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Case Reports
. 2015 Jun 1;211(11):1842-51.
doi: 10.1093/infdis/jiu667. Epub 2014 Dec 9.

Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma

Mervi Aavikko  1 , Eevi Kaasinen  1 , Janne K Nieminen  2 , Minji Byun  3 , Iikki Donner  1 , Roberta Mancuso  4 , Pasquale Ferrante  5 , Mario Clerici  6 , Lucia Brambilla  7 , Athanasia Tourlaki  7 , Ronit Sarid  8 , Emma Guttman-Yassky  9 , Minna Taipale  10 , Ekaterina Morgunova  11 , Pirita Pekkonen  12 , Päivi M Ojala  13 , Eero Pukkala  14 , Jean-Laurent Casanova  15 , Outi Vaarala  2 , Pia Vahteristo  1 , Lauri A Aaltonen  1
Affiliations
Case Reports

Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma

Mervi Aavikko et al. J Infect Dis. .

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.

Keywords: HHV8; STAT4; classic Kaposi sarcoma; genetic predisposition; genome sequencing.

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