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. 1998 Jul;78(1):73–78. doi: 10.1038/bjc.1998.445

Genetic analysis of lung tumours of non-smoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity at the FHIT locus.

A Marchetti 1, S Pellegrini 1, G Sozzi 1, G Bertacca 1, P Gaeta 1, F Buttitta 1, V Carnicelli 1, P Griseri 1, A Chella 1, C A Angeletti 1, M Pierotti 1, G Bevilacqua 1
PMCID: PMC2062949  PMID: 9662254

Abstract

Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathological features, being prevalently adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinomas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinomas caused by smoking. In tumours developed in heavy-smoking subjects, the frequency of LOH at the FHIT locus was significantly higher (P = 0.006) than in tumours from non-smoking subjects. The frequency of p53 mutations in adenocarcinomas caused by smoking was not different from that seen in non-smoking subjects. However, in the group of smoking subjects we observed mostly G:C --> T:A transversions, whereas frameshift mutations and G:C --> A:T transitions were more frequently found in tumours from non-smoking subjects. No point mutations of the K-ras gene at codon 12 were seen in subjects who had never smoked, whereas they were present (mostly G:C --> T:A transversions) in 34% of tumours caused by smoking (P = 0.002). Our data suggest that lung adenocarcinomas developed in subjects who had never smoked represent a distinct biological entity involving a co-alteration of the p53 gene and the FHIT locus in 20% of cases.

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Selected References

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  1. Blin N., Stafford D. W. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976 Sep;3(9):2303–2308. doi: 10.1093/nar/3.9.2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boldog F., Gemmill R. M., West J., Robinson M., Robinson L., Li E., Roche J., Todd S., Waggoner B., Lundstrom R. Chromosome 3p14 homozygous deletions and sequence analysis of FRA3B. Hum Mol Genet. 1997 Feb;6(2):193–203. doi: 10.1093/hmg/6.2.193. [DOI] [PubMed] [Google Scholar]
  3. Brownson R. C., Loy T. S., Ingram E., Myers J. L., Alavanja M. C., Sharp D. J., Chang J. C. Lung cancer in nonsmoking women. Histology and survival patterns. Cancer. 1995 Jan 1;75(1):29–33. doi: 10.1002/1097-0142(19950101)75:1<29::aid-cncr2820750107>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  4. Denissenko M. F., Pao A., Tang M., Pfeifer G. P. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996 Oct 18;274(5286):430–432. doi: 10.1126/science.274.5286.430. [DOI] [PubMed] [Google Scholar]
  5. Lee L. N., Shew J. Y., Sheu J. C., Lee Y. C., Lee W. C., Fang M. T., Chang H. F., Yu C. J., Yang P. C., Luh K. T. Exon 8 mutation of p53 gene associated with nodal metastasis in non-small-cell lung cancer. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 1):1667–1671. doi: 10.1164/ajrccm.150.6.7952630. [DOI] [PubMed] [Google Scholar]
  6. Li Z. H., Zheng J., Weiss L. M., Shibata D. c-k-ras and p53 mutations occur very early in adenocarcinoma of the lung. Am J Pathol. 1994 Feb;144(2):303–309. [PMC free article] [PubMed] [Google Scholar]
  7. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. doi: 10.1016/0092-8674(92)90243-6. [DOI] [PubMed] [Google Scholar]
  8. Marchetti A., Buttitta F., Merlo G., Diella F., Pellegrini S., Pepe S., Macchiarini P., Chella A., Angeletti C. A., Callahan R. p53 alterations in non-small cell lung cancers correlate with metastatic involvement of hilar and mediastinal lymph nodes. Cancer Res. 1993 Jun 15;53(12):2846–2851. [PubMed] [Google Scholar]
  9. Mountain C. F. A new international staging system for lung cancer. Chest. 1986 Apr;89(4 Suppl):225S–233S. doi: 10.1378/chest.89.4_supplement.225s. [DOI] [PubMed] [Google Scholar]
  10. Renault B., Calistri D., Buonsanti G., Nanni O., Amadori D., Ranzani G. N. Microsatellite instability and mutations of p53 and TGF-beta RII genes in gastric cancer. Hum Genet. 1996 Nov;98(5):601–607. doi: 10.1007/s004390050267. [DOI] [PubMed] [Google Scholar]
  11. Rodenhuis S., Slebos R. J., Boot A. J., Evers S. G., Mooi W. J., Wagenaar S. S., van Bodegom P. C., Bos J. L. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res. 1988 Oct 15;48(20):5738–5741. [PubMed] [Google Scholar]
  12. Shopland D. R., Eyre H. J., Pechacek T. F. Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States? J Natl Cancer Inst. 1991 Aug 21;83(16):1142–1148. doi: 10.1093/jnci/83.16.1142. [DOI] [PubMed] [Google Scholar]
  13. Slebos R. J., Hruban R. H., Dalesio O., Mooi W. J., Offerhaus G. J., Rodenhuis S. Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst. 1991 Jul 17;83(14):1024–1027. doi: 10.1093/jnci/83.14.1024. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Suzuki H., Takahashi T., Kuroishi T., Suyama M., Ariyoshi Y., Takahashi T., Ueda R. p53 mutations in non-small cell lung cancer in Japan: association between mutations and smoking. Cancer Res. 1992 Feb 1;52(3):734–736. [PubMed] [Google Scholar]
  16. Takahashi T., Nau M. M., Chiba I., Birrer M. J., Rosenberg R. K., Vinocour M., Levitt M., Pass H., Gazdar A. F., Minna J. D. p53: a frequent target for genetic abnormalities in lung cancer. Science. 1989 Oct 27;246(4929):491–494. doi: 10.1126/science.2554494. [DOI] [PubMed] [Google Scholar]
  17. Takeshima Y., Seyama T., Bennett W. P., Akiyama M., Tokuoka S., Inai K., Mabuchi K., Land C. E., Harris C. C. p53 mutations in lung cancers from non-smoking atomic-bomb survivors. Lancet. 1993 Dec 18;342(8886-8887):1520–1521. doi: 10.1016/s0140-6736(05)80087-x. [DOI] [PubMed] [Google Scholar]
  18. Wu C., Akiyama Y., Imai K., Miyake S., Nagasaki H., Oto M., Okabe S., Iwama T., Mitamura K., Masumitsu H. DNA alterations in cells from hereditary non-polyposis colorectal cancer patients. Oncogene. 1994 Mar;9(3):991–994. [PubMed] [Google Scholar]
  19. Yin Y., Tainsky M. A., Bischoff F. Z., Strong L. C., Wahl G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell. 1992 Sep 18;70(6):937–948. doi: 10.1016/0092-8674(92)90244-7. [DOI] [PubMed] [Google Scholar]

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