Different Subtypes of Human Lung Adenocarcinoma Caused by Different Etiological Factors
2000; Elsevier BV; Volume: 157; Issue: 6 Linguagem: Inglês
10.1016/s0002-9440(10)64851-1
ISSN1525-2191
AutoresTakehisa Hashimoto, Yoshio Tokuchi, Moriaki Hayashi, Yasuhito Kobayashi, Kazunori Nishida, Shinichi Hayashi, Yuichi Ishikawa, Ken Nakagawa, Jun‐Ichi Hayashi, Eiju Tsuchiya,
Tópico(s)Lung Cancer Treatments and Mutations
ResumoHuman lung adenocarcinomas are only relatively weakly associated with tobacco smoke, and other etiological factors need to be clarified. These may also vary with the histopathology. Because the p53 mutation status (frequency and spectrum) of a carcinoma can provide clues to causative agents, we subclassified 113 adenocarcinomas into five cell types. hobnail, columnar/cuboidal, mixed, polygonal, and goblet (54, 23, 18, 13, and 5, respectively) and investigated relationships with p53 mutations and smoking history. In the hobnail cell type, a low mutational frequency (37%) and a high proportion of transitions (65%), especially G:C to A:T transitions at CpG dinucleotides (45%) associated with spontaneous mutations, were found with a weak relation to tobacco smoke. In contrast, a high mutation frequency (70%. with a higher proportion of transversions (50%), especially G:C to T:A (44%) on the nontranscribed DNA strand, caused by exogenous carcinogenic agents like tobacco smoke, were observed for the columnar cell type, as with squamous cell carcinomas. These results indicate that two major subtypes of lung adenocarcinoma exist, one probably caused by tobacco smoke, and the other possibly due to spontaneous mutations. For the prevention of lung adenocarcinomas, in addition to stopping tobacco smoking, the elucidation of endogenous mechanisms is important. Human lung adenocarcinomas are only relatively weakly associated with tobacco smoke, and other etiological factors need to be clarified. These may also vary with the histopathology. Because the p53 mutation status (frequency and spectrum) of a carcinoma can provide clues to causative agents, we subclassified 113 adenocarcinomas into five cell types. hobnail, columnar/cuboidal, mixed, polygonal, and goblet (54, 23, 18, 13, and 5, respectively) and investigated relationships with p53 mutations and smoking history. In the hobnail cell type, a low mutational frequency (37%) and a high proportion of transitions (65%), especially G:C to A:T transitions at CpG dinucleotides (45%) associated with spontaneous mutations, were found with a weak relation to tobacco smoke. In contrast, a high mutation frequency (70%. with a higher proportion of transversions (50%), especially G:C to T:A (44%) on the nontranscribed DNA strand, caused by exogenous carcinogenic agents like tobacco smoke, were observed for the columnar cell type, as with squamous cell carcinomas. These results indicate that two major subtypes of lung adenocarcinoma exist, one probably caused by tobacco smoke, and the other possibly due to spontaneous mutations. For the prevention of lung adenocarcinomas, in addition to stopping tobacco smoking, the elucidation of endogenous mechanisms is important. Lung cancer constitutes one of the leading causes of cancer death in the world,1Parkin DM Pisani P Ferlay J Estimates of the world wide incidence of eighteen major cancers in 1985.Int J Cancer. 1993; 54: 594-606Crossref PubMed Scopus (1600) Google Scholar, 2Travis WD Travis LB Devesa SS Lung cancer.Cancer. 1995; 75: 191-202Crossref PubMed Scopus (738) Google Scholar and its incidence is increasing in Japan.3Ministry of Health and Welfare Statistics and Information Department Vital Statistics Japan, 1997. Ministry of Health and Welfare, Tokyo1999: 280-295Google Scholar Histologically lung cancer is classified into four major types: squamous cell carcinoma, small cell carcinoma, adenocarcinoma, and large cell carcinoma, based on the 1999 WHO classification.4World Health Organization Histological Typing of Lung and Pleural Tumours.in: Travis WD Colby TV Corrin B Shimosato Y Brambilla E ed 3. Springer-Verlag, Berlin1999Google Scholar Of the four types, adenocarcinoma is now the most common, and its proportion is increasing not only in Japan but also in the United States.5Hanai A Benn T Fujimoto I Muir CS Comparison of lung cancer incidence rates by histological type in high and low incidence countries, with reference to the limited role of smoking.Jpn J Cancer Res. 1988; 79: 445-452Crossref PubMed Scopus (31) Google Scholar, 6Thun MJ Lally CA Flannery JT Calle EE Flanders WD Heath Jr, CW Cigarette smoking and changes in the histopathology of lung cancer.J Natl Cancer Inst. 1997; 89: 1580-1586Crossref PubMed Scopus (455) Google Scholar Therefore, it is necessary to develop new approaches for its prevention, early detection, and treatment. To achievement of this goal, elucidation of etiological factors and carcinogenic mechanisms is important. Exogenous factors, especially tobacco smoke, are established causes of squamous cell and small cell carcinomas, but other, as yet unknown, endogenous factors may be more important for adenocarcinomas.6Thun MJ Lally CA Flannery JT Calle EE Flanders WD Heath Jr, CW Cigarette smoking and changes in the histopathology of lung cancer.J Natl Cancer Inst. 1997; 89: 1580-1586Crossref PubMed Scopus (455) Google Scholar, 7Sobue T Suzuki T Fujimoto I Matsuda M Doi O Mori T Furuse K Fukuoka M Yasumitsu T Kuwahara O Kono K Taki T Kuwabara M Nakahara K Endo S Sawamura K Kurata M Ichitani M Hattori S Case-control study for lung cancer and cigarette smoking in Osaka, Japan: Comparison with the results from western Europe.Jpn J Cancer Res. 1994; 85: 464-473Crossref PubMed Scopus (45) Google Scholar, 8Greenblatt MS Bennett WP Hollstein M Harris CC Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis.Cancer Res. 1994; 54: 4855-4878PubMed Google Scholar One reason why little is known about their nature may be that adenocarcinomas have generally been analyzed as a discrete group. However, their histopathology is very complicated, and the several subtypes may each have their own etiology.4World Health Organization Histological Typing of Lung and Pleural Tumours.in: Travis WD Colby TV Corrin B Shimosato Y Brambilla E ed 3. Springer-Verlag, Berlin1999Google Scholar, 9Kimula Y A histochemical and ultrastructural study of adenocarcinoma of the lung.Am J Surg Pathol. 1978; 2: 253-264Crossref PubMed Scopus (98) Google Scholar, 10Shimosato Y Kodama T Kameya T Morphogenesis of peripheral type adenocarcinoma of the lung. Morphogenesis of Lung Cancer, vol I.in: Shimosato Y Melamed MR Nettesheim P CRC Press, Boca Raton, FL1982: 65-89Google Scholar Mutations in the p53 tumor suppressor gene appear to be important for the genesis of many kinds of tumors, including lung cancers.8Greenblatt MS Bennett WP Hollstein M Harris CC Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis.Cancer Res. 1994; 54: 4855-4878PubMed Google Scholar, 11Nigro JM Baker SJ Preisinger AC Jessup JM Hostetter R Cleary K Bigner SH Davidson N Baylin S Devilee P Glover T Collins FS Weston A Modali R Harris CC Vogelstein B Mutations in the p53 gene occur in diverse human tumor types.Nature. 1989; 342: 705-708Crossref PubMed Scopus (2822) Google Scholar, 12Hollstein M Sidransky D Vogelstein B Harris CC p53 mutations in human cancers.Science. 1991; 253: 49-53Crossref PubMed Scopus (7785) Google Scholar, 13Harris CC Hollstein M Clinical implications of the p53 tumor-suppressor gene.New Engl J Med. 1993; 329: 1318-1327Crossref PubMed Scopus (1386) Google Scholar, 14Takahashi T Nau MM Chiba I Birrer MJ Rosenberg RK Vinocour M Levitt M Pass H Gazdar AF Minna JD p53: A frequent target for genetic abnormalities in lung cancer.Science. 1989; 246: 491-494Crossref PubMed Scopus (1235) Google Scholar Their frequency and mutational spectra can be said to reflect carcinogenesis by exogenous or endogenous factors and thus may be helpful for identification of the responsible agents.8Greenblatt MS Bennett WP Hollstein M Harris CC Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis.Cancer Res. 1994; 54: 4855-4878PubMed Google Scholar, 11Nigro JM Baker SJ Preisinger AC Jessup JM Hostetter R Cleary K Bigner SH Davidson N Baylin S Devilee P Glover T Collins FS Weston A Modali R Harris CC Vogelstein B Mutations in the p53 gene occur in diverse human tumor types.Nature. 1989; 342: 705-708Crossref PubMed Scopus (2822) Google Scholar, 12Hollstein M Sidransky D Vogelstein B Harris CC p53 mutations in human cancers.Science. 1991; 253: 49-53Crossref PubMed Scopus (7785) Google Scholar, 13Harris CC Hollstein M Clinical implications of the p53 tumor-suppressor gene.New Engl J Med. 1993; 329: 1318-1327Crossref PubMed Scopus (1386) Google Scholar With lung cancers, tobacco smoke, one of the most important exogenous carcinogenic agents, has been shown to frequently cause p53 mutations, especially G:C to T:A transversions.8Greenblatt MS Bennett WP Hollstein M Harris CC Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis.Cancer Res. 1994; 54: 4855-4878PubMed Google Scholar, 12Hollstein M Sidransky D Vogelstein B Harris CC p53 mutations in human cancers.Science. 1991; 253: 49-53Crossref PubMed Scopus (7785) Google Scholar, 15Suzuki 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; 52: 734-736PubMed Google Scholar, 16Eisenstadt E Warren AJ Porter J Atkins D Miller JH Carcinogenic epoxides of benzo[a]pyrene and cyclopenta[cd]pyrene induce base substitutions via specific transversions.Proc Natl Acad Sci USA. 1982; 79: 1945-1949Crossref PubMed Scopus (183) Google Scholar, 17Denissenko MF Pao A Tang M-S Pfeifer GP Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53.Science. 1996; 274: 430-432Crossref PubMed Scopus (1514) Google Scholar On the other hand, transitions, especially G:C to A:T transitions at CpG sites, are thought to be caused by endogenous mechanisms involved in spontaneous mutations.8Greenblatt MS Bennett WP Hollstein M Harris CC Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis.Cancer Res. 1994; 54: 4855-4878PubMed Google Scholar, 12Hollstein M Sidransky D Vogelstein B Harris CC p53 mutations in human cancers.Science. 1991; 253: 49-53Crossref PubMed Scopus (7785) Google Scholar Therefore the mutation frequency and spectrum may provide information on the etiological factors for lung cancer. Working on the hypothesis that different subtypes of adenocarcinoma are caused by different etiological factors, we first subclassified a large series and examined p53 gene mutations in exons 4–8 and 10. As controls, squamous cell carcinomas were also examined. Then the relationships among histological subtypes, p53 mutational status, and smoking history were assessed. We examined 151 non-small-cell lung carcinomas (113 adenocarcinomas and 38 squamous cell carcinomas) that had been resected consecutively from 1989 to 1993 at Cancer Institute Hospital, Tokyo, Japan. None of the patients had received chemotherapy or radiotherapy before surgery, but 79 patients (60 with adenocarcinoma and 19 with squamous cell carcinoma) underwent postoperative adjuvant therapy. The study population was aged 26–84 (median 62) years and comprised 98 men and 53 women. Data for other clinicopathological parameters, differentiation and location of the tumor, pathological stages, and patient's smoking status are presented in Table 1. Differentiation of tumors was determined according to the 1999 WHO classification of lung tumors.4World Health Organization Histological Typing of Lung and Pleural Tumours.in: Travis WD Colby TV Corrin B Shimosato Y Brambilla E ed 3. Springer-Verlag, Berlin1999Google Scholar The location of a tumor in the lung was classified as central when it was considered to have arisen in a main to segmental bronchus, and peripheral when in a subsegmental or more distal bronchus.18Tsuchiya E Chan JKC Chan S-H Saw D Ho JHC Tominaga S Comparative histopathology of resected bronchial cancers of women in Hong Kong and Japan.Int J Cancer. 1988; 41: 661-665Crossref PubMed Scopus (4) Google Scholar The pathological stages (pStages) were determined using the International Union Against Cancer (UICC) TNM staging system,19Mountain CF Revisions in the international system for staging lung cancer.Chest. 1997; 111: 1710-1717Crossref PubMed Scopus (4567) Google Scholar and statistical difference was calculated between two groups, pStage I and pStages II–IV. The patient's smoking history (number of cigarettes per day, starting age, and duration of smoking) was obtained from preoperative personal interviews and expressed as nonsmokers and smokers, the latter including both patients with a past history of smoking and current smokers.Table 1p53 Mutations and Clinicopathological ParametersNo. of cases (%)AdenocarcinomasSquamous cell carcinomasTotalExaminedMutatedExaminedMutatedExaminedMutatedAll cases11346 (41)3822 (58)15168 (45)Age at surgery (years)Mean± SD60 ± 1159 ± 1167 ± 967 ± 962 ± 1162 ± 11SexMale6329 (46)3520 (57)9849 (50)Female5017 (34)32 (67)5319 (36)LocationCentral 001510 (67)1510 (67)Peripheral11346 (41)2312 (52)13658 (43)DifferentiationWell4316 (37)21 (50)4517 (38)Moderately5020 (40)2817 (61)7837 (47)Poorly2010 (50)84 (50)2814 (50)Pathological stageIA4317 (40)63 (50)*Stage I vs. stages II–IV, P = 0.038 (by Fisher's exact probability test).4920 (41)†Stage I vs. stages II–IV, P = 0.022 (by χ2 test).IB143 (21)82 (25)225 (23)IIA 62 (33)11 (100)73 (43)IIB 10 (0)75 (71)85 (63)IIIA178 (47)54 (80)2212 (55)IIIB2914 (48)117 (64)4021 (53)IV 32 (67)0032 (67)Smoking statusNonsmoker5017 (34)53 (60)5520 (36)Smoker6347 (75)3319 (58)9648 (50)Adenocarcinoma subtypesWHO classificationAcinar2212 (55)Papillary165 (31)Bronchioloalveolar carcinoma 21 (50)Solid adenocarcinoma with mucin 54 (80)Adenocarcinoma with mixed subtypes6824 (35)Cell type classificationHobnail cell type5420 (37)Columnar cell type2316 (70)Mixed cell type182 (11)Polygonal cell type136 (46)Goblet cell type 52 (40)* Stage I vs. stages II–IV, P = 0.038 (by Fisher's exact probability test).† Stage I vs. stages II–IV, P = 0.022 (by χ2 test). Open table in a new tab Histopathological classification of the tumors and subtypes of adenocarcinomas was achieved by two of the authors (E. T. and Y. I.) according to the 1999 WHO classification of lung tumors.4World Health Organization Histological Typing of Lung and Pleural Tumours.in: Travis WD Colby TV Corrin B Shimosato Y Brambilla E ed 3. Springer-Verlag, Berlin1999Google Scholar Subclassification of adenocarcinomas was carried out with reference to the predominant cell type occupying more than 70% of the area, except for the mixed type: 1) hobnail, 2. columnar/cuboidal, 3) mixed, 4) polygonal, and 5) goblet cell types (Figure 1).20Tsuchiya E Furuta R Wada N Nakagawa K Ishikawa Y Kawabuchi B Nakamura Y Sugano H High K-ras mutation rates in goblet-cell-type adenocarcinomas of the lungs.J Cancer Res Clin Oncol. 1995; 121: 577-581Crossref PubMed Scopus (34) Google Scholar The first consists of cells with cytoplasmic protrusions or dome formation at their apices and hobnail- or tadpole-shaped cells. The second is composed of columnar/cuboidal cells with flat apices. Cytoplasmic mucus is usually absent, and if it is present it is scanty and is located near the free cell surface. The third demonstrates a mixture of hobnail, columnar/cuboidal, and goblet cells or two of these. Most of this type consists of both the former two cells, in which each cell type occupies more than 30% of the area. Polygonal cells with or without mucus in their cytoplasm, proliferating in sheets, are sometimes observed in tumors of the first three types, but when such areas made up more than 95% of the tumor, it was diagnosed as the polygonal cell type. The goblet cell type is composed of columnar or cuboidal cells with abundant mucus in their cytoplasm. Distribution by cell type and 1999 WHO classification of adenocarcinomas are presented in Table 1. By the WHO classification, more than half of the tumors were classified as adenocarcinomas with mixed subtypes. There were only two bronchioloalveolar carcinoma, and no papillary adenocarcinomas consisting entirely of tall columnar or cuboidal cells were observed. Almost half of the cells were hobnail type, then columnar, mixed polygonal, and goblet, in that order. Table 2 shows the relationship between WHO and the cell type classification of adenocarcinomas. More than half of the acinar and papillary adenocarcinomas, respectively, were of columnar and hobnail cell types. The two bronchioloalveolar carcinomas consisted primarily of hobnail and goblet cells, in one case each, and all of the solid adenocarcinomas with mucin were of the polygonal cell type. The adenocarcinomas with mixed subtypes included various cell types, of which the hobnail type was the most common.Table 2Relationship between WHO and Cell Type Classifications of Lung AdenocarcinomasNo. of cases (%)Cell type classificationWHO ClassificationHobnailColumnarMixedPolygonalGobletAcinar015 (68)2 (9)5 (23)0Papillary14 (88)01 (6)1 (6)0Bronchioloalveolar carcinoma1 (50)0001 (50)Solid adenocarcinoma with mucin0005 (100)0Adenocarcinoma with mixed subtypes39 (57)8 (12)15 (22)2 (3)4 (6) Open table in a new tab As for the relationship between differentiation and the subtypes, many cases of papillary (94%), bronchioloalveolar (100%), and adenocarcinoma with mixed subtypes (94%) by WHO classification or hobnail (100%), mixed (89%), and goblet (100%) cell type by cell type classification were well or moderately differentiated, whereas most acinar (95%) and solid adenocarcinomas with mucin (100%) (by the WHO classification) or columnar (91%) and polygonal cell types (100%) (by the cell type classification) were moderately or poorly differentiated. Fresh tumor samples paired with corresponding normal tissue were obtained from all patients, quickly frozen in liquid nitrogen, and stored at −80°C until DNA extraction analysis, as previously described.21Tsuchiya E Nakamura Y Weng S-Y Nakagawa K Tsuchiya S Sugano H Kitagawa T Allelotype of non-small cell lung carcinoma: Comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma.Cancer Res. 1992; 52: 2478-2481PubMed Google Scholar Genomic DNAs were prepared, and exons 4–8 and 10 of the p53 gene were analyzed by the polymerase chain reaction (PCR)–SSCP method.22Orita M Iwahana H Kanazawa H Hayashi K Sekiya T Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms.Proc Natl Acad Sci USA. 1989; 86: 2766-2770Crossref PubMed Scopus (3480) Google Scholar Coding sequences including exon-intron boundaries were amplified by PCR. The sequences of primers and PCR conditions were described previously.23Tokuchi Y Hashimoto T Kobayashi Y Hayashi M Nishida K Hayashi S-I Imai K Nakachi K Ishikawa Y Nakagawa K Kawakami Y Tsuchiya E The expression of p73 is increased in lung cancer, independent of p53 gene alteration.Br J Cancer. 1999; 80: 1623-1629Crossref PubMed Scopus (77) Google Scholar, 24Hashimoto T Tokuchi Y Hayashi M Kobayashi Y Nishida K Hayashi S Ishikawa Y Tsuchiya S Nakagawa N Hayashi J Tsuchiya E p53 null mutations undetected by immunohistochemical staining predict a poor outcome with early stage non-small-cell lung carcinomas.Cancer Res. 1999; 59: 5572-5577PubMed Google Scholar The 5′ end of each primer was labeled with a fluorescent marker, sense primers were labeled with 6-carboxyfluorescein, and the antisense primer was labeled with 4,7,2′,7′-tetrachloro-6-carboxyfluorescein (Japan Bio Service Corp., Asaka, Japan). SSCP using ABI PRISM 377 (Perkin-Elmer Corp., Norwalk, CT) and fluorescent-labeled primers was performed at 22°C, loading onto nondenaturing 4% polyacrylamide gels with 10% glycerol. SSCP data were processed with GeneScan Analysis 2.0.2 computer software (Perkin-Elmer Corp.). When genomic DNA extracted from tumors showed a SSCP pattern different from that of corresponding normal lung tissues, both genomic DNAs were amplified with the primers in the presence of [α-32P]dCTP to elute the shifted DNA fragment for sequence analysis. After PCR under the same cycling conditions, products were electrophoresed in nondenaturing 5% polyacrylamide gels with 10% glycerol at the most suitable temperature (exon 4, 10°C. exons 5–7 and 10, 25°C; exon 8, 15°C) and 35 W of constant power for 2–3 hours. The gels were subjected to drying at 80°C for 1 hour and autoradiographed at room temperature overnight. Both normal and abnormal DNA fragments were eluted from the dried gels and reamplified using the same primers and PCR conditions. To characterize p53 gene mutations, we sequenced the reamplified DNAs using a dRhodamine terminator cycle sequencing kit (Applied Biosystems) and ABI PRISM 377. Some DNA for which mutations could not be identified by direct sequencing, despite showing abnormal bands in fluorescently labeled SSCP, were subcloned into plasmid vector pGEM-7Zf(+) (Promega. and sequenced with an AutoRead sequencing kit (Pharmacia Biotech), using fluorescently labeled SP6, T7 primers and an A.L.F. DNA Sequencer II (Pharmacia LKB Biotechnology AB). To establish any correlations among the p53 gene mutation status and clinicopathological data, the χ2Travis WD Travis LB Devesa SS Lung cancer.Cancer. 1995; 75: 191-202Crossref PubMed Scopus (738) Google Scholar test or Fisher's exact probability when expected values in the χ2Travis WD Travis LB Devesa SS Lung cancer.Cancer. 1995; 75: 191-202Crossref PubMed Scopus (738) Google Scholar test were <5, the Mann-Whitney U-test and Student's t-test were used. Differences were considered to be significant when the P value was <0.05. Screening of all tumor samples for p53 mutations in exons 4–8 and 10, using a fluorescently labeled PCR-SSCP, technique revealed mutations in 68 of 151 non-small-cell lung carcinomas (45%) (Table 1, Table 3). One case (case no. 17. had two mutations: a 19-bp deletion in exon 4 and a 1-bp deletion in exon 8. Of the 68 mutations, four (6%) were located in exon 4, 17 (25%) in exon 5, 9 (13%) in exon 6, 15 (22%) in exon 7, 16 (23%) in exon 8, four (6%) in exon 10, and 4 (6%) in splicing junctions of exons. No mutations were found in normal lung tissue samples, except in patients carrying a polymorphism in exon 4, codon 72.25Matlashewsky GJ Tuck S Pim D Lamb P Schneider J Crawford LV Primary structure polymorphism at amino acid residue 72 of human p53.Mol Cell Biol. 1987; 7: 961-963PubMed Google Scholar Histologically, a trend toward more frequent mutations in squamous cell carcinomas (58%) than in adenocarcinomas (41%) was found (Table 4 and Figure 2A), in line with earlier results of a Japanese study of mutations in exons 2–11 in 115 cases of non-small-cell lung cancer.26Kishimoto Y Murakami Y Shiraishi M Hayashi K Sekiya T Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung.Cancer Res. 1992; 52: 4799-4804PubMed Google Scholar By the WHO classification, papillary adenocarcinomas and adenocarcinomas with mixed subtypes showed the lowest frequency of mutations, although statistically significant differences from other individual subtypes were not found (Table 1). Using our cytological classification, the highest frequency of the mutations was observed in the columnar cell type (70%), which is similar to the finding for for squamous cell lesions, followed by polygonal (46%), goblet (40%), hobnail (37%), and mixed (11%) cell types. The differences compared with the latter two were statistically significant (Table 4 and Figure 2A). This was also the case for the squamous cell carcinomas (hobnail, P = 0.048; mixed cell, P < 0.001; by χ2Travis WD Travis LB Devesa SS Lung cancer.Cancer. 1995; 75: 191-202Crossref PubMed Scopus (738) Google Scholar test).Table 3p53 Mutations in Lung Adenocarcinomas and Squamous Cell CarcinomasTumorMutation*Ref. 24.Case no.Sex†M, male; F, female.Age (years)Smoking‡(+), smoker; (−), nonsmoker.Histology§Ad, adenocarcinoma; Sq, squamous cell carcinoma.Location∥Location of tumors; C, central; P, peripheral.WHO¶WHO subclassification of adenocarcinoma. Pap, papillary; BAca, bronchioloalveolar carcinoma; Solid, solid adenocarcinoma with mucin; mix, adenocarcinoma with mixed subtypes.Cell type#Cell type classification; Hob, hobnail cell type; Col, columnar cell type; Mix, mixed cell type; Poly, polygonal cell type; Gob, goblet cell type.Diff**Differentiation of the tumor. W, well differentiated; M, moderately differentiated; P, poorly differentiated.pStagePathological stage.Exon (intron)CodonBase changeDel, deletion; Ins, insertion.Amino acid198M55(+)AdPMixHobMIA446Ins of 16 bpFrameshift138M44(−)AdPAcinarColPIIIA4120AAG to AGGLys to Arg17M69(+)AdPMixColMIA4113–119Del of 19 bpFrameshift8301CCA to C AFrameshift203F67(−)AdPMixHobWIIIB5132AAG to AGGLys to Arg105M61(+)AdPAcinarColPIIIB5135TGC to TTCCys to Phe11F72(−)AdPMixHobWIIIB5138GCC to GTCAla to Val19F57(−)AdPAcinarColMIIIA5138GCC to CCCAla to Pro208M71(+)AdPMixColMIIIA5157GTC to TTCVal to Phe22M72(+)AdPAcinarColMIIIB5158CGC to CACArg to His96M60(+)AdPSolidPolyPIIA5158CGC to CACArg to His197M47(+)AdPSolidPolyPIIIA5158CGC to CCCArg to Pro173M54(+)AdPMixColMIA5158CGC to CTCArg to Leu79M56(+)AdPPapHobWIIIB5159GCC to _CFrameshift103M74(+)AdPMixHobWIA5175CGC to CACArg to His134F26(−)AdPPapHobWIIIB5176TGC to TTCCys to Phe191M50(+)AdPAcinarColMIA5179–185Del of 18 bpFrameshift89M41(+)AdPPapPolyPIB(5)Acceptorag G to at GSplicing160M50(+)AdPAcinarColMIV6189GCC to G_CFrameshift97M54(+)AdPAcinarColMIIIA6198GAA to TAAGlu to Stop122F74(+)AdPMixHobWIIIB6209AGA to TGAArg to Stop205F49(−)AdPPapHobMIB6213CGA to TGAArg to Stop186M74(+)AdPMixGobMIB(6)DonorAG gt to AG atSplicing23M58(+)AdPMixHobWIA7234TAC to TGCTyr to Cys38F77(−)AdPMixHobWIIIB7237ATG to ATTMet to Ile157M49(+)AdPMixMixWIIA7238TGT to AGTCys to Ser80F65(−)AdPMixGobMIA7241TCC to TCFrameshift101F68(+)AdPAcinarColMIIIB7242TGC to TACCys to Tyr66F51(−)AdPMixColWIIIB7245GGC to AGCGly to Ser28M47(+)AdPAcinarColPIIIA7245GGC to TGCGly to Cys33F37(+)AdPMixHobMIA7248CGG to TGGArg to Trp139F70(−)AdPMixHobWIA7248CGG to CAGArg to Glu3M73(−)AdPSolidPolyPIIIB7259GAC to AACAsp to Ile69M58(+)AdPAcinarPolyPIIIA8273CGT to TGTAsp to Cys182M56(+)AdPMixHobWIA8273CGT to TGTAsp to Cys49F49(−)AdPMixHobWIIIB8273CGT to CATAsp to His174M72(+)AdPPapHobMIA8273CGT to CATAsp to His100M48(+)AdPSolidPolyPIA8273CGT to CTTAsp to Leu152F68(−)AdPBAcaHobWIA8273CGT to CTTAsp to Leu154M72(+)AdPMixColMIV8274GTT to _TFrameshift34M59(+)AdPAcinarColMIA8274GTT to TTTVal to Phe156M65(−)AdPMixHobWIA8275TGT to TATCys to Tyr155F63(−)AdPMixHobWIIIB8282CGG to TGGArg to Trp185M67(+)AdPMixHobMIIIB8305–306Ins of 23 bpFrameshift15M64(+)AdPAcinarColMIA(8)DonorAG gt to AG ttSplicing83F65(−)AdPMixHobWIA10335CGT to CATArg to His148F51(−)AdPMixMixMIIIA10341TTC to T_CFrameshift200M71(+)SqCPIIIB4103TAC to TAGTyr to Stop146M76(+)SqCMIIB5144CAG to CCGGln to Pro187M69(+)SqPMIA5166TCA to TAASer to Stop70M59(+)SqCMIIIA5175CGC to CACArg to His54M70(+)SqPMIIIB5149–175Del of 79 bpFrameshift113M63(+)SqCMIIB6190CCT to C_TFrameshift179M70(+)SqPMIIB6195ATC to ACCIle to Thr135M49(+)SqPMIIIA6196CGA to CCAArg to Pro7M71(−)SqPMIA6220TAT to TGTTyr to Cys167M82(+)SqPMIIIB6220TAT to TGTTyr to Cys87M65(+)SqPMIB7244GGC to TGCGly to Cys20F70(+)SqPMIIIB7245GGC to TGCGly to Cys40M79(+)SqPPIA7245GGC to CGCGly to Arg73M66(+)SqPMIIIB7245GGC to CGCGly to Arg193M68(+)SqCPIIIA7245GGC to GTCGly to Val188M53(+)SqCMIIB8271GAG to TAGGlu to Stop109M68(+)SqCMIIIA8273CGT to TGTArg to Cys56M59(+)SqCWIIIB8282CGG to TGGArg to Trp183F75(−)SqCPIIB8282CGG to TGGArg to Trp159M51(+)SqCMIIA(9)AcceptoragAT to tgATSplicing4M61(−)SqPMIIIB10337CGC to CTCArg to Leu29M76(+)SqPMIB10342CGA to TGAArg to Stop* 24Hashimoto T Tokuchi Y Hayashi M Kobayashi Y Nishida K Hayashi S Ishikawa Y Tsuchiya S Nakagawa N Hayashi J Tsuchiya E p53 null mutations undetected by immunohistochemical staining predict a poor outcome with early stage non-small-cell lung carcinomas.Cancer Res. 1999; 59: 5572-5577PubMed Google Scholar.† M, male; F, female.‡ (+), smoker; (−), nonsmoker.§ Ad, adenocarcinoma; Sq, squamous cell carcinoma.∥ Location of tumors; C, central; P, peripheral.¶ WHO subclassification of adenocarcinoma. Pap, papillary; BAca, bronchioloalveolar carcinoma; Solid, solid adenocarcinoma with mucin; mix, adenocarcinoma with mixed subtypes.# Cell type classification; Hob, hobnail cell type; Col, columnar cell type; Mix, mixed cell type; Poly, polygonal cell type; Gob, goblet cell type.** Differentiation of the tumor. W, well differentiated; M, moderately differentiated; P, poorly differentiated.†† Pathological stage.‡‡ Del, deletion; Ins, insertion. Open table in a new tab Table 4p53 Mutational Spectra for Types of Adenocarcinomas, and Squamous Cell Carcinomas and Relation to SmokingNo. of cases (%)TransitionTransversionHistology and smoking statusExaminedWith p53 mutationCpG G:C to A:TNon-CpG G:C to A:TA:T to G:CTotalG:C to T:AG:C to C:GA:T to T:AA:T to C:GTotalDel/Ins*Deletion/insertion.All cases15168 (45)18 (26)5 (7)6 (9)29 (43)18 (26)6 (9)3 (4)1 (2)28 (41)11 (16)HistologyAdenocarcinoma11346 (41)13 (28)5 (11)3 (7)21 (46)12 (26)2 (4)2 (4)016 (35)9 (20)Squamous cell carcinoma3822 (58)5 (23)03 (14)8 (36)6 (27)4 (18)1 (5)1 (5)12 (55)2 (9)Cell type classification of adenocarcinomaHobnail cell type5420 (37)9 (45)2 (10)2 (10)13 (65)3 (15)01 (5)04 (20)3 (15)Columnar cell type2316 (70)2 (13)1 (6)1 (6)4 (25)7 (44)1 (6)008 (50)4 (25)Mixed cell type182 (11)0000001 (50)01 (50)1 (50)Polygonal cell type136 (46)2 (33)1 (17)03 (50)2 (33)1 (17)003 (50)0Goblet cell type52 (40)01 (50)01 (50)000001 (50)Smoking statusNonsmoker5520 (36)†Nonsmoker vs. smoker, P = 0.105 (by χ2 test).7 (35)3 (15)3 (15)13 (65)‡Nonsmoker vs. smoker, P = 0.016 (by χ2 test).4 (20)1 (5)005 (25)§Nons
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