title: Enhanced lymphocyte interferon (IFN)-γ responses in a PTEN mutation-negative Cowden disease kindred.
abstract: Identification of immune modifiers of inherited cancer syndromes may provide a rationale for preventive therapy. Cowden disease (CD) is a genetically heterogeneous inherited cancer syndrome that arises predominantly from germline phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation and increased phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) signalling. However, many patients with classic CD diagnostic features are mutation-negative for PTEN (PTEN M-Neg). Interferon (IFN)-γ can modulate the PI3K/mTOR pathway, but its association with PTEN M-Neg CD remains unclear. This study assessed IFN-γ secretion by multi-colour flow cytometry in a CD kindred that was mutation-negative for PTEN and other known susceptibility genes. Because IFN-γ responses may be regulated by killer cell immunoglobulin-like receptors (KIR) and respective human leucocyte antigen (HLA) ligands, KIR/HLA genotypes were also assessed. Activating treatments induced greater IFN-γ secretion in PTEN M-Neg CD peripheral blood lymphocytes versus healthy controls. Increased frequency of activating KIR genes, potentially activating KIR/HLA compound genotypes and reduced frequency of inhibitory genotypes, were found in the PTEN M-Neg CD kindred. Differences of IFN-γ secretion were observed among PTEN M-Neg CD patients with distinct KIR/HLA compound genotypes. Taken together, these findings show enhanced lymphocyte secretion of IFN-γ that may influence the PI3K/mTOR CD causal molecular pathway in a PTEN mutation-negative CD kindred.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University of Belfast, UK.
authors.forename: R
authors.initials: R
authors.lastname: Stevenson
authors.forename: A
authors.initials: A
authors.lastname: Fatehullah
authors.forename: I
authors.initials: I
authors.lastname: Jagan
authors.forename: R K
authors.initials: RK
authors.lastname: Deevi
authors.forename: V
authors.initials: V
authors.lastname: Bingham
authors.forename: A E
authors.initials: AE
authors.lastname: Irvine
authors.forename: M
authors.initials: M
authors.lastname: Armstrong
authors.forename: P J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: I
authors.initials: I
authors.lastname: Dimmick
authors.forename: R
authors.initials: R
authors.lastname: Stewart
authors.forename: F C
authors.initials: FC
authors.lastname: Campbell
mesh_terms: D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006680:HLA Antigens / Q000096:biosynthesis; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics / Q000378:metabolism*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D051059:PTEN Phosphohydrolase / Q000032:analysis; D010375:Pedigree; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D054340:Receptors, KIR / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D006680:HLA Antigens; D007371:Interferon-gamma; D015759:Ionomycin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D054340:Receptors, KIR; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human