title: Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma.
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.
authors.affiliation: Department of Medical Genetics Genome-Scale Biology Research Programs Unit.
authors.forename: Mervi
authors.initials: M
authors.lastname: Aavikko
authors.affiliation: Department of Medical Genetics Genome-Scale Biology Research Programs Unit.
authors.forename: Eevi
authors.initials: E
authors.lastname: Kaasinen
authors.affiliation: Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare.
authors.forename: Janne K
authors.initials: JK
authors.lastname: Nieminen
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University Howard Hughes Medical Institute.
authors.forename: Minji
authors.initials: M
authors.lastname: Byun
authors.affiliation: Department of Medical Genetics Genome-Scale Biology Research Programs Unit.
authors.forename: Iikki
authors.initials: I
authors.lastname: Donner
authors.affiliation: Don C. Gnocchi Foundation, ONLUS.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: Department of Biomedical, Surgery, and Dental Sciences.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Ferrante
authors.affiliation: Don C. Gnocchi Foundation, ONLUS Department of Physiopathology and Transplantation, University of Milan.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Dermatology Unit, IRCCS Ca' Granda Foundation-Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Brambilla
authors.affiliation: Dermatology Unit, IRCCS Ca' Granda Foundation-Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Tourlaki
authors.affiliation: Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Sarid
authors.affiliation: Department of Dermatology Immunology Institute, Mount Sinai Medical Center at Icahn School of Medicine, New York, New York.
authors.forename: Emma
authors.initials: E
authors.lastname: Guttman-Yassky
authors.affiliation: Genome-Scale Biology Research Programs Unit Science for Life Center Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Minna
authors.initials: M
authors.lastname: Taipale
authors.affiliation: Science for Life Center Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Morgunova
authors.affiliation: Genome-Scale Biology Research Programs Unit Institute of Biotechnology, University of Helsinki.
authors.forename: Pirita
authors.initials: P
authors.lastname: Pekkonen
authors.affiliation: Genome-Scale Biology Research Programs Unit Institute of Biotechnology, University of Helsinki Finnish Cancer Institute.
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Ojala
authors.affiliation: Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki School of Health Sciences, University of Tampere, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Pukkala
authors.affiliation: 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.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare.
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
authors.affiliation: Department of Medical Genetics Genome-Scale Biology Research Programs Unit.
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.affiliation: Department of Medical Genetics Genome-Scale Biology Research Programs Unit.
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D050797:STAT4 Transcription Factor / Q000235:genetics*; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes
chemical_list: D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D007371:Interferon-gamma
keywords: HHV8; STAT4; classic Kaposi sarcoma; genetic predisposition; genome sequencing