Skip to main content

Advertisement

SpringerLink
Log in

Mutational Status of CDKN2A and TP53 Genes in Laryngeal Squamous Cell Carcinoma

  • Research
  • Published:
Pathology & Oncology Research

Abstract

Laryngeal squamous cell carcinoma (LSCC) is the second most common tumour of the head and neck. It is characterized by frequent aberrations in two cell-cycle regulators—CDKN2A and TP53. However, LSCC has been often studied as a part of the group of head and neck cancers and not as an individual entity. In the current study we aimed to examine mutation status of CDKN2A and TP53 genes in 108 LSCC patients. DNA was extracted from fresh-frozen tumour tissues; exons 1–3 of CDKN2A and exons 5–8 of TP53 were screened for mutations by direct sequencing. Genetic aberrations in CDKN2A were found in 16 (14.2 %) and those in TP53—in 56/108 (51.9 %) tumours. Seven mutations (two insertions, three deletions, one missense and one silent) detected in CDKN2A were not described previously. Also, we found seven novel deletions and a novel indel in TP53. No significant associations with clinical features were found. However, TP53 mutations were predominantly observed in smokers with advanced stage tumours. Screening for genetic aberrations in a defined group of LSCC contributes to the knowledge about laryngeal carcinogenesis. Further investigations are required to confirm the observed trends in associations with clinical features.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Leemans CR, Braakhuis BJM, Brakenhoff RH (2011) The molecular biology of head and neck cancer. Nat Rev Cancer 11:9–22

    Article  CAS  PubMed  Google Scholar 

  2. Temam S, Koka V, Mamelle G et al (2005) Treatment of the N0 neck during salvage surgery after radiotherapy of head and neck squamous cell carcinoma. Head Neck 27:653–658

    Article  PubMed  Google Scholar 

  3. Almadori G, Bussu F, Cadoni G et al (2004) Multistep laryngeal carcinogenesis helps our understanding of the field cancerisation phenomenon: a review. Eur J Cancer 40:2383–2388

    Article  PubMed  Google Scholar 

  4. Perez-Ordoñez B, Beauchemin M, Jordan RCK (2006) Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol 59:445–453

    Article  PubMed Central  PubMed  Google Scholar 

  5. Kim MM, Califano JA (2004) Molecular pathology of head-and-neck cancer. Int J Cancer 112:545–553

    Article  CAS  PubMed  Google Scholar 

  6. Loyo M, Pai SI (2008) The molecular genetics of laryngeal cancer. Otolaryngol Clin N Am 41:657–672

    Article  Google Scholar 

  7. Longworth MS, Laimins LA (2004) Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev 68:362–372

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Van der Riet P, Nawroz H, Hruban RH et al (1994) Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res 54:1156–1158

    PubMed  Google Scholar 

  9. Nobori T, Miura K, Wu DJ et al (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756

    Article  CAS  PubMed  Google Scholar 

  10. Caldas C, Hahn SA, da Costa LT et al (1994) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8:27–32

    Article  CAS  PubMed  Google Scholar 

  11. Agnese V, Corsale S, Calò V et al (2006) Significance of P16INK4A hypermethylation gene in primary head/neck and colorectal tumors: it is a specific tissue event? Results of a 3-year GOIM (Gruppo Oncologico dell’Italia Meridionale) prospective study. Ann Oncol 17(Suppl 7):vii137–vii141

    PubMed  Google Scholar 

  12. Pierini S, Jordanov SH, Mitkova AV et al (2013) Promoter hypermethylation of CDKN2A, MGMT, MLH1 and DAPK genes in laryngeal squamous cell carcinoma and their associations with clinical profiles of the patients. Head Neck. doi:10.1002/hed.23413

    PubMed  Google Scholar 

  13. Kamijo T, Zindy F, Roussel MF et al (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19 ARF. Cell 91:649–659

    Article  CAS  PubMed  Google Scholar 

  14. Rocco JW, Sidransky D (2001) p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res 264:42–55

    Article  CAS  PubMed  Google Scholar 

  15. Califano J, van der Riet P, Westra W et al (1996) Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 56:2488–2492

    CAS  PubMed  Google Scholar 

  16. Mountzios G, Rampias T, Psyrri A (2014) The mutational spectrum of squamous-cell carcinoma of the head and neck: Targetable genetic events and clinical impact. Ann Oncol. doi:10.1093/annonc/mdu143

    PubMed  Google Scholar 

  17. Xu J, Reumers J, Couceiro JR et al (2011) Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat Chem Biol 7:285–295

    Article  CAS  PubMed  Google Scholar 

  18. Sanger F, Air GM, Barrell BG et al (1997) Nucleotide sequence of bacteriophage phi X174 DNA. Nature 265:687–695

    Article  Google Scholar 

  19. Liu L, Dilworth D, Gao L et al (1999) Mutation of the CDKN2A 5’ UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet 21:128–132

    Article  PubMed  Google Scholar 

  20. Debniak T, Scott RJ, Huzarski T et al (2005) CDKN2A common variants and their association with melanoma risk: a population-based study. Cancer Res 65:835–839

    CAS  PubMed  Google Scholar 

  21. Nakagawa K, Conrad NK, Williams JP, Johnson BE, Kelley MJ (1995) Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. Oncogene 11:1843–1851

    CAS  PubMed  Google Scholar 

  22. Zhang SY, Klein-Szanto AJ, Sauter ER et al (1994) Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res 54:5050–5053

    CAS  PubMed  Google Scholar 

  23. Ohta M, Nagai H, Shimizu M et al (1994) Rarity of somatic and germline mutations of the cyclin-dependent kinase 4 inhibitor gene, CDK4I, in melanoma. Cancer Res 54:5269–5272

    CAS  PubMed  Google Scholar 

  24. Zhao Y, Zhang S, Fu B, Xiao C (1999) Abnormalities of tumor suppressor genes P16 and P15 in primary maxillofacial squamous cell carcinomas. Cancer Genet Cytogenet 112:26–33

    Article  CAS  PubMed  Google Scholar 

  25. Casula M, Colombino M, Satta MP et al (2007) Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy. Eur J Cancer 43:137–143

    Article  CAS  PubMed  Google Scholar 

  26. Jares P, Nadal A, Fernández PL et al (1999) Disregulation of p16MTS1/CDK4I protein and mRNA expression is associated with gene alterations in squamous-cell carcinoma of the larynx. Int J Cancer 81:705–711

    Article  CAS  PubMed  Google Scholar 

  27. Agarwalla PK, Dunn IF, Turner CD et al (2008) A novel TP53 germline mutation in a family with a history of multiple malignancies: case report and review of the literature. Pediatr Neurosurg 44:501–508

    Article  PubMed  Google Scholar 

  28. Goi K, Takagi M, Iwata S et al (1997) DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation. Cancer Res 57:1895–1902

    CAS  PubMed  Google Scholar 

  29. Varley JM, McGown G, Thorncroft M et al (1997) Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res 57:3245–3252

    CAS  PubMed  Google Scholar 

  30. Wolf P, Kreimer-Erlacher H, Seidl H et al (2004) The ultraviolet fingerprint dominates the mutational spectrum of the p53 and Ha-ras genes in psoralen + ultraviolet A keratoses from psoriasis patients. J Invest Dermatol 122:190–200

    Article  CAS  PubMed  Google Scholar 

  31. Kyritsis APP, Bondy MLL, Xiao M et al (1994) Germline p53 gene mutations in subsets of glioma patients. J Natl Cancer Inst 86:344–349

    Article  CAS  PubMed  Google Scholar 

  32. Salani R, Kurman RJ, Giuntoli R et al (2008) Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer 18:487–491

    Article  CAS  PubMed  Google Scholar 

  33. Oda H, Nakatsuru Y, Imai Y, Sugimura H, Ishikawa T (1995) A mutational hot spot in the p53 gene is associated with hepatoblastomas. Int J Cancer 60:786–790

    Article  CAS  PubMed  Google Scholar 

  34. Chen C-H, Dickman KG, Moriya M et al (2012) Aristolochic acid-associated urothelial cancer in Taiwan. PNAS 109:8241–8246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Sheu JC, Huang GT, Lee PH et al (1992) Mutation of p53 gene in hepatocellular carcinoma in Taiwan. Cancer Res 52:6098–6100

    CAS  PubMed  Google Scholar 

  36. McIntyre JFF, Smith-Sorensen B, Friend SHH et al (1994) Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol 12:925–930

    CAS  PubMed  Google Scholar 

  37. Gleeson CMM, Sloan JMM, McGuigan JAA, Ritchie AJJ, Russell SEE (1995) Base transitions at CpG dinucleotides in the p53 gene are common in esophageal adenocarcinoma. Cancer Res 55:3406–3411

    CAS  PubMed  Google Scholar 

  38. Imazeki F, Omata M, Nose H, Ohto M, Isono K (1992) p53 gene mutations in gastric and esophageal cancers. Gastroenterology 103:892–896

    CAS  PubMed  Google Scholar 

  39. Cabelguenne A, Blons H, de Waziers I et al (2000) p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: a prospective series. J Clin Oncol 18:1465–1473

    CAS  PubMed  Google Scholar 

  40. Frebourg T, Barbier N, Yan YXX et al (1995) Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. Am J Hum Genet 56:608–615

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Andersen TI, Holm R, Nesland JM et al (1993) Prognostic significance of TP53 alterations in breast carcinoma. Br J Cancer 68:540–548

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Matsushita K, Kobayashi S, Kato M et al (1996) Reduced messenger RNA expression level of p21 CIP1 in human colorectal carcinoma tissues and its association with p53 gene mutation. Int J Cancer 69:259–264

    Article  CAS  PubMed  Google Scholar 

  43. Horio Y, Suzuki H, Ueda R et al (1994) Predominantly tumor-limited expression of a mutant allele in a Japanese family carrying a germline p53 mutation. Oncogene 9:1231–1235

    CAS  PubMed  Google Scholar 

  44. James CDD, Galanis E, Frederick L et al (1999) Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation. Int J Oncol 15:547–553

    CAS  PubMed  Google Scholar 

  45. Birch JMM, Hartley ALL, Tricker KJJ et al (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54:1298–1304

    CAS  PubMed  Google Scholar 

  46. Tenti P, Pavanello S, Padovan L et al (1998) Analysis and clinical implications of p53 gene mutations and human papillomavirus type 16 and 18 infection in primary adenocarcinoma of the uterine cervix. Am J Pathol 152:1057–1063

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Diller L, Sexsmith E, Gottlieb A, Li FP, Malkin D (1995) Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest 95:1606–1611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. McGregor JM, Berkhout RJ, Rozycka M et al (1997) p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status. Oncogene 15:1737–1740

    Article  CAS  PubMed  Google Scholar 

  49. Naito M, Satake M, Sakai E et al (1992) Detection of p53 gene mutations in human ovarian and endometrial cancers by polymerase chain reaction single strand conformation polymorphism analysis. Japan J Cancer Res 83:1030–1036

    Article  CAS  Google Scholar 

  50. Meinhold-Heerlein I, Ninci E, Ikenberg H et al (2001) Evaluation of methods to detect p53 mutations in ovarian cancer. Oncology 60:176–188

    Article  CAS  PubMed  Google Scholar 

  51. Mok CH, Tsao SW, Knapp RC, Fishbaugh PM, Lau CC (1992) Unifocal origin of advanced human epithelial ovarian cancers. Cancer Res 52:5119–5122

    CAS  PubMed  Google Scholar 

  52. Malkin D, Li FPP, Strong LCC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238

    Article  CAS  PubMed  Google Scholar 

  53. Milner BJJ, Allan LAA, Eccles DMM et al (1993) p53 mutation is a common genetic event in ovarian carcinoma. Cancer Res 53:2128–2132

    CAS  PubMed  Google Scholar 

  54. Chompret A, Brugières L, Ronsin M et al (2000) P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer 82:1932–1937

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Trkova M, Prochazkova K, Krutilkova V, Sumerauer D, Sedlacek Z (2007) Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer 110:694–702

    Article  CAS  PubMed  Google Scholar 

  56. Toguchida J, Yamaguchi T, Dayton SH et al (1992) Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 326:1301–1308

    Article  CAS  PubMed  Google Scholar 

  57. Shibata A, Parsonnet J, Longacre TA et al (2002) CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma. Carcinogenesis 23:419–424

    Article  CAS  PubMed  Google Scholar 

  58. Pang A, Ng IOO, Fan STT, Kwong YLL (2003) Clinicopathologic significance of genetic alterations in hepatocellular carcinoma. Cancer Genet Cytogenet 146:8–15

    Article  CAS  PubMed  Google Scholar 

  59. Boyle JO, Hakim J, Koch W et al (1993) The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res 53:4477–4480

    CAS  PubMed  Google Scholar 

  60. Nishida N, Fukuda Y, Kokuryu H et al (1993) Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res 53:368–372

    CAS  PubMed  Google Scholar 

  61. Hwang S-J, Lozano G, Amos CI, Strong LC (2003) Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 72:975–983

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Kiwerska K, Rydzanicz M, Kram A et al (2010) Mutational analysis of CDKN2A gene in a group of 390 larynx cancer patients. Mol Biol Rep 37:325–332

    Article  CAS  PubMed  Google Scholar 

  63. Gleich LL, Salamone FN (2002) Molecular genetics of head and neck cancer. Cancer Control 9:369–378

    PubMed  Google Scholar 

  64. Agrawal N, Frederick MJ, Pickering CR et al (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333:1154–1157

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Smigiel R, Sasiadek M, Krecicki T et al (2004) Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene in squamous cell carcinoma of the larynx. Mol Carcinog 39:147–154

    Article  CAS  PubMed  Google Scholar 

  66. Soussi T (2007) p53 alterations in human cancer: more questions than answers. Oncogene 26:2145–2156

    Article  CAS  PubMed  Google Scholar 

  67. Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265:346–355

    Article  CAS  PubMed  Google Scholar 

  68. Bosch FX, Ritter D, Enders C et al (2004) Head and neck tumor sites differ in prevalence and spectrum of p53 alterations but these have limited prognostic value. Int J Cancer 111:530–538

    Article  CAS  PubMed  Google Scholar 

  69. Partridge M, Costea DE, Huang X (2007) The changing face of p53 in head and neck cancer. Int J Oral Maxillofac Surg 36:1123–1138

    Article  CAS  PubMed  Google Scholar 

  70. Poeta ML, Manola J, Goldwasser MA et al (2007) TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 357:2552–2561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Van Houten VMM, Tabor MP, van den Brekel MWM et al (2002) Mutated p53 as a molecular marker for the diagnosis of head and neck cancer. J Pathol 198:476–486

    Article  PubMed  Google Scholar 

  72. Balz V, Scheckenbach K, Götte K et al (2003) Is the p53 inactivation frequency in squamous cell carcinomas of the head and neck underestimated? Analysis of p53 exons 2–11 and human papillomavirus 16/18 E6 transcripts in 123 unselected tumor specimens. Cancer Res 63:1188–1191

    CAS  PubMed  Google Scholar 

  73. Tabor MP, Brakenhoff RH, van Houten VM et al (2001) Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 7:1523–1532

    CAS  PubMed  Google Scholar 

  74. Brennan JA, Boyle JO, Koch WM et al (1995) Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med 332:712–717

    Article  CAS  PubMed  Google Scholar 

  75. Blons H, Laurent-Puig P (2003) TP53 and head and neck neoplasms. Hum Mutat 21:252–257

    Article  CAS  PubMed  Google Scholar 

  76. Kress S, Sutter C, Strickland PT et al (1992) Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin. Cancer Res 52:6400–6403

    CAS  PubMed  Google Scholar 

  77. Paget V, Lechevrel M, André V et al (2012) Benzo[a]pyrene, aflatoxine B1 and acetaldehyde mutational patterns in TP53 gene using a functional assay: relevance to human cancer aetiology. PLoS One 7:e30921

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Urashima M, Hama T, Suda T et al (2013) Distinct effects of alcohol consumption and smoking on genetic alterations in head and neck carcinoma. PLoS One 8:e80828

    Article  PubMed Central  PubMed  Google Scholar 

  79. Sigal A, Rotter V (2000) Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 60:6788–6793

    CAS  PubMed  Google Scholar 

  80. Bullock AN, Henckel J, DeDecker BS et al (1997) Thermodynamic stability of wild-type and mutant p53 core domain. PNAS 94:14338–14342

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Suzuki HI, Yamagata K, Sugimoto K et al (2009) Modulation of microRNA processing by p53. Nature 460:529–533

    Article  CAS  PubMed  Google Scholar 

  82. Hermeking H (2012) MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer 12:613–626

    Article  CAS  PubMed  Google Scholar 

  83. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    Article  CAS  PubMed  Google Scholar 

  84. Hermeking H (2007) p53 enters the microRNA world. Cancer Cell 12:414–418

    Article  CAS  PubMed  Google Scholar 

  85. Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199

    Article  CAS  PubMed  Google Scholar 

  86. Menendez D, Inga A, Resnick MA (2009) The expanding universe of p53 targets. Nat Rev Cancer 9:724–737

    Article  CAS  PubMed  Google Scholar 

  87. Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691–700

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank all the patients who took part in this study.

This work was supported by grants from the National Science Fund, Ministry of Education, Youth and Science (DDVU02-33/2010; DUNK01-2/2009) and the Science Fund, Medical University—Sofia, Bulgaria (8D-2010).

Author information

Authors and Affiliations

  1. Molecular Medicine Center, Medical University—Sofia, 2 Zdrave street, Sofia, 1431, Bulgaria

    Teodora A. Todorova, Gergana S. Stancheva, Vanio I. Mitev, Radka P. Kaneva & Teodora E. Goranova

  2. Department of Otorhinolaryngology, Medical University—Sofia, Clinic of Otorhinolaryngology, UMHAT “Tsaritsa Yoanna—ISUL” Sofia, 8 Byalo More Street, Sofia, 1527, Bulgaria

    Stanislav H. Jordanov, Ivan J. Chalakov, Mincho B. Melnicharov & Kuncho V. Kunev

  3. Department of Medical Chemistry and Biochemistry, Medical University—Sofia, 2 Zdrave Street, Sofia, 1431, Bulgaria

    Gergana S. Stancheva, Vanio I. Mitev & Radka P. Kaneva

Authors
  1. Teodora A. Todorova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stanislav H. Jordanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gergana S. Stancheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ivan J. Chalakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mincho B. Melnicharov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kuncho V. Kunev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vanio I. Mitev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Radka P. Kaneva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Teodora E. Goranova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Teodora E. Goranova.

Additional information

Kuncho V. Kunev is deceased.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Todorova, T.A., Jordanov, S.H., Stancheva, G.S. et al. Mutational Status of CDKN2A and TP53 Genes in Laryngeal Squamous Cell Carcinoma. Pathol. Oncol. Res. 21, 413–421 (2015). https://doi.org/10.1007/s12253-014-9836-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-014-9836-0

Keywords

Search

Navigation