Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Feb 21;82(6):1191–1197. doi: 10.1054/bjoc.1999.1062

Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features

J Geradts 1,#, K M Fong 2,#, P V Zimmerman 2, J D Minna 3
PMCID: PMC2363352  PMID: 10735505

Abstract

The FHIT gene is located at a chromosomal site (3p14.2) which is commonly affected by translocations and deletions in human neoplasia. Although FHIT alterations at the DNA and RNA level are frequent in many types of tumours, the biological and clinical significance of these changes is not clear. In this study we aimed at correlating loss of Fhit protein expression with a large number of molecular genetic and clinical parameters in a well-characterized cohort of non-small-cell lung cancers (NSCLCs). Paraffin sections of 99 non-small-cell carcinomas were reacted with an anti-Fhit polyclonal antibody in a standard immunohistochemical reaction. Abnormal cases were characterized by complete loss of cytoplasmic Fhit staining. The Fhit staining results were then correlated with previously obtained clinical and molecular data. Fifty-two of 99 tumours lacked cytoplasmic Fhit staining, with preserved reactivity in adjacent normal cells. Lack of Fhit staining correlated with: loss of heterozygosity (LOH) at the FHIT 3p14.2 locus, but not at other loci on 3p; squamous histology; LOH at 17p13 and 5q but not with LOH at multiple other suspected tumour suppressor gene loci; and was inversely correlated with codon 12 mutations in K- ras. Fhit expression was not correlated overall with a variety of clinical parameters including survival and was not associated with abnormalities of immunohistochemical expression of p53, RB, and p16. All of these findings are consistent with loss of Fhit protein expression being as frequent an abnormality in lung cancer pathogenesis as are p53 and p16 protein abnormalities and that such loss occurs independently of the commitment to the metastatic state and of most other molecular abnormalities. © 2000 Cancer Research Campaign

Keywords: FHIT, immunohistochemistry, lung cancer, prognosis, loss of heterozygosity

Full Text

The Full Text of this article is available as a PDF (243.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baffa R., Veronese M. L., Santoro R., Mandes B., Palazzo J. P., Rugge M., Santoro E., Croce C. M., Huebner K. Loss of FHIT expression in gastric carcinoma. Cancer Res. 1998 Oct 15;58(20):4708–4714. [PubMed] [Google Scholar]
  2. Burke L., Khan M. A., Freedman A. N., Gemma A., Rusin M., Guinee D. G., Bennett W. P., Caporaso N. E., Fleming M. V., Travis W. D. Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer. Cancer Res. 1998 Jun 15;58(12):2533–2536. [PubMed] [Google Scholar]
  3. Fong K. M., Biesterveld E. J., Virmani A., Wistuba I., Sekido Y., Bader S. A., Ahmadian M., Ong S. T., Rassool F. V., Zimmerman P. V. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res. 1997 Jun 1;57(11):2256–2267. [PubMed] [Google Scholar]
  4. Fong K. M., Kida Y., Zimmerman P. V., Ikenaga M., Smith P. J. Loss of heterozygosity frequently affects chromosome 17q in non-small cell lung cancer. Cancer Res. 1995 Oct 1;55(19):4268–4272. [PubMed] [Google Scholar]
  5. Fong K. M., Zimmerman P. V., Smith P. J. Correlation of loss of heterozygosity at 11p with tumour progression and survival in non-small cell lung cancer. Genes Chromosomes Cancer. 1994 Jul;10(3):183–189. doi: 10.1002/gcc.2870100306. [DOI] [PubMed] [Google Scholar]
  6. Fong K. M., Zimmerman P. V., Smith P. J. KRAS codon 12 mutations in Australian non-small cell lung cancer. Aust N Z J Med. 1998 Apr;28(2):184–189. doi: 10.1111/j.1445-5994.1998.tb02967.x. [DOI] [PubMed] [Google Scholar]
  7. Fong K. M., Zimmerman P. V., Smith P. J. Microsatellite instability and other molecular abnormalities in non-small cell lung cancer. Cancer Res. 1995 Jan 1;55(1):28–30. [PubMed] [Google Scholar]
  8. Fong K. M., Zimmerman P. V., Smith P. J. Tumor progression and loss of heterozygosity at 5q and 18q in non-small cell lung cancer. Cancer Res. 1995 Jan 15;55(2):220–223. [PubMed] [Google Scholar]
  9. Geradts J., Fong K. M., Zimmerman P. V., Maynard R., Minna J. D. Correlation of abnormal RB, p16ink4a, and p53 expression with 3p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. Clin Cancer Res. 1999 Apr;5(4):791–800. [PubMed] [Google Scholar]
  10. Greenspan D. L., Connolly D. C., Wu R., Lei R. Y., Vogelstein J. T., Kim Y. T., Mok J. E., Muñoz N., Bosch F. X., Shah K. Loss of FHIT expression in cervical carcinoma cell lines and primary tumors. Cancer Res. 1997 Nov 1;57(21):4692–4698. [PubMed] [Google Scholar]
  11. Hadaczek P., Siprashvili Z., Markiewski M., Domagala W., Druck T., McCue P. A., Pekarsky Y., Ohta M., Huebner K., Lubinski J. Absence or reduction of Fhit expression in most clear cell renal carcinomas. Cancer Res. 1998 Jul 15;58(14):2946–2951. [PubMed] [Google Scholar]
  12. Kovatich A., Friedland D. M., Druck T., Hadaczek P., Huebner K., Comis R. L., Hauck W., McCue P. A. Molecular alterations to human chromosome 3p loci in neuroendocrine lung tumors. Cancer. 1998 Sep 15;83(6):1109–1117. doi: 10.1002/(sici)1097-0142(19980915)83:6<1109::aid-cncr9>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  13. Marchetti A., Pellegrini S., Bertacca G., Buttitta F., Gaeta P., Carnicelli V., Nardini V., Griseri P., Chella A., Angeletti C. A. FHIT and p53 gene abnormalities in bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras mutations. J Pathol. 1998 Mar;184(3):240–246. doi: 10.1002/(SICI)1096-9896(199803)184:3<240::AID-PATH20>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  14. Marchetti A., Pellegrini S., Sozzi G., Bertacca G., Gaeta P., Buttitta F., Carnicelli V., Griseri P., Chella A., Angeletti C. A. Genetic analysis of lung tumours of non-smoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity at the FHIT locus. Br J Cancer. 1998 Jul;78(1):73–78. doi: 10.1038/bjc.1998.445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nelson H. H., Wiencke J. K., Gunn L., Wain J. C., Christiani D. C., Kelsey K. T. Chromosome 3p14 alterations in lung cancer: evidence that FHIT exon deletion is a target of tobacco carcinogens and asbestos. Cancer Res. 1998 May 1;58(9):1804–1807. [PubMed] [Google Scholar]
  16. Ohta M., Inoue H., Cotticelli M. G., Kastury K., Baffa R., Palazzo J., Siprashvili Z., Mori M., McCue P., Druck T. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell. 1996 Feb 23;84(4):587–597. doi: 10.1016/s0092-8674(00)81034-x. [DOI] [PubMed] [Google Scholar]
  17. Otterson G. A., Xiao G. H., Geradts J., Jin F., Chen W. D., Niklinska W., Kaye F. J., Yeung R. S. Protein expression and functional analysis of the FHIT gene in human tumor cells. J Natl Cancer Inst. 1998 Mar 18;90(6):426–432. doi: 10.1093/jnci/90.6.426. [DOI] [PubMed] [Google Scholar]
  18. Simon B., Bartsch D., Barth P., Prasnikar N., Münch K., Blum A., Arnold R., Göke B. Frequent abnormalities of the putative tumor suppressor gene FHIT at 3p14.2 in pancreatic carcinoma cell lines. Cancer Res. 1998 Apr 15;58(8):1583–1587. [PubMed] [Google Scholar]
  19. Siprashvili Z., Sozzi G., Barnes L. D., McCue P., Robinson A. K., Eryomin V., Sard L., Tagliabue E., Greco A., Fusetti L. Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13771–13776. doi: 10.1073/pnas.94.25.13771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sozzi G., Pastorino U., Moiraghi L., Tagliabue E., Pezzella F., Ghirelli C., Tornielli S., Sard L., Huebner K., Pierotti M. A. Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res. 1998 Nov 15;58(22):5032–5037. [PubMed] [Google Scholar]
  21. Sozzi G., Sard L., De Gregorio L., Marchetti A., Musso K., Buttitta F., Tornielli S., Pellegrini S., Veronese M. L., Manenti G. Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res. 1997 Jun 1;57(11):2121–2123. [PubMed] [Google Scholar]
  22. Sozzi G., Tornielli S., Tagliabue E., Sard L., Pezzella F., Pastorino U., Minoletti F., Pilotti S., Ratcliffe C., Veronese M. L. Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities. Cancer Res. 1997 Dec 1;57(23):5207–5212. [PubMed] [Google Scholar]
  23. Sozzi G., Veronese M. L., Negrini M., Baffa R., Cotticelli M. G., Inoue H., Tornielli S., Pilotti S., De Gregorio L., Pastorino U. The FHIT gene 3p14.2 is abnormal in lung cancer. Cell. 1996 Apr 5;85(1):17–26. doi: 10.1016/s0092-8674(00)81078-8. [DOI] [PubMed] [Google Scholar]
  24. Tomizawa Y., Nakajima T., Kohno T., Saito R., Yamaguchi N., Yokota J. Clinicopathological significance of Fhit protein expression in stage I non-small cell lung carcinoma. Cancer Res. 1998 Dec 1;58(23):5478–5483. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES