, Lauri A Aaltonen1. 1. Department of Medical Genetics Genome-Scale Biology Research Programs Unit. 2. Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare. 3. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University Howard Hughes Medical Institute. 4. Don C. Gnocchi Foundation, ONLUS. 5. Department of Biomedical, Surgery, and Dental Sciences. 6. Don C. Gnocchi Foundation, ONLUS Department of Physiopathology and Transplantation, University of Milan. 7. Dermatology Unit, IRCCS Ca' Granda Foundation-Ospedale Maggiore Policlinico, Milan, Italy. 8. Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel. 9. Department of Dermatology Immunology Institute, Mount Sinai Medical Center at Icahn School of Medicine, New York, New York. 10. Genome-Scale Biology Research Programs Unit Science for Life Center Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 11. Science for Life Center Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 12. Genome-Scale Biology Research Programs Unit Institute of Biotechnology, University of Helsinki. 13. Genome-Scale Biology Research Programs Unit Institute of Biotechnology, University of Helsinki Finnish Cancer Institute. 14. Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki School of Health Sciences, University of Tampere, Finland. 15. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University Howard Hughes Medical Institute Laboratory of Human Genetics of Infectious Diseases, Necker Hospital School for Sick Children Imagine Institute, University Paris Descartes, France.
Abstract
BACKGROUND: Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection. METHODS: We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family. RESULTS: We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C>T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon γ production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations. CONCLUSIONS: Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed.
BACKGROUND:Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection. METHODS: We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family. RESULTS: We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C>T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon γ production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations. CONCLUSIONS: Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed.
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