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Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma
  1. Fanélie Jouenne1,2,
  2. Isaure Chauvot de Beauchene3,
  3. Emeline Bollaert4,
  4. Marie-Françoise Avril5,6,
  5. Olivier Caron7,
  6. Olivier Ingster8,
  7. Axel Lecesne7,
  8. Patrick Benusiglio7,
  9. Philippe Terrier1,
  10. Vincent Caumette1,
  11. Daniel Pissaloux9,
  12. Arnaud de la Fouchardière9,
  13. Odile Cabaret1,
  14. Birama N'Diaye1,
  15. Amélie Velghe4,
  16. Gaelle Bougeard10,11,
  17. Graham J Mann12,
  18. Serge Koscielny13,14,
  19. Jennifer H Barrett15,
  20. Mark Harland15,
  21. Julia Newton- Bishop15,
  22. Nelleke Gruis16,
  23. Remco Van Doorn16,
  24. Marion Gauthier-Villars17,
  25. Gaelle Pierron17,
  26. Dominique Stoppa-Lyonnet17,
  27. Isabelle Coupier18,19,
  28. Rosine Guimbaud20,
  29. Capucine Delnatte21,
  30. Jean-Yves Scoazec1,
  31. Alexander M Eggermont22,
  32. Jean Feunteun23,
  33. Luba Tchertanov24,
  34. Jean-Baptiste Demoulin4,
  35. Thierry Frebourg10,11,
  36. Brigitte Bressac-de Paillerets1,2
  1. 1Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France
  2. 2INSERM, U1186, Université Paris-Saclay, Villejuif, France
  3. 3Department of Physics T38, Technical University of Munich, Garching, Germany
  4. 4De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
  5. 5Department of Dermatology, Assistance Publique—Hopitaux de Paris, Hopital Cochin Tarnier, Paris, France
  6. 6Faculté de Médecine, Paris 5 Descartes, Paris, France
  7. 7Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France
  8. 8Service de Génétique Médicale, CHU d'Angers, Angers, France
  9. 9Department of Pathology, Centre Leon Bérard, Lyon, Rhône-Alpes, France
  10. 10Faculty of Medicine, INSERM U1079, Normandy University, Rouen, France
  11. 11Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and personalized Medicine, Rouen, Haute-Normandie, France
  12. 12Centre for Cancer Research, Weastmead Institute for Medical Research and Melanoma Institute, Sydney, New South Wales, Australia
  13. 13Service de Biostatistiques et d'Epidemiologie, Gustave Roussy, Villejuif, France
  14. 14INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
  15. 15Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
  16. 16Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
  17. 17Institut Curie Hospital Group, Service de Génétique, Paris, France
  18. 18Hopital Arnaud de Villeneuve, Service de Génétique Médicale et Oncogénétique, CHU de Montpellier, Montpellier, France
  19. 19CRCM Val d'Aurellle, INSERM U896, Montpellier, France
  20. 20Toulouse University Hospital, Toulouse, France
  21. 21Unité d'Oncogénétique, Centre René Gauducheau, Nantes Saint Herblain, France
  22. 22INSERM U1015 and Faculté de médecine, Gustave Roussy, Université Paris-Saclay, Villejuif, France
  23. 23CNRS UMR8200, Gustave Roussy, Université Paris-Saclay, Villejuif, France
  24. 24Centre de Mathématiques et de leurs applications, Ecole Normale Supérieure de Cachan, Université Paris-Saclay, Cachan, France
  1. Correspondence to Dr Brigitte Bressac-de Paillerets, Département de Biopathologie, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France; brigitte.bressac{at}


Background Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology.

Methods and results We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CDKN2A tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a CDKN2A-/+ genotype and for CDKN2A mutations in 190 TP53-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the CDKN2A/p16INK4A gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline CDKN2A mutations sites demonstrating complete loss of function. As sarcomas are rare in CDKN2A/p16INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (PDGFRA) gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure.

Conclusion Germline mutations in CDKN2A/P16INK4A, a gene known to predispose to hereditary melanoma, pancreatic cancer and tobacco-related cancers, account also for a subset of hereditary sarcoma. In addition, we identified PDGFRA as a candidate modifier gene.

  • Genetic epidemiology
  • Molecular genetics
  • Connective tissue disease
  • Cancer: dermatological

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  • Contributors BB-deP, J-BD, LT and TF designed the study; TF, OC, OI, M-FA, AL, PB, PT, DP, AdlaF, OC, IC, GJM, MH, JN-B, NG, RVD, RG, CD, MG-V, GP and DS-L provided patients clinical data and samples. FJ, EB, VC, IC-de B, GB and AV performed the experiments. FJ, IC-deB, BND, BB-deP, J-BD, LT, JB and SK were involved with data analyses and interpretation. FJ, BB-deP, JF, LT, JB-D, AE, PB, M-FA, TF and J-YS wrote and reviewed the manuscript.

  • Funding This work was supported by an INCA grant 2013-1-MELA-05 and personal donations from C. and N. de Paillerets and M-H. Wagner, awarded to B.B.- d.P. The work of R.v.D and N.A.G. was supported by the Dutch Cancer Society (UL 2012-5489) and grant # R01 CA83115 from the National Cancer Institute to GenoMEL international consortium.

  • Competing interests None declared.

  • Patient consent All patients signed informed consent for research genetic analysis, approved by the concerned IRBs.

  • Ethics approval CPP Nord Ouest N2015/160/HP; CPP Ile de France 2, IRB#00001072, N2010-01-09.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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