Abstract
It is well established that genetic alterations may be associated to prognosis in tumor patients. This study investigates chromosomal changes that predict the clinical outcome of head and neck squamous cell carcinoma (HNSCC) and correlate to characteristic clinicopathological parameters. We applied comparative genomic hybridization (CGH) to tissue samples from 117 HNSCC patients scheduled for radiotherapy. Genomic aberrations occurring in more than five patients were studied for impact on locoregional progression (LRP)-free survival. p values were adjusted by the Hochberg–Benjamini procedure and significant aberrations and clinical variables subjected to a stepwise backwards Cox proportional model. Significant alterations were further analyzed by array-CGH and fluorescence in situ hybridization (FISH). In multivariate survival analysis gains on 1q and 16q predict reduced LRP-free survival independently from known prognostic factors. Cluster analysis separated the HNSCC cases into two groups (cluster 1 and 2) that are characterized by significant differences for imbalances in 13 chromosomal regions. Moreover, it became apparent that cluster 1 correlates to nonanemic patients, while cluster 2 represents predominantly anemic cases. Array-CGH pinpoints 16q24.3 to be the region of interest on chromosome 16 which was further verified by FISH analysis where an increased copy number of FANCA, a member of the Fanconi anemia/breast cancer pathway, could be identified. This study demonstrates that chromosomal gains on 1q and 16q as well as chromosomal loss on 18q represent prognostic markers in HNSCC and that these alterations may explain to some extent the dismal course of a subgroup of patients.
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Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer Statistics, 2008. CA Cancer J Clin 58:71–96
Cooper JS, Pajak TF, Forastiere A, Jacobs J, Fu KK, Ang KK, Laramore GE, Al-Sarraf M (1998) Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy? Head Neck 20:588–594
Snow GB, Annyas AA, van Slooten EA, Bartelink H, Hart AA (1982) Prognostic factors of neck node metastasis. Clin Otolaryngol Allied Sci 7:185–192
Frommhold H, Guttenberger R, Henke M (1998) The impact of blood hemoglobin content on the outcome of radiotherapy. The Freiburg experience. Strahlenther Onkol 4:31–34
Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C, Frommhold H (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362:1255–1260
Leyland-Jones B, Semiglazov V, Pawlicki M, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, Makhson A, Roth A, Dodwell D, Baselga J, Biakhov M, Valuckas K, Voznyi E, Liu X, Vercammen E (2005) Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 23:5960–5972
Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, Szechtman B, Roa W, Mulroy L, Rudinskas L, Gagnon B, Okawara GS, Levine MN (2007) Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 25:1027–1032
Henke M, Laszig R, Frommhold H (2004) Erythropoietin to treat anaemia in patients with head and neck cancer. Lancet 363:81–82
Sidransky D (1995) Molecular genetics of head and neck cancer. Curr Opin Oncol 7:229–233
Estilo CL, O-Charoenrat P, Ngai I, Patel SG, Reddy PG, Dao S, Shaha AR, Kraus DH, Boyle JO, Wong RJ, Pfister DG, Huryn JM, Zlotolow IM, Shah JP, Singh B (2003) The role of novel oncogenes squamous cell carcinoma-related oncogene and phosphatidylinositol 3-kinase p110alpha in squamous cell carcinoma of the oral tongue. Clin Cancer Res 9:2300–2306
Wreesmann VB, Shi W, Thaler HT, Poluri A, Kraus DH, Pfister D, Shaha AR, Shah JP, Rao PH, Singh B (2004) Identification of novel prognosticators of outcome in squamous cell carcinoma of the head and neck. J Clin Oncol 22:3965–3972
Partridge M, Emilion G, Falworth M, A’Hern R, Phillips E, Pateromichelakis S, Langdon J (1999) Patient-specific mutation databases for oral cancer. Int J Cancer 84:284–292
Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, Berean K, Epstein JB, Priddy R, Le ND, Zhang L (2000) Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia [comment]. Clin Cancer Res 6:357–362
Bockmühl U, Schwendel A, Dietel M, Petersen I (1996) Distinct patterns of chromosomal alterations in high- and low-grade head and neck squamous cell carcinomas. Cancer Res 56:5325–5329
Singh B, Gogineni SK, Sacks PG, Shaha AR, Shah JP, Stoffel A, Rao PH (2001) Molecular cytogenetic characterization of head and neck squamous cell carcinoma and refinement of 3q amplification. Cancer Res 61:4506–4513
Bockmühl U, Schlüns K, Küchler I, Petersen S, Petersen I (2000) Genetic imbalances with impact on survival in head and neck cancer patients. Am J Pathol 57:369–375
Bockmühl U, Ishwad CS, Ferrell RE, Gollin SM (2001) Association of 8p23 deletions with poor survival in head and neck cancer. Otolaryngol Head Neck Surg 124:451–455
Pearlstein RP, Benninger MS, Carey TE, Zarbo RJ, Torres FX, Rybicki BA, Dyke DL (1998) Loss of 18q predicts poor survival of patients with squamous cell carcinoma of the head and neck. Genes Chromosomes Cancer 21:333–339
Ashman JN, Patmore HS, Condon LT, Cawkwell L, Stafford ND, Greenman J (2003) Prognostic value of genomic alterations in head and neck squamous cell carcinoma detected by comparative genomic hybridization. Br J Cancer 89:864–869
Parikh RA, White JS, Huang X, Schoppy DW, Baysal BE, Baskaran R, Bakkenist CJ, Saunders WS, Hsu L, Romkes M, Gollin SM (2007) Loss of distal 11q is associated with DNA-repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma. Genes Chromosomes Cancer 46:761–775
Snijders AM, Pinkel D, Albertson DG (2003) Current status and future prospects of array-based comparative genomic hybridisation. Brief Funct Genomic Proteomic 2:37–45
Pinkel D, Albertson DG (2005) Comparative genomic hybridization. Annu Rev Genomics Hum Genet 6:331–335
Barnes L, Everson JW, Reichart P, Sidransky D (eds) (2005) World health organisation classification of tumours: pathology and genetics of head and neck tumours. IARC, Lyon
Sobin LH, Wittekind Ch (eds) (2002) UICC: TNM classification of malignant tumours, 6th ed. Wiley-Liss, New York
Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258:818–821
Kallioniemi OP, Kallioniemi A, Piper J, Isola J, Waldman FM, Gray JW, Pinkel D (1994) Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer 10:231–243
Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE, Smith J, Vetrie D, Gorman P, Tomlinson IP, Carter NP (2003) DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36:361–374
van Beers EH, Joosse SA, Ligtenberg MJ, Fles R, Hogervorst FB, Verhoef S, Nederlof PM (2006) A multiplex PCR predictor for a CGH success of FFPE samples. Br J Cancer 94:333–337
Hupé P, Stransky N, Thiery JP, Radvanyi F, Barillot F (2004) Analysis of array-CGH data: from signal ratio to gain and loss of DNA regions. Bioinformatics 20:3413–3422
Unger K, Zitzelsberger H, Salvatore G, Santoro M, Bogdanova T, Braselmann H, Kastner P, Zurnadzhy L, Tronko N, Hutzler P, Thomas G (2004) Heterogeneity in the distribution of RET/PTC rearrangements within individual post-Chernobyl papillary thyroid carcinomas. J Clin Endocrin Metab 89:4272–4279
Merkelbach-Bruse S, Jakob C, Tietze L, Schroder W, Rath W, Fuzesi L (1999) Consensus polymerase chain reaction and enzyme-linked immunosorbent assay for human papillomavirus detection and typing in cervical specimens. Diagn Mol Pathol 8:32–38
Lassmann S, Gerlach UV, Technau-Ihling K, Werner M, Fisch P (2005) Application of BIOMED-2 primers in fixed and decalcified bone marrow biopsies: analysis of immunoglobulin H receptor rearrangements in B-cell non-Hodgkin’s lymphomas. J Mol Diagn 7:582–591
Lehmann EL (1975) Nonparametrics, statistical methods based on ranks. McGraw Hill Higher Education, New York
Kaplan E, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481
Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data. Wiley series in probability and statistics. Wiley, New York
Cox D (1972) Regression models and life tables (with discussion). J R Stat Soc B 34:187–220
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289–300
Speicher MR, Howe C, Crotty P, du Manoir S, Costa J, Ward DC (1995) Comparative genomic hybridization detects novel deletions and amplifications in head and neck squamous cell carcinomas. Cancer Res 55:1010–1013
Bockmühl U, Wolf G, Schmidt S, Schwendel A, Jahnke V, Dietel M, Petersen I (1998) Genomic alterations associated with malignancy in head and neck cancer. Head Neck 20:145–151
Gollin SM (2001) Chromosomal alterations in squamous cell carcinomas of the head and neck: window to the biology of disease. Head Neck 23:238–253
Struski S, Doco-Fenzy M, Cornillet-Lefebvre P (2002) Compilation of published comparative genomic hybridization studies. Cancer Genet Cytogenet 135:63–90
Baudis M, Cleary ML (2001) Progenetix.net: an online repository for molecular cytogenetic aberration data. Bioinformatics 17:1228–1229
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91
D’Andrea AD, Grompe M (2003) The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 3:23–24
Blons H, Laccourreye O, Houllier AM, Carnot F, Brasnu D, Beaune P, Zucman-Rossi J, Laurent-Puig P (2002) Delineation and candidate gene mutation screening of the 18q22 minimal region of deletion in head and neck squamous cell carcinoma. Oncogene 21:5016–5023
Hajra KM, Fearon ER (2002) Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer 34:255–268
Storojeva I, Boulay JL, Ballabeni P, Buess M, Terracciano L, Laffer U, Mild G, Herrmann R, Rochlitz C (2005) Prognostic and predictive relevance of DNAM-1, SOCS6 and CADH-7 genes on chromosome 18q in colorectal cancer. Oncology 68:246–255
Levy Y, Arbel-Goren R, Hadari YR, Eshhar S, Ronen D, Elhanany E, Geider B, Zick Y (2001) Galectin-8 functions as a matricellular modulator of cell adhesion. J Biol Chem 276:31285–31295
Wu Y, Berends MJ, Post JG, Mensink RG, Verlind E, Van der Sluis T, Kempinga C, Sijmons RH, van der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM (2001) Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. Gastroenterol 120:1580–1587
Suzuki T, Matsuo K, Hasegawa Y, Hiraki A, Wakai K, Hirose K, Saito T, Sato S, Ueda R, Tajima K (2007) One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study. Cancer Sci 98:1439–1446
Acknowledgements
The skilful technical assistance of E. Konhäuser and Anja Schöpflin is gratefully acknowledged. We would like to acknowledge Cordelia Langford and the Wellcome Trust Sanger Institute microarray facility for providing the 1-Mb BAC arrays.
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Bauer, V.L., Braselmann, H., Henke, M. et al. Chromosomal changes characterize head and neck cancer with poor prognosis. J Mol Med 86, 1353–1365 (2008). https://doi.org/10.1007/s00109-008-0397-0
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DOI: https://doi.org/10.1007/s00109-008-0397-0