P. Du and . Marion, 14 Centre régional de transfusion sanguine de Sousse, CHU F. Hached, Avenue Ibn El Jazzar

A. Grakoui, S. Bromley, C. Sumen, M. Davis, A. Shaw et al., The Immunological Synapse: A Molecular Machine Controlling T Cell Activation, Science, vol.285, issue.5425, pp.221-227, 1999.
DOI : 10.1126/science.285.5425.221

J. Stinchcombe, G. Bossi, S. Booth, and G. Griffiths, The Immunological Synapse of CTL Contains a Secretory Domain and Membrane Bridges, Immunity, vol.15, issue.5, pp.751-761, 2001.
DOI : 10.1016/S1074-7613(01)00234-5

J. Lieberman, Cell death and immunity: The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal, Nature Reviews Immunology, vol.3, issue.5, pp.361-370, 2003.
DOI : 10.1038/nri1083

P. Bolitho, I. Voskoboinik, J. Trapani, and M. Smyth, Apoptosis induced by the lymphocyte effector molecule perforin, Current Opinion in Immunology, vol.19, issue.3, pp.339-347, 2007.
DOI : 10.1016/j.coi.2007.04.007

S. Stepp, R. Dufourcq-lagelouse, L. Deist, F. Bhawan, S. Certain et al., Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis, Science, vol.286, issue.5446, pp.1957-1959, 1999.
DOI : 10.1126/science.286.5446.1957

K. Goransdotter-ericson, B. Fadeel, S. Nilsson-ardnor, C. Soderhall, A. Samuelsson et al., Spectrum of Perforin Gene Mutations in Familial Hemophagocytic Lymphohistiocytosis, The American Journal of Human Genetics, vol.68, issue.3, pp.590-597, 2001.
DOI : 10.1086/318796

I. Ueda, A. Morimoto, T. Inaba, T. Yagi, S. Hibi et al., Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan, British Journal of Haematology, vol.44, issue.3, pp.503-510, 2003.
DOI : 10.1182/blood.V98.4.1268

N. Suga, H. Takada, A. Nomura, S. Ohga, E. Ishii et al., Perforin defects of primary haemophagocytic lymphohistiocytosis in Japan, British Journal of Haematology, vol.12, issue.2, pp.346-349, 2002.
DOI : 10.1126/science.286.5446.1957

M. Lee, S. Villanueva, J. Sumegi, J. Zhang, K. Kogawa et al., Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis, J Med Genet, vol.41, pp.137-144, 2004.

K. Kogawa, S. Lee, J. Villanueva, D. Marmer, J. Sumegi et al., Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members, Blood, vol.99, issue.1, pp.61-66, 2002.
DOI : 10.1182/blood.V99.1.61

E. Ishii, S. Ohga, S. Imashuku, N. Kimura, I. Ueda et al., Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences, Critical Reviews in Oncology/Hematology, vol.53, issue.3, pp.209-223, 2005.
DOI : 10.1016/j.critrevonc.2004.11.002

S. Imashuku, I. Ueda, T. Teramura, K. Mori, A. Morimoto et al., Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients, European Journal of Pediatrics, vol.41, issue.5, pp.315-319, 2005.
DOI : 10.1007/s00431-005-1636-9

J. Feldmann, L. Deist, F. Ouachee-chardin, M. Certain, S. Alexander et al., Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis, British Journal of Haematology, vol.18, issue.4, pp.965-972, 2002.
DOI : 10.1046/j.1365-2141.2002.03534.x

R. Clementi, U. Zur-stadt, G. Savoldi, S. Varoitto, V. Conter et al., Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis, Journal of Medical Genetics, vol.38, issue.9, pp.643-646, 2001.
DOI : 10.1136/jmg.38.9.643

H. Katano, M. Ali, A. Patera, M. Catalfamo, E. Jaffe et al., Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation, Blood, vol.103, issue.4, pp.1244-1252, 2004.
DOI : 10.1182/blood-2003-06-2171

R. Clementi, L. Emmi, R. Maccario, F. Liotta, L. Moretta et al., Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations, Blood, vol.100, issue.6, pp.2266-2267, 2002.
DOI : 10.1182/blood-2002-04-1030

R. Clementi, L. Dagna, U. Dianzani, L. Dupre, I. Dianzani et al., Mutations in a Patient with Autoimmune Lymphoproliferative Syndrome and Lymphoma, New England Journal of Medicine, vol.351, issue.14, pp.1419-1424, 2004.
DOI : 10.1056/NEJMoa041432

R. Clementi, F. Locatelli, L. Dupre, A. Garaventa, L. Emmi et al., A proportion of patients with lymphoma may harbor mutations of the perforin gene, Blood, vol.105, issue.11, pp.4424-4428, 2005.
DOI : 10.1182/blood-2004-04-1477

P. Bolitho, S. Street, J. Westwood, W. Edelmann, D. Macgregor et al., Perforin-mediated suppression of B-cell lymphoma, Proceedings of the National Academy of Sciences, vol.106, issue.8, pp.2723-2728, 2009.
DOI : 10.1073/pnas.0809008106
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650333

A. Corthay, D. Skovseth, K. Lundin, E. Rosjo, H. Omholt et al., Primary Antitumor Immune Response Mediated by CD4+ T Cells, Immunity, vol.22, issue.3, pp.371-383, 2005.
DOI : 10.1016/j.immuni.2005.02.003
URL : http://doi.org/10.1016/j.immuni.2005.02.003

S. Street, Y. Hayakawa, Y. Zhan, A. Lew, D. Macgregor et al., Innate Immune Surveillance of Spontaneous B Cell Lymphomas by Natural Killer Cells and ???? T Cells, The Journal of Experimental Medicine, vol.154, issue.6, pp.879-884, 2004.
DOI : 10.1073/pnas.201238598

L. Zitvogel, A. Tesniere, and G. Kroemer, Cancer despite immunosurveillance: immunoselection and immunosubversion, Nature Reviews Immunology, vol.65, issue.10, pp.715-727, 2006.
DOI : 10.1038/nri1936

D. Kagi, F. Vignaux, B. Ledermann, K. Burki, V. Depraetere et al., Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity, Science, vol.265, issue.5171, pp.528-530, 1994.
DOI : 10.1126/science.7518614

M. Smyth, K. Thia, E. Cretney, J. Kelly, M. Snook et al., Perforin is a major contributor to NK cell control of tumor metastasis, J Immunol, vol.162, pp.6658-6662, 1999.

M. Smyth, K. Thia, S. Street, D. Macgregor, D. Godfrey et al., Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma, The Journal of Experimental Medicine, vol.73, issue.5, pp.755-760, 2000.
DOI : 10.1126/science.286.5446.1957

M. Van-den-broek, D. Kagi, F. Ossendorp, R. Toes, S. Vamvakas et al., Decreased tumor surveillance in perforin-deficient mice, Journal of Experimental Medicine, vol.184, issue.5, pp.1781-1790, 1996.
DOI : 10.1084/jem.184.5.1781

M. Yuille, E. Matutes, A. Marossy, B. Hilditch, D. Catovsky et al., Familial chronic lymphocytic leukaemia: a survey and review of published studies, British Journal of Haematology, vol.12, issue.4, pp.794-799, 2000.
DOI : 10.1038/sj.leu.2401176

R. Houlston, D. Catovsky, and M. Yuille, Genetic susceptibility to chronic lymphocytic leukemia, Leukemia, vol.16, issue.6, pp.1008-1014, 2002.
DOI : 10.1038/sj.leu.2402538

K. Bielawski, A. Zaczek, U. Lisowska, A. Dybikowska, A. Kowalska et al., The suitability of DNA extracted from formalin-fixed, pp.paraffin-embedded

E. Abed, Hereditary Cancer in Clinical Practice, 2011.

C. Greer, C. Wheeler, and M. Manos, Sample preparation and PCR amplification from paraffin-embedded tissues. PCR Methods Appl, pp.113-122, 1994.
DOI : 10.1101/gr.3.6.s113
URL : http://genome.cshlp.org/cgi/content/short/3/6/S113

S. Tavtigian, A. Deffenbaugh, L. Yin, T. Judkins, T. Scholl et al., Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral, Journal of Medical Genetics, vol.43, issue.4, pp.295-305, 2006.
DOI : 10.1136/jmg.2005.033878

W. Tong, L. Li, and Z. Weng, Computational prediction of binding hotspots, The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, pp.2980-2983, 2004.
DOI : 10.1109/IEMBS.2004.1403845

L. Cartegni, J. Wang, Z. Zhu, M. Zhang, and A. Krainer, ESEfinder: a web resource to identify exonic splicing enhancers, Nucleic Acids Research, vol.31, issue.13, pp.3568-3571, 2003.
DOI : 10.1093/nar/gkg616

P. Smith, C. Zhang, J. Wang, S. Chew, M. Zhang et al., An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers, Human Molecular Genetics, vol.15, issue.16, pp.2490-2508, 2006.
DOI : 10.1093/hmg/ddl171

W. Fairbrother, R. Yeh, P. Sharp, and C. Burge, Predictive Identification of Exonic Splicing Enhancers in Human Genes, Science, vol.297, issue.5583, pp.1007-1013, 2002.
DOI : 10.1126/science.1073774

I. Voskoboinik, M. Thia, D. Bono, A. Browne, K. Cretney et al., ) Gene, The Journal of Experimental Medicine, vol.54, issue.6, pp.811-816, 2004.
DOI : 10.1093/emboj/16.24.7287

I. Voskoboinik, M. Thia, and J. Trapani, A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis, Blood, vol.105, issue.12, pp.4700-4706, 2005.
DOI : 10.1182/blood-2004-12-4935

R. Clementi, A. Chiocchetti, G. Cappellano, E. Cerutti, M. Ferretti et al., Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function, Blood, vol.108, issue.9, pp.3079-3084, 2006.
DOI : 10.1182/blood-2006-02-001412

E. Solomou, F. Gibellini, B. Stewart, D. Malide, M. Berg et al., Perforin gene mutations in patients with acquired aplastic anemia, Blood, vol.109, issue.12, pp.5234-5237, 2007.
DOI : 10.1182/blood-2006-12-063495

I. Voskoboinik, V. Sutton, A. Ciccone, C. House, J. Chia et al., Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function, Blood, vol.110, issue.4, pp.1184-1190, 2007.
DOI : 10.1182/blood-2007-02-072850

P. Jones and S. Baylin, The fundamental role of epigenetic events in cancer, Nat Rev Genet, vol.3, pp.415-428, 2002.

M. Esteller, P. Corn, S. Baylin, and J. Herman, A gene hypermethylation profile of human cancer, Cancer Res, vol.61, pp.3225-3229, 2001.

Q. Lu, A. Wu, D. Ray, C. Deng, J. Attwood et al., DNA Methylation and Chromatin Structure Regulate T Cell Perforin Gene Expression, The Journal of Immunology, vol.170, issue.10, pp.5124-5132, 2003.
DOI : 10.4049/jimmunol.170.10.5124

X. Gao, J. Lin, L. Wang, and L. Yu, Demethylating treatment suppresses natural killer cell cytolytic activity, Molecular Immunology, vol.46, issue.10, pp.2064-2070, 2009.
DOI : 10.1016/j.molimm.2009.02.033