Advertisement

Familial Cancer

, Volume 15, Issue 4, pp 497–506 | Cite as

Ovarian cancer patients at high risk of BRCA mutation: the constitutional genetic characterization does not change prognosis

  • Renaud Sabatier
  • Elise Lavit
  • Jessica Moretta
  • Eric Lambaudie
  • Tetsuro Noguchi
  • François Eisinger
  • Elisabeth Cherau
  • Magali Provansal
  • Doriane Livon
  • Laetitia Rabayrol
  • Cornel Popovici
  • Emmanuelle Charaffe-Jauffret
  • Hagay Sobol
  • Patrice Viens
Original Article

Abstract

Ovarian neoplasms secondary to germline BRCA mutations had been described to have a more favourable survival. There is only few data concerning the prognosis of non mutated patients presenting clinical features evocative of BRCA alterations. We retrospectively collected data from patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. Patients considered at high risk of BRCA mutation were tested for BRCA1/2 germline mutations. We described clinical, pathological and therapeutic features and compared prognosis of BRCA mutation carriers and non-mutated patients. Out of 617 ovarian cancer patients, we identified 104 patients who were considered at high risk of mutation. The 33 mutated patients were more likely to present a personal (33 vs. 10 %, p = 0.003) or a family (42 vs. 24 %, p = 0.06) history of breast/ovarian cancers. BRCA1/2 mutation carriers and wild type patients displayed similar prognosis: median progression–free survival (PFS) of 20.9 versus 37.7 months (p = 0.21); median overall survival (OS) of 151.2 versus 122.5 months (p = 0.52). Personal history of breast cancer increased both PFS [HR = 0.45 (95CI 0.25–0.81)] and OS [HR = 0.35 (95CI 0.16–0.75)]. In multivariate analysis, this parameter was an independent prognostic feature, whereas the identification of a BRCA1/2 mutation was not. In our cohort, all patients at high risk of BRCA mutation share a similar prognosis, whatever is their germline mutation status. Prognosis seems to be more influenced by clinical history than by germline mutations identification. If it is confirmed in larger and independent series, this result suggests that the hypothesis of other BRCA pathway alterations (BRCAness phenotype) deserves to be deeply explored.

Keywords

Ovarian cancer BRCA Mutation Prognosis 

Notes

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Supplementary material

10689_2016_9873_MOESM1_ESM.tif (1.2 mb)
Online Resource 1: Overall survival curves according to BRCA1/2 mutation risk prediction. N = 513 for the ‘low risk of mutation’ cohort, and n = 100 for the ‘high risk of mutation’ cohort (TIFF 1230 kb)

References

  1. 1.
    Binder-Foucard F, Belot A, Delafosse P, et al. (2013) Estimation nationale de l’incidence et de la mortalité par cancer en France entre 1980 et 2012. Partie 1—Tumeurs solides. Institut de veille sanitaireGoogle Scholar
  2. 2.
    Rooth C (2013) Ovarian cancer: risk factors, treatment and management. Br J Nurs Mark Allen Publ 22:S23–S30CrossRefGoogle Scholar
  3. 3.
    Rigakos G, Razis E (2012) BRCAness: finding the Achilles heel in ovarian cancer. Oncologist 17:956–962. doi: 10.1634/theoncologist.2012-0028 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    de Pauw A, Jolissaint L, Fréneaux P et al (2012) Hereditary forms of ovarian cancer. Bull Cancer (Paris) 99:453–462. doi: 10.1684/bdc.2012.1544 Google Scholar
  5. 5.
    Prat J, Ribé A, Gallardo A (2005) Hereditary ovarian cancer. Hum Pathol 36:861–870. doi: 10.1016/j.humpath.2005.06.006 CrossRefPubMedGoogle Scholar
  6. 6.
    Antoniou A, Pharoah PDP, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Brose MS, Rebbeck TR, Calzone KA et al (2002) Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94:1365–1372CrossRefPubMedGoogle Scholar
  8. 8.
    Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329–1333. doi: 10.1200/JCO.2006.09.1066 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Vencken PMLH, Kriege M, Hoogwerf D et al (2011) Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22:1346–1352. doi: 10.1093/annonc/mdq628 CrossRefPubMedGoogle Scholar
  10. 10.
    Tan DSP, Rothermundt C, Thomas K et al (2008) “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 26:5530–5536. doi: 10.1200/JCO.2008.16.1703 CrossRefPubMedGoogle Scholar
  11. 11.
    Aida H, Takakuwa K, Nagata H et al (1998) Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4:235–240PubMedGoogle Scholar
  12. 12.
    Lacour RA, Westin SN, Meyer LA et al (2011) Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations. Gynecol Oncol 121:358–363. doi: 10.1016/j.ygyno.2010.12.354 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bolton KL, Chenevix-Trench G, Goh C et al (2012) Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307:382–390. doi: 10.1001/jama.2012.20 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hyman DM, Zhou Q, Iasonos A et al (2012) Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer. Cancer 118:3703–3709. doi: 10.1002/cncr.26655 CrossRefPubMedGoogle Scholar
  15. 15.
    Alsop K, Fereday S, Meldrum C et al (2012) BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 30:2654–2663. doi: 10.1200/JCO.2011.39.8545 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ben David Y, Chetrit A, Hirsh-Yechezkel G et al (2002) Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20:463–466CrossRefPubMedGoogle Scholar
  17. 17.
    Gallagher DJ, Konner JA, Bell-McGuinn KM et al (2011) Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity. Ann Oncol 22:1127–1132. doi: 10.1093/annonc/mdq577 CrossRefPubMedGoogle Scholar
  18. 18.
    Boyd J, Sonoda Y, Federici MG et al (2000) Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283:2260–2265CrossRefPubMedGoogle Scholar
  19. 19.
    Chetrit A, Hirsh-Yechezkel G, Ben-David Y et al (2008) Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol 26:20–25. doi: 10.1200/JCO.2007.11.6905 CrossRefPubMedGoogle Scholar
  20. 20.
    Zhong Q, Peng H-L, Zhao X et al (2015) Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis. Clin Cancer Res 21:211–220. doi: 10.1158/1078-0432.CCR-14-1816 CrossRefPubMedGoogle Scholar
  21. 21.
    Sun C, Li N, Ding D et al (2014) The role of BRCA status on the prognosis of patients with epithelial ovarian cancer: a systematic review of the literature with a meta-analysis. PLoS One 9:e95285. doi: 10.1371/journal.pone.0095285 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rudaitis V, Zvirblis T, Kanopiene D et al (2014) BRCA1/2 mutation status is an independent factor of improved survival for advanced (stage III–IV) ovarian cancer. Int J Gynecol Cancer 24:1395–1400. doi: 10.1097/IGC.0000000000000247 CrossRefPubMedGoogle Scholar
  23. 23.
    Turner N, Tutt A, Ashworth A (2004) Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer 4:814–819. doi: 10.1038/nrc1457 CrossRefPubMedGoogle Scholar
  24. 24.
    Hennessy BTJ, Timms KM, Carey MS et al (2010) Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 28:3570–3576. doi: 10.1200/JCO.2009.27.2997 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Weberpals JI, Clark-Knowles KV, Vanderhyden BC (2008) Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. J Clin Oncol 26:3259–3267. doi: 10.1200/JCO.2007.11.3902 CrossRefPubMedGoogle Scholar
  26. 26.
    Baldwin RL, Nemeth E, Tran H et al (2000) BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res 60:5329–5333PubMedGoogle Scholar
  27. 27.
    Vietri MT, Caliendo G, Schiano C et al (2015) Analysis of PALB2 in a cohort of Italian breast cancer patients: identification of a novel PALB2 truncating mutation. Fam Cancer 14:341–348. doi: 10.1007/s10689-015-9786-z CrossRefPubMedGoogle Scholar
  28. 28.
    Lu W, Wang X, Lin H et al (2012) Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer 11:381–385. doi: 10.1007/s10689-012-9523-9 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Pennington KP, Walsh T, Harrell MI et al (2014) Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20:764–775. doi: 10.1158/1078-0432.CCR-13-2287 CrossRefPubMedGoogle Scholar
  30. 30.
    Kanchi KL, Johnson KJ, Lu C et al (2014) Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun 5:3156. doi: 10.1038/ncomms4156 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hilton JL, Geisler JP, Rathe JA et al (2002) Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 94:1396–1406CrossRefPubMedGoogle Scholar
  32. 32.
    Sabatier R, Adélaïde J, Finetti P et al (2010) BARD1 homozygous deletion, a possible alternative to BRCA1 mutation in basal breast cancer. Genes Chromosomes Cancer 49:1143–1151. doi: 10.1002/gcc.20822 CrossRefPubMedGoogle Scholar
  33. 33.
    Konstantinopoulos PA, Spentzos D, Karlan BY et al (2010) Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 28:3555–3561. doi: 10.1200/JCO.2009.27.5719 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Berry DA, Iversen ES, Gudbjartsson DF et al (2002) BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20:2701–2712CrossRefPubMedGoogle Scholar
  35. 35.
    Evans DGR, Eccles DM, Rahman N et al (2004) A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 41:474–480CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Antoniou AC, Casadei S, Heikkinen T et al (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497–506. doi: 10.1056/NEJMoa1400382 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Vandenbroucke JP, von Elm E, Altman DG et al (2007) Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. PLoS Med 4:e297. doi: 10.1371/journal.pmed.0040297 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Liu J, Cristea MC, Frankel P et al (2012) Clinical characteristics and outcomes of BRCA-associated ovarian cancer (OC): genotype and survival. Cancer Genet 205:34–41. doi: 10.1016/j.cancergen.2012.01.008 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lorusso D, Cirillo F, Mancini M et al (2013) The different impact of BRCA mutations on the survival of epithelial ovarian cancer patients: a retrospective single-center experience. Oncology 85:122–127. doi: 10.1159/000353786 CrossRefPubMedGoogle Scholar
  40. 40.
    Doufekas K, Olaitan A (2014) Clinical epidemiology of epithelial ovarian cancer in the UK. Int J Womens Health 6:537–545. doi: 10.2147/IJWH.S40894 PubMedPubMedCentralGoogle Scholar
  41. 41.
    Artioli G, Borgato L, Cappetta A et al (2010) Overall survival in BRCA-associated ovarian cancer: case-control study of an Italian series. Eur J Gynaecol Oncol 31:658–661PubMedGoogle Scholar
  42. 42.
    McGuire WP, Hoskins WJ, Brady MF et al (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1–6. doi: 10.1056/NEJM199601043340101 CrossRefPubMedGoogle Scholar
  43. 43.
    Ozols RF, Bundy BN, Greer BE et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a gynecologic oncology group study. J Clin Oncol 21:3194–3200. doi: 10.1200/JCO.2003.02.153 CrossRefPubMedGoogle Scholar
  44. 44.
    Vergote I, Tropé CG, Amant F et al (2010) Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943–953. doi: 10.1056/NEJMoa0908806 CrossRefPubMedGoogle Scholar
  45. 45.
    von Minckwitz G, Blohmer JU, Costa SD et al (2013) Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 31:3623–3630. doi: 10.1200/JCO.2012.45.0940 CrossRefGoogle Scholar
  46. 46.
    Ferron J-G, Uzan C, Rey A et al (2009) Histological response is not a prognostic factor after neoadjuvant chemotherapy in advanced-stage ovarian cancer with no residual disease. Eur J Obstet Gynecol Reprod Biol 147:101–105. doi: 10.1016/j.ejogrb.2009.07.016 CrossRefPubMedGoogle Scholar
  47. 47.
    Bilici A, Salepci T, Dane F et al (2010) Neoadjuvant chemotherapy followed by interval cytoreductive surgery in patients with unresectable, advanced stage epithelial ovarian cancer: a single centre experience. Arch Gynecol Obstet 282:417–425. doi: 10.1007/s00404-009-1330-7 CrossRefPubMedGoogle Scholar
  48. 48.
    Zweemer RP, Verheijen RH, Coebergh JW et al (2001) Survival analysis in familial ovarian cancer, a case control study. Eur J Obstet Gynecol Reprod Biol 98:219–223CrossRefPubMedGoogle Scholar
  49. 49.
    Buller RE, Shahin MS, Geisler JP et al (2002) Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res 8:1196–1202PubMedGoogle Scholar
  50. 50.
    Jóhannsson OT, Ranstam J, Borg A, Olsson H (1998) Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 16:397–404PubMedGoogle Scholar
  51. 51.
    Cass I, Baldwin RL, Varkey T et al (2003) Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 97:2187–2195. doi: 10.1002/cncr.11310 CrossRefPubMedGoogle Scholar
  52. 52.
    Ramus SJ, Fishman A, Pharoah PD et al (2001) Ovarian cancer survival in Ashkenazi Jewish patients with BRCA1 and BRCA2 mutations. Eur J Surg Oncol 27:278–281. doi: 10.1053/ejso.2000.1097 CrossRefPubMedGoogle Scholar
  53. 53.
    Kringen P, Wang Y, Dumeaux V et al (2005) TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival. BMC Cancer 5:134. doi: 10.1186/1471-2407-5-134 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Pal T, Permuth-Wey J, Kapoor R et al (2007) Improved survival in BRCA2 carriers with ovarian cancer. Fam Cancer 6:113–119. doi: 10.1007/s10689-006-9112-x CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Dann RB, DeLoia JA, Timms KM et al (2012) BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol 125:677–682. doi: 10.1016/j.ygyno.2012.03.006 CrossRefPubMedGoogle Scholar
  56. 56.
    Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921. doi: 10.1038/nature03445 CrossRefPubMedGoogle Scholar
  57. 57.
    Muggia F, Safra T (2014) “BRCAness” and its implications for platinum action in gynecologic cancer. Anticancer Res 34:551–556PubMedPubMedCentralGoogle Scholar
  58. 58.
    Sabatier R, Gonçalves A, Bertucci F et al (2012) Are there candidates for high-dose chemotherapy in ovarian carcinoma? J Exp Clin Cancer Res CR 31:87. doi: 10.1186/1756-9966-31-87 CrossRefPubMedGoogle Scholar
  59. 59.
    Buys SS, Partridge E, Black A et al (2011) Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial. JAMA 305:2295–2303. doi: 10.1001/jama.2011.766 CrossRefPubMedGoogle Scholar
  60. 60.
    Reade CJ, Riva JJ, Busse JW et al (2013) Risks and benefits of screening asymptomatic women for ovarian cancer: a systematic review and meta-analysis. Gynecol Oncol 130:674–681. doi: 10.1016/j.ygyno.2013.06.029 CrossRefPubMedGoogle Scholar
  61. 61.
    Vuorela M, Pylkäs K, Hartikainen JM et al (2011) Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat 130:1003–1010. doi: 10.1007/s10549-011-1677-x CrossRefPubMedGoogle Scholar
  62. 62.
    Atchley DP, Albarracin CT, Lopez A et al (2008) Clinical and pathologic characteristics of patients with BRCA-Positive and BRCA-negative breast cancer. J Clin Oncol 26:4282–4288. doi: 10.1200/JCO.2008.16.6231 CrossRefPubMedGoogle Scholar
  63. 63.
    Lokich E, Stuckey A, Raker C et al (2014) Preoperative genetic testing affects surgical decision making in breast cancer patients. Gynecol Oncol 134:326–330. doi: 10.1016/j.ygyno.2014.05.028 CrossRefPubMedGoogle Scholar
  64. 64.
    Winter WE, Maxwell GL, Tian C et al (2007) Prognostic factors for stage III epithelial ovarian cancer: a gynecologic oncology group study. J Clin Oncol 25:3621–3627. doi: 10.1200/JCO.2006.10.2517 CrossRefPubMedGoogle Scholar
  65. 65.
    van Houwelingen JC, ten Bokkel Huinink WW, van der Burg ME et al (1989) Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol 7:769–773Google Scholar
  66. 66.
    Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134. doi: 10.1056/NEJMoa0900212 CrossRefPubMedGoogle Scholar
  67. 67.
    Ledermann J, Harter P, Gourley C et al (2014) Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852–861. doi: 10.1016/S1470-2045(14)70228-1 CrossRefPubMedGoogle Scholar
  68. 68.
    Oza AM, Cibula D, Benzaquen AO et al (2015) Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol 16:87–97. doi: 10.1016/S1470-2045(14)71135-0 CrossRefPubMedGoogle Scholar
  69. 69.
    Liu JF, Konstantinopoulos PA, Matulonis UA (2014) PARP inhibitors in ovarian cancer: current status and future promise. Gynecol Oncol 133:362–369. doi: 10.1016/j.ygyno.2014.02.039 CrossRefPubMedGoogle Scholar
  70. 70.
    Liu JF, Barry WT, Birrer M et al (2014) Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15:1207–1214. doi: 10.1016/S1470-2045(14)70391-2 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Renaud Sabatier
    • 1
    • 2
    • 3
  • Elise Lavit
    • 1
  • Jessica Moretta
    • 4
  • Eric Lambaudie
    • 2
    • 5
  • Tetsuro Noguchi
    • 6
  • François Eisinger
    • 4
  • Elisabeth Cherau
    • 5
  • Magali Provansal
    • 1
  • Doriane Livon
    • 4
  • Laetitia Rabayrol
    • 4
  • Cornel Popovici
    • 6
  • Emmanuelle Charaffe-Jauffret
    • 2
    • 3
    • 7
  • Hagay Sobol
    • 3
    • 6
  • Patrice Viens
    • 1
    • 2
    • 3
  1. 1.Department of Medical OncologyInstitut Paoli-CalmettesMarseille Cedex 09France
  2. 2.Centre de Recherche en Cancérologie de MarseilleINSERM U1068, CNRS U7258MarseilleFrance
  3. 3.Aix-Marseille UniversityMarseilleFrance
  4. 4.Cancer Control DepartmentInstitut Paoli-CalmettesMarseilleFrance
  5. 5.Department of Surgical OncologyInstitut Paoli-CalmettesMarseilleFrance
  6. 6.Department of Cancer Biology, Laboratory of Molecular OncogeneticsInstitut Paoli-CalmettesMarseilleFrance
  7. 7.Department of Cancer Biology, Laboratory of BiopathologyInstitut Paoli-CalmettesMarseilleFrance

Personalised recommendations