title: Human perforin mutations and susceptibility to multiple primary cancers.
abstract: Loss-of-function mutations in the gene coding for perforin (PRF1) markedly reduce the ability of cytotoxic T lymphocytes and natural killer cells to kill target cells, causing immunosuppression and impairing immune regulation. In humans, nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelicPRF1mutations. The partial inactivation of PRF1 due to mutations that promote protein misfolding or the common hypomorphic allele coding for the A91V substitution have been associated with lymphoid malignancies in childhood and adolescence. To investigate whetherPRF1mutations also predispose adults to cancer, we genotyped 566 individuals diagnosed with melanoma (101), lymphoma (65), colorectal carcinoma (30) or ovarian cancer (370). The frequency ofPRF1genotypes was similar in all disease groups and 424 matched controls, indicating that thePRF1status is not associated with an increased susceptibility to these malignancies. However, four out of 15 additional individuals diagnosed with melanoma and B-cell lymphoma during their lifetime expressed either PRF1A91Vor the rare pathogenic PRF1R28Cvariant (p = 0.04), and developed melanoma relatively early in life. Both PRF1A91V- and PRF1R28C-expressing lymphocytes exhibited severely impaired but measurable cytotoxic function. Our results suggest that defects in human PRF1 predispose individuals to develop both melanoma and lymphoma. However, these findings require validation in larger patient cohorts.
authors.affiliation: Cancer Immunology Program; Peter MacCallum Cancer Institute; East Melbourne, VIC Australia; and Sir Peter MacCallum Department of Oncology; The University of Melbourne; Melbourne, VIC Australia ; Research Division; Peter MacCallum Cancer Centre; East Melbourne, VIC Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Kevin Y T
authors.initials: KY
authors.lastname: Thia
authors.forename: Miles
authors.initials: M
authors.lastname: Andrews
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Craig
authors.initials: C
authors.lastname: Gedye
authors.forename: Philip
authors.initials: P
authors.lastname: Parente
authors.forename: Suzanne
authors.initials: S
authors.lastname: Svobodova
authors.forename: Jenny
authors.initials: J
authors.lastname: Chia
authors.forename: Kylie
authors.initials: K
authors.lastname: Browne
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.forename: Ilia
authors.initials: I
authors.lastname: Voskoboinik
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Cebon
keywords: A91V; FHL; dual tumors; lymphoma; melanoma; perforin