The common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. A number of the CFSs have been found to span genes that extend over large genomic regions (>700 kb). The expression of these genes is frequently abrogated in a number of different cancers and several of them have already been shown to function as tumor suppressor genes, both in vitro and in vivo. We analyzed the expression of 14 large CFS genes in two distinct groups of head and neck cancers using real-time RT-PCR. The first were oral tongue squamous cell carcinomas (SCCs) and the second were base of tongue/tonsillar (oropharyngeal) SCCs. These two groups were previously examined for the presence of human papillomavirus (HPV) and while 46% of the oropharyngeal cancers were positive for HPV16 only one of 52 oral cancers contained HPV16 sequences. We observed a distinct pattern of loss of expression of the large CFS genes in the two groups of head and neck cancers. In addition, there was no correlation between the relative instability in different CFS regions and which genes were inactivated. Thus, this report demonstrates another distinction between these two groups of head and neck cancer. In addition, it suggests that there is selection for loss of expression of specific CFS genes in these cancers.

1.
Arlt MF, Casper AM, Glover TW: Common fragile sites. Cytogenet Genome Res 100:92–100 (2003).
2.
Arlt MF, Durkin SG, Ragland RL, Glover TW: Common fragile sites as targets for chromosome rearrangements. DNA Repair (Amst) 5:1126–1135 (2006).
3.
Bauer HM, Ting Y, Greer CE, Chambers JC, Tashiro CJ, et al: Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 265:472–477 (1991).
4.
Becker NA, Thorland EC, Denison SR, Phillips LA, Smith DI: Evidence that instability within the FRA3B region extends four megabases. Oncogene 21:8713–8722 (2002).
5.
Callahan G, Denison SR, Phillips LA, Shridhar V, Smith DI: Characterization of the common fragile site FRA9E and its potential role in ovarian cancer. Oncogene 22:590–601 (2003).
6.
Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, et al: Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci USA 100:5956–5961 (2003).
7.
Chang NS, Doherty J, Ensign A, Lewis J, Heath J, et al: Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses. Biochem Pharmacol 66:1347–1354 (2003).
8.
Chen JK, Katz RV, Krutchkoff DJ: Intraoral squamous cell carcinoma. Epidemiologic patterns in Connecticut from 1935 to 1985. Cancer 66:1288–1296 (1990).
9.
Cox C, Bignell G, Greenman C, Stabenau A, Warren W, et al: A survey of homozygous deletions in human cancer genomes. Proc Natl Acad Sci USA 102:4542–4547 (2005).
10.
Dahlgren L, Dahlstrand HM, Lindquist D, Hogmo A, Bjornestal L, et al: Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients. Int J Cancer 112:1015–1019 (2004).
11.
de Roda Husman AM, Walboomers JM, van den Brule AJ, Meijer CJ, Snijders PJ: The use of general primers GP5 and GP6 elongated at their 3′ ends with adjacent highly conserved sequences improves human papillomavirus detection by PCR. J Gen Virol 76:1057–1062 (1995).
12.
Denison SR, Callahan G, Becker NA, Phillips LA, Smith DI: Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Genes Chromosomes Cancer 38:40–52 (2003).
13.
Dumon KR, Ishii H, Fong LY, Zanesi N, Fidanza V, et al: FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proc Natl Acad Sci USA 98:3346–3351 (2001).
14.
Durkin SG, Ragland RL, Arlt MF, Mulle JG, Warren ST, Glover TW: Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc Natl Acad Sci USA 105:246–251 (2008).
15.
Fabbri M, Iliopoulos D, Trapasso F, Aqeilan RI, Cimmino A, et al: WWOX gene restoration prevents lung cancer growth in vitro and in vivo. Proc Natl Acad Sci USA 102:15611–15616 (2005).
16.
Gillison ML, Shah KV: Human papillomavirus-associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol 13:183–188 (2001).
17.
Glover TW: Instability at chromosomal fragile sites. Recent Results Cancer Res 154:185–199 (1998).
18.
Glover TW: Common fragile sites. Cancer Lett 232:4–12 (2006).
19.
Hellman A, Zlotorynski E, Scherer SW, Cheung J, Vincent JB, et al: A role for common fragile site induction in amplification of human oncogenes. Cancer Cell 1:89–97 (2002).
20.
Helmrich A, Stout-Weider K, Matthaei A, Hermann K, Heiden T, Schrock E: Identification of the human/mouse syntenic common fragile site FRA7K/Fra12C1 – relation of FRA7K and other human common fragile sites on chromosome 7 to evolutionary breakpoints. Int J Cancer 120:48–54 (2007).
21.
Huang LW, Chao SL, Chen TJ: Reduced Fhit expression in cervical carcinoma: correlation with tumor progression and poor prognosis. Gynecol Oncol 90:331–337 (2003).
22.
Ingvarsson S: FHIT alterations in breast cancer. Semin Cancer Biol 11:361–366 (2001).
23.
Ishii H, Furukawa Y: Alterations of common chromosome fragile sites in hematopoietic malignancies. Int J Hematol 79:238–242 (2004).
24.
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8–29 (2004).
25.
Kademani D: Oral cancer. Mayo Clin Proc 82:878–887 (2007).
26.
Krummel KA, Roberts LR, Kawakami M, Glover TW, Smith DI: The characterization of the common fragile site FRA16D and its involvement in multiple myeloma translocations. Genomics 69:37–46 (2000).
27.
Langbein S, Szakacs O, Wilhelm M, Sukosd F, Weber S, et al: Alteration of the LRP1B gene region is associated with high grade of urothelial cancer. Lab Invest 82:639–643 (2002).
28.
Lee JI, Soria JC, Hassan K, Liu D, Tang X, et al: Loss of Fhit expression is a predictor of poor outcome in tongue cancer. Cancer Res 61:837–841 (2001).
29.
Llewellyn CD, Johnson NW, Warnakulasuriya KA: Risk factors for squamous cell carcinoma of the oral cavity in young people – a comprehensive literature review. Oral Oncol 37:401–418 (2001).
30.
Mao L, Hong WK, Papadimitrakopoulou VA: Focus on head and neck cancer. Cancer Cell 5:311–316 (2004).
31.
Matsuyama A, Croce CM, Huebner K: Common fragile genes. Eur J Histochem 48:29–36 (2004).
32.
McAvoy S, Ganapathiraju SC, Ducharme-Smith AL, Pritchett JR, Kosari F, et al: Non-random inactivation of large common fragile site genes in different cancers. Cytogenet Genome Res 118:260–269 (2007a).
33.
McAvoy S, Ganapathiraju S, Perez DS, James CD, Smith DI: DMD and IL1RAPL1: two large adjacent genes localized within a common fragile site (FRAXC) have reduced expression in cultured brain tumors. Cytogenet Genome Res 119:196–203 (2007b).
34.
McAvoy S, Zhu Y, Perez DS, James CD, Smith DI: Disabled-1 is a large common fragile site gene, inactivated in multiple cancers. Genes Chromosomes Cancer 47:165–174 (2008).
35.
McKaig RG, Baric RS, Olshan AF: Human papillomavirus and head and neck cancer: epidemiology and molecular biology. Head Neck 20:250–265 (1998).
36.
Nunez MI, Rosen DG, Ludes-Meyers JH, Abba MC, Kil H, et al: WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome. BMC Cancer 5:64 (2005).
37.
Paige AJ, Taylor KJ, Taylor C, Hillier SG, Farrington S, et al: WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci USA 98:11417–11422 (2001).
38.
Pelliccia F, Curatolo A, Limongi ZM, Bosco N, Rocchi A: Transcriptional profiling of genes at the human common fragile site FRA1H in tumor-derived cell lines. Cancer Genet Cytogenet 178:144–150 (2007).
39.
Pluciennik E, Kusinska R, Potemski P, Kubiak R, Kordek R, Bednarek AK: WWOX – the FRA1 6D cancer gene: expression correlation with breast cancer progression and prognosis. Eur J Surg Oncol 32:153–157 (2006).
40.
Reshmi SC, Huang X, Schoppy DW, Black RC, Saunders WS, et al: Relationship between FRA11F and 11q13 gene amplification in oral cancer. Genes Chromosomes Cancer 46:143–154 (2007).
41.
Rocco A, Schandl L, Chen J, Wang H, Tulassay Z, et al: Loss of FHIT protein expression correlates with disease progression and poor differentiation in gastric cancer. J Cancer Res Clin Oncol 129:84–88 (2003).
42.
Rozier L, El-Achkar E, Apiou F, Debatisse M: Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer. Oncogene 23:6872–6880 (2004).
43.
Savelyeva L, Sagulenko E, Schmitt JG, Schwab M: The neurobeachin gene spans the common fragile site FRA13A. Hum Genet 118:551–558 (2006).
44.
Schantz SP, Yu GP: Head and neck cancer incidence trends in young Americans, 1973–1997, with a special analysis for tongue cancer. Arch Otolaryngol Head Neck Surg 128:268–274 (2002).
45.
Shridhar V, Wang L, Rosati R, Paradee W, Shridhar R, et al: Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas. Oncogene 14:1269–1277 (1997).
46.
Silverman S, Jr: Demographics and occurrence of oral and pharyngeal cancers. The outcomes, the trends, the challenge. J Am Dent Assoc 132 Suppl:7S–11S (2001).
47.
Silverman S, Jr, Gorsky M: Epidemiologic and demographic update in oral cancer: California and national data – 1973 to 1985. J Am Dent Assoc 120:495–499 (1990).
48.
Singh B, Bhaya M, Zimbler M, Stern J, Roland JT, et al: Impact of comorbidity on outcome of young patients with head and neck squamous cell carcinoma. Head Neck 20:1–7 (1998).
49.
Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, et al: Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA 94:13771–13776 (1997).
50.
Smith DI, Huang H, Wang L: Common fragile sites and cancer (review). Int J Oncol 12:187–196 (1998).
51.
Smith DI, Zhu Y, McAvoy S, Kuhn R: Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett 232:48–57 (2006).
52.
Smith DI, McAvoy S, Zhu Y, Perez DS: Large common fragile site genes and cancer. Semin Cancer Biol 17:31–41 (2007).
53.
Sonoda I, Imoto I, Inoue J, Shibata T, Shimada Y, et al: Frequent silencing of low density lipoprotein receptor-related protein 1B (LRP1B) expression by genetic and epigenetic mechanisms in esophageal squamous cell carcinoma. Cancer Res 64:3741–3747 (2004).
54.
Sotlar K, Diemer D, Dethleffs A, Hack Y, Stubner A, et al: Detection and typing of human papillomavirus by e6 nested multiplex PCR. J Clin Microbiol 42:3176–3184 (2004).
55.
Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, et al: The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 85:17–26 (1996).
56.
Strome SE, Savva A, Brissett AE, Gostout BS, Lewis J, et al: Squamous cell carcinoma of the tonsils: a molecular analysis of HPV associations. Clin Cancer Res 8:1093–1100 (2002).
57.
Sutherland GR: Rare fragile sites. Cytogenet Genome Res 100:77–84 (2003).
58.
Swango PA: Cancers of the oral cavity and pharynx in the United States: an epidemiologic overview. J Public Health Dent 56:309–318 (1996).
59.
Virgilio L, Shuster M, Gollin SM, Veronese ML, Ohta M, et al: FHIT gene alterations in head and neck squamous cell carcinomas. Proc Natl Acad Sci USA 93:9770–9775 (1996).
60.
Wang F, Denison S, Lai JP, Philips LA, Montoya D, et al: Parkin gene alterations in hepatocellular carcinoma. Genes Chromosomes Cancer 40:85–96 (2004).
61.
Yendamuri S, Kuroki T, Trapasso F, Henry AC, Dumon KR, et al: WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer. Cancer Res 63:878–881 (2003).
62.
Zhu Y, McAvoy S, Kuhn R, Smith DI: RORA, a large common fragile site gene, is involved in cellular stress response. Oncogene 25:2901–2908 (2006).
63.
Zimonjic DB, Druck T, Ohta M, Kastury K, Croce CM, et al: Positions of chromosome 3p14.2 fragile sites (FRA3B) within the FHIT gene. Cancer Res 57:1166–1170 (1997).
64.
Zlotorynski E, Rahat A, Skaug J, Ben-Porat N, Ozeri E, et al: Molecular basis for expression of common and rare fragile sites. Mol Cell Biol 23:7143–7151 (2003).
© 2008 S. Karger AG, Basel
2008
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.