Localization of centromeric breaks in head and neck squamous cell carcinoma

      Head and neck squamous cell carcinoma (HNSCC) have very complex karyotypes that show all types of structural rearrangements. The most frequent aberrations are whole-arm translocations, which appear to have their breakpoints in centromeric or pericentromeric regions. We aimed to pinpoint the exact location of the breakpoints of these marker chromosomes with high-resolution cytogenetic and genetic analyses using microarray comparative genomic hybridization (CGH), multiplex ligation-dependent probe amplification (MLPA), and fiber fluorescence in situ hybridization (FISH). Among the seven cell lines in this study, six (84%) harbored one or more centromeric breakpoints or whole-arm translocations. In total, microarray CGH identified 163 breakpoints, 47 (29%) of which were in centromeric regions. Microarray CGH and MLPA results indicated that the translocation breakpoints were localized between the microarray oligonucleotide clones and MLPA probes closest to the centromere. High-resolution fiber-FISH revealed adjacent or minimally overlapping signals of probes that recognize the pericentromeric sequences of the two participating chromosomes. This indicates that whole chromosome arm translocation breakpoints occur within the pericentromeric chromatin and not the centromere core sequences.


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        • Draviam V.M.
        • Xie S.
        • Sorger P.K.
        Chromosome segregation and genomic stability.
        Curr Opin Genet Dev. 2004; 14: 120-125
        • Charames G.S.
        • Bapat B.
        Genomic instability and cancer.
        Curr Mol Med. 2003; 3: 589-596
        • Pihan G.
        • Doxsey S.J.
        Mutations and aneuploidy: co-conspirators in cancer?.
        Cancer Cell. 2003; 4: 89-94
        • Nowak M.A.
        • Komarova N.L.
        • Sengupta A.
        • et al.
        The role of chromosomal instability in tumor initiation.
        Proc Natl Acad Sci U S A. 2002; 99: 16226-16231
        • Rajagopalan H.
        • Lengauer C.
        Aneuploidy and cancer.
        Nature. 2004; 432: 338-341
        • Guerrero A.A.
        • Gamero M.C.
        • Trachana V.
        • et al.
        Centromere-localized breaks indicate the generation of DNA damage by the mitotic spindle.
        Proc Natl Acad Sci U S A. 2010; 107: 4159-4164
        • Beroukhim R.
        • Mermel C.H.
        • Porter D.
        • et al.
        The landscape of somatic copy-number alteration across human cancers.
        Nature. 2010; 463: 899-905
        • Hermsen M.A.
        • Joenje H.
        • Arwert F.
        • et al.
        Centromeric breakage as a major cause of cytogenetic abnormalities in oral squamous cell carcinoma.
        Genes Chromosomes Cancer. 1996; 15: 1-9
        • Torras-Llort M.
        • Moreno-Moreno O.
        • Azorin F.
        Focus on the centre: the role of chromatin on the regulation of centromere identity and function.
        EMBO J. 2009; 28: 2337-2348
        • Hermsen M.A.
        • Baak J.P.
        • Meijer G.A.
        • et al.
        Genetic analysis of 53 lymph node-negative breast carcinomas by CGH and relation to clinical, pathological, morphometric, and DNA cytometric prognostic factors.
        J Pathol. 1998; 186: 356-362
        • Hermsen M.
        • Guervos M.A.
        • Meijer G.
        • et al.
        New chromosomal regions with high-level amplifications in squamous cell carcinomas of the larynx and pharynx, identified by comparative genomic hybridization.
        J Pathol. 2001; 194: 177-182
        • Hermsen M.
        • Postma C.
        • Baak J.
        • et al.
        Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability.
        Gastroenterology. 2002; 123: 1109-1119
        • Meijer G.A.
        • Hermsen M.A.
        • Baak J.P.
        • et al.
        Progression from colorectal adenoma to carcinoma is associated with non-random chromosomal gains as detected by comparative genomic hybridisation.
        J Clin Pathol. 1998; 51: 901-909
        • Jin C.
        • Jin Y.
        • Wennerberg J.
        • et al.
        Nonrandom pattern of cytogenetic abnormalities in squamous cell carcinoma of the larynx.
        Genes Chromosomes Cancer. 2000; 28: 66-76
        • Weiss M.M.
        • Kuipers E.J.
        • Hermsen M.A.
        • et al.
        Barrett's adenocarcinomas resemble adenocarcinomas of the gastric cardia in terms of chromosomal copy number changes, but relate to squamous cell carcinomas of the distal oesophagus with respect to the presence of high-level amplifications.
        J Pathol. 2003; 199: 157-165
        • Hermsen M.
        • Snijders A.
        • Guervos M.A.
        • et al.
        Centromeric chromosomal translocations show tissue-specific differences between squamous cell carcinomas and adenocarcinomas.
        Oncogene. 2005; 24: 1571-1579
        • Bignell G.R.
        • Greenman C.D.
        • Davies H.
        • et al.
        Signatures of mutation and selection in the cancer genome.
        Nature. 2010; 463: 893-898
        • Buffart T.E.
        • Israeli D.
        • Tijssen M.
        • et al.
        Across array comparative genomic hybridization: a strategy to reduce reference channel hybridizations.
        Genes Chromosomes Cancer. 2008; 47: 994-1004
        • Willard H.F.
        Chromosome-specific organization of human alpha satellite DNA.
        Am J Hum Genet. 1985; 37: 524-532
        • Lee C.
        • Wevrick R.
        • Fisher R.B.
        • et al.
        Human centromeric DNAs.
        Hum Genet. 1997; 100: 291-304
        • Schindelhauer D.
        • Schwarz T.
        Evidence for a fast, intrachromosomal conversion mechanism from mapping of nucleotide variants within a homogeneous alpha-satellite DNA array.
        Genome Res. 2002; 12: 1815-1826
        • Nusbaum C.
        • Mikkelsen T.S.
        • Zody M.C.
        • et al.
        DNA sequence and analysis of human chromosome 8.
        Nature. 2006; 439: 331-335
        • Ross M.T.
        • Grafham D.V.
        • Coffey A.J.
        • et al.
        The DNA sequence of the human X chromosome.
        Nature. 2005; 434: 325-337
        • Rudd M.K.
        • Willard H.F.
        Analysis of the centromeric regions of the human genome assembly.
        Trends Genet. 2004; 20: 529-533
        • Schueler M.G.
        • Dunn J.M.
        • Bird C.P.
        • et al.
        Progressive proximal expansion of the primate X chromosome centromere.
        Proc Natl Acad Sci U S A. 2005; 102: 10563-10568
        • Schueler M.G.
        • Higgins A.W.
        • Rudd M.K.
        • et al.
        Genomic and genetic definition of a functional human centromere.
        Science. 2001; 294: 109-115
        • Padilla-Nash H.M.
        • Heselmeyer-Haddad K.
        • Wangsa D.
        • et al.
        Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms.
        Genes Chromosomes Cancer. 2001; 30: 349-363
        • zur Hausen H.
        Human papillomaviruses in the pathogenesis of anogenital cancer.
        Virology. 1991; 184: 9-13
        • Gillison M.L.
        • Koch W.M.
        • Capone R.B.
        • et al.
        Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.
        J Natl Cancer Inst. 2000; 92: 709-720
        • Steenbergen R.D.
        • Hermsen M.A.
        • Walboomers J.M.
        • et al.
        Integrated human papillomavirus type 16 and loss of heterozygosity at 11q22 and 18q21 in an oral carcinoma and its derivative cell line.
        Cancer Res. 1995; 55: 5465-5471
        • Ragin C.C.
        • Reshmi S.C.
        • Gollin S.M.
        Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line.
        Int J Cancer. 2004; 110: 701-709
        • Backsch C.
        • Pauly B.
        • Liesenfeld M.
        • et al.
        Two novel unbalanced whole arm translocations are frequently detected in cervical squamous cell carcinoma.
        Cancer Genet. 2011; 204: 646-653
        • van Zeeburg H.J.
        • Snijders P.J.
        • Pals G.
        • et al.
        Generation and molecular characterization of head and neck squamous carcinoma cell lines of fanconi anemia patients.
        Cancer Res. 2005; 65: 1271-1276
        • Cimini D.
        • Howell B.
        • Maddox P.
        • et al.
        Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells.
        J Cell Biol. 2001; 153: 517-527
        • Thompson S.L.
        • Compton D.A.
        Examining the link between chromosomal instability and aneuploidy in human cells.
        J Cell Biol. 2008; 180: 665-672
        • Martins C.
        • Jin Y.
        • Jin C.
        • et al.
        Fluorescent in situ hybridisation (FISH) characterisation of pericentromeric breakpoints on chromosome 5 in head and neck squamous cell carcinomas.
        Eur J Cancer. 1999; 35: 498-501
        • Jin Y.
        • Jin C.
        • Salemark L.
        • et al.
        Centromere cleavage is a mechanism underlying isochromosome formation in skin and head and neck carcinomas.
        Chromosoma. 2000; 109: 476-481
        • Chueh A.C.
        • Northrop E.L.
        • Brettingham-Moore K.H.
        • et al.
        LINE retrotransposon RNA is an essential structural and functional epigenetic component of a core neocentromeric chromatin.
        PLoS Genet. 2009; 5: e1000354
        • Richards K.L.
        • Zhang B.
        • Baggerly K.A.
        • et al.
        Genome-wide hypomethylation in head and neck cancer is more pronounced in HPV-negative tumors and is associated with genomic instability.
        PLoS One. 2009; 4: e4941
        • Martinez G.J.
        • Perez-Escuredo J.
        • Castro-Santos P.
        • et al.
        Hypomethylation of LINE-1, and not centromeric SAT-α, is associated with centromeric instability in head and neck squamous cell carcinoma.
        Cell Oncol (Dordr). 2012; 35: 259-267
        • Slee R.B.
        • Steiner C.M.
        • Herbert B.S.
        • et al.
        Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability.
        Oncogene. 2012; 31: 3244-3253
      1. Mitelman F, Johansson B, Mertens F. Database of Chromosome Aberrations and Gene Fusions in Cancer. Available at Accessed on July 8, 2011.