Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition.
Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein, we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumors that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition.
Department of Haematology, Imperial College London , London, UK.
Mohammed S
MS
Chaudhry
Department of Immunology, Great Ormond Street Hospital , London, UK.
Kimberly C
KC
Gilmour
Cancer Immunology Program, Peter MacCallum Cancer Center , East Melbourne, Victoria, Australia.
Imran G
IG
House
Department of Haematology, Imperial College London , London, UK.
Mark
M
Layton
Department of Haematology, Imperial College London , London, UK.
Nicki
N
Panoskaltsis
Department of Haematology, Ealing Hospital , London, UK.
Mamta
M
Sohal
Cancer Immunology Program, Peter MacCallum Cancer Center , East Melbourne, Victoria, Australia.
Joseph A
JA
Trapani
Cancer Immunology Program, Peter MacCallum Cancer Center , East Melbourne, Victoria, Australia.
Ilia
I
Voskoboinik
Hereditary cancer; perforin; protein misfolding