Abstract
Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic alteration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours with concordant deletion in the 4 most involved loci (3p21, 5q11–13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours without deletions at the corresponding loci (P< 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11–13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Albertoni M, Daub DM, Arden KC, Viars CS, Powell C and Van Meir EG (1998) Genetic instability leads to loss of both p53 alleles in a human glioblastoma. Oncogene 16: 321–326
Benachenhou N, Guiral S, Gorska-Flipot I, Labuda D and Sinnett D (1998) High resolution deletion mapping reveals frequent allelic losses at the DNA mismatch repair loci hMLH1 and hMSH3 in non-small cell lung cancer. Int J Cancer 77: 173–180
Benachenhou N, Guiral S, Gorska-Flipot I, Labuda D and Sinnett D (1999) Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer. Br J Cancer 79: 1012–1017
Bennett WP (1995) p53 alterations in progenitor lesions of the bronchus, esophagus, oral cavity, and colon. Cancer Detect Prev 19: 503–511
Bennett WP, Colby TV, Travis WD, Borkowski A, Jones RT, Lane DP, Metcalf RA, Samet JM, Takeshima Y and Gu JR (1993) p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 53: 4817–4822
Buchhop S, Gibson MK, Wang XW, Wagner P, Sturzbecher HW and Harris CC (1997) Interaction of p53 with the human Rad51 protein. Nucleic Acids Res 25: 3868–3874
Burke L, Khan MA, Freedman AN, Gemma A, Rusin M, Guinee DG, Bennett WP, Caporaso NE, Fleming MV, Travis WD, Colby TV, Trastek V, Pairolero PC, Tazelaar HD, Midthun DE, Liotta LA and Harris CC (1998) Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer. Cancer Res 58: 2533–2536
Caligo MA, Ghimenti C, Marchetti A, Lonobile A, Buttitta F, Pellegrini S and Bevilacqua G (1998) Microsatellite alterations and p53, TGF betaRII, IGFIIR and BAX mutations in sporadic non-small-cell lung cancer. Int J Cancer 78: 606–609
Canzian F, Salovaara R, Hemminki A, Kristo P, Chadwick RB, Aaltonen LA and de la Chapelle A (1996) Semiautomated assessment of loss of heterozygosity and replication error in tumors. Cancer Res 56: 3331–3337
Chevillard S, Radicella JP, Levalois C, Lebeau J, Poupon MF, Oudard S, Dutrillaux B and Boiteux S (1998) Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene 16: 3083–3086
Davis TW, Wilson-Van PC, Meyers M, Kunugi KA, Cuthill S, Reznikoff C, Garces C, Boland CR, Kinsella TJ, Fishel R and Boothman DA (1998) Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation. Cancer Res 58: 767–778
de Wind N, Dekker M, Berns A, Radman M and te RH (1995) Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82: 321–330
Denissenko MF, Pao A, Tang M and Pfeifer GP (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274: 430–432
Eshleman JR and Markowitz SD (1996) Mismatch repair defects in human carcinogenesis. Hum Mol Genet 5: 1489–1494
Gazdar AF (1994) The molecular and cellular basis of human lung cancer. Anticancer Res 14: 261–267
Greenblatt MS, Bennett WP, Hollstein M and Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878
Gupta PK, Sahota A, Boyadjiev SA, Bye S, Shao C, O'Neill JP, Hunter TC, Albertini RJ, Stambrook PJ and Tischfield JA (1997) High frequency in vivo loss of heterozygosity is primarily a consequence of mitotic recombination. Cancer Res 57: 1188–1193
Hartwell L (1992) Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71: 543–546
Hirao T, Nelson HH, Ashok TDS, Wiencke JK, Zu Z-F, Gunn L, Wain JC, Mark EW, Christiani DC and Kelsey KT (2000) Early smoking and increased DNA adduct burden predict LOH at 3p21 in NSCLC. Proc Am Ass Cancer Res 41: 321 (Abstract)
Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R and Harris CC (1994) Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res 22: 3551–3555
Horio Y, Takahashi T, Kuroishi T, Hibi K, Suyama M, Niimi T, Shimokata K, Yamakawa K, Nakamura Y and Ueda R (1993) Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res 53: 1–4
Kohno H, Hiroshima K, Toyozaki T, Fujisawa T and Ohwada H (1999) p53 mutation and allelic loss of chromosome 3p, 9p of preneoplastic lesions in patients with nonsmall cell lung carcinoma. Cancer 85: 341–347
Kohno T and Yokota J (1999) How many tumor suppressor genes are involved in human lung carcinogenesis?. Carcinogenesis 20: 1403–1410
Kure EH, Ryberg D, Hewer A, Phillips DH, Skaug V, Baera R and Haugen A (1996) p53 mutations in lung tumours: relationship to gender and lung DNA adduct levels. Carcinogenesis 17: 2201–2205
Lengauer C, Kinzler KW and Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386: 623–627
Lindstedt BA, Ryberg D, Zienolddiny S, Khan H and Haugen A (1999) Hras 1 VNTR alleles as susceptibility markers for lung cancer: relationship to microsatellite instability in tumors. Anticancer Res 19: 5523–5527
Livingstone LR, White A, Sprouse J, Livanos E, Jacks T and Tlsty TD (1992) Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70: 923–935
Marchetti A, Pellegrini S, Sozzi G, Bertacca G, Gaeta P, Buttitta F, Carnicelli V, Griseri P, Chella A, Angeletti CA, Pierotti M and Bevilacqua G (1998) 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 78: 73–78
Mekeel KL, Tang W, Kachnic LA, Luo CM, DeFrank JS and Powell SN (1997) Inactivation of p53 results in high rates of homologous recombination. Oncogene 14: 1847–1857
Mellon I, Rajpal DK, Koi M, Boland CR and Champe GN (1996) Transcription-coupled repair deficiency and mutations in human mismatch repair genes. Science 272: 557–560
Meyers M, Theodosiou M, Acharya S, Odegaard E, Wilson T, Lewis JE, Davis TW, Wilson-Van PC, Fishel R and Boothman DA (1997) Cell cycle regulation of the human DNA mismatch repair genes hMSH2, hMLH1, and hPMS2. Cancer Res 57: 206–208
Mitsudomi T, Oyama T, Nishida K, Ogami A, Osaki T, Sugio K, Yasumoto K, Sugimachi K and Gazdar AF (1996) Loss of heterozygosity at 3p in non-small cell lung cancer and its prognostic implication. Clin Cancer Res 2: 1185–1189
Mollerup S, Ryberg D, Hewer A, Phillips DH and Haugen A (1999) Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res 59: 3317–3320
Nelson HH, Wiencke JK, Gunn L, Wain JC, Christiani DC and Kelsey KT (1998) Chromosome 3p14 alterations in lung cancer: evidence that FHIT exon deletion is a target of tobacco carcinogens and asbestos. Cancer Res 58: 1804–1807
Pellegrini S, Bertacca G, Buttitta F, Bevilacqua G and Marchetti A (1999) Lung tumours from non-smoking subjects: A p53 -related genetic instability in a subset of cases. Int J Mol Med 4: 419–424
Ryberg D, Hewer A, Phillips DH and Haugen A (1994a) Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients. Cancer Res 54: 5801–5803
Ryberg D, Kure E, Lystad S, Skaug V, Stangeland L, Mercy I, Borresen AL and Haugen A (1994b) p53 mutations in lung tumors: relationship to putative susceptibility markers for cancer. Cancer Res 54: 1551–1555
Sato S, Nakamura Y and Tsuchiya E (1994) Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res 54: 5652–5655
Schreiber G, Fong KM, Peterson B, Johnson BE, O'Briant KC and Bepler G (1997) Smoking, gender, and survival association with allele loss for the LOH11B lung cancer region on chromosome 11. Cancer Epidemiol Biomarkers Prev 6: 315–319
Skaug V, Ryberg D, Kure EH, Arab MO, Stangeland L, Myking AO and Haugen A (2000) p53 mutations in defined structural and functional domains are related to poor clinical outcome in non-small cell lung cancer patients. Clin Cancer Res 6: 1031–1037
Sozzi G, Sard L, De Gregorio L, Marchetti A, Musso K, Buttitta F, Tornielli S, Pellegrini S, Veronese ML, Manenti G, Incarbone M, Chella A, Angeletti CA, Pastorino U, Huebner K, Bevilaqua G, Pilotti S, Croce CM and Pierotti MA (1997) Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res 57: 2121–2123
Takagi Y, Osada H, Kuroishi T, Mitsudomi T, Kondo M, Niimi T, Saji S, Gazdar AF, Takahashi T and Minna JD (1998) p53 mutations in non-small-cell lung cancers occurring in individuals without a past history of active smoking. Br J Cancer 77: 1568–1572
Todd S, Franklin WA, Varella-Garcia M, Kennedy T, Hilliker CEJ, Hahner L, Anderson M, Wiest JS, Drabkin HA and Gemmill RM (1997) Homozygous deletions of human chromosome 3p in lung tumors. Cancer Res 57: 1344–1352
Tomizawa Y, Nakajima T, Kohno T, Saito R, Yamaguchi N and Yokota J (1998) Clinicopathological significance of Fhit protein expression in stage I non-small cell lung carcinoma. Cancer Res 58: 5478–5483
Walker DR, Bond JP, Tarone RE, Harris CC, Makalowski W, Boguski MS and Greenblatt MS (1999) Evolutionary conservation and somatic mutation hotspot maps of p53: correlation with p53 protein structural and functional features. Oncogene 18: 211–218
Wei Q and Spitz MR (1997) The role of DNA repair capacity in susceptibility to lung cancer: a review. Cancer Metastasis Rev 16: 295–307
Wei Q, Cheng L, Hong WK and Spitz MR (1996) Reduced DNA repair capacity in lung cancer patients. Cancer Res 56: 4103–4107
Wei Q, Eicher SA, Guan Y, Cheng L, Xu J, Young LN, Saunders KC, Jiang H, Hong WK, Spitz MR and Strom SS (1998) Reduced expression of hMLH1 and hGTBP/hMSH6: a risk factor for head and neck cancer. Cancer Epidemiol Biomakers Prev 7: 309–314
Wistuba II, Montellano FD, Milchgrub S, Virmani AK, Behrens C, Chen H, Ahmadian M, Nowak JA, Muller C, Minna JD and Gazdar AF (1997) Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma. Cancer Res 57: 3154–3158
Wistuba II, Behrens C, Milchgrub S, Bryant D, Hung J, Minna JD and Gazdar AF (1999) Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene 18: 643–650
Wu X, Zhao Y, Honn SE, Tomlinson GE, Minna JD, Hong WK and Spitz MR (1998) Benzo[a]pyrene diol epoxide-induced 3p21.3 aberrations and genetic predisposition to lung cancer. Cancer Res 58: 1605–1608
Yin Y, Tainsky MA, Bischoff FZ, Strong LC and Wahl GM (1992) Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70: 937–948
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Zienolddiny, S., Ryberg, D., Arab, M. et al. Loss of heterozygosity is related to p53 mutations and smoking in lung cancer. Br J Cancer 84, 226–231 (2001). https://doi.org/10.1054/bjoc.2000.1528
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DOI: https://doi.org/10.1054/bjoc.2000.1528
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