Difference of Allelotype Between Squamous Cell Carcinoma and Adenocarcinoma of the Lung1

[CANCERRESEARCH54, 5652â€”5655,November1, 1994] Difference of Allelotype between Squamous Cell Carcinoma and Adenocarcinoma of the Lung1

Shuji Sato, Yusuke Nakamura, and Eiju Tsuchiya2

Departments of Pathology [S. S., E. T.] and Biochemistry (V. N.], Cancer Institute, Tokyo 170, Japan, and Department of Surgery. Daisan Hospital, The Jikei University School ofMedicine. Tokyo 201, Japan (S. S.]

ABSTRACT MATERIALS AND METHODS

We compared the frequency of loss of heterozygosity on all autosomal Materials and Histological Classification. Surgically resected tumors and chromosomes among 41 squamous cell carcinomas and 119 adenocarci corresponding normal tissue were obtained from 160 patients with non-small nomas, to analyze possible relationships of specific tumor suppressor cell lung cancers, at the Cancer Institute Hospital (Tokyo, Japan). None had gene(s) to each histological type. On the majority (28 of 36) of chrome received any preoperative treatment. Histopathological diagnosis based on the somal arms tested, loss ofheterozygosity was observed more frequently in World HealthOrganizationclassification(22) was performedby one of the squamous cell carcinomas than in adenocardnomas; in nine of these authors (E.T.); 41 tumors were squamous cell carcinomas and 119 were locations (3p, 3q, 4q, 7p, 9q, 13q, 16q, l7p, and 21q), the frequency was adenocarcinomas. The stage of each tumor was determined according to the statistically significant (3p, 3q, 4q, 9q, 13q, and lip, P < 0.01; 7p, 16q, and TNM Classificationof MalignantTumorsdefinedby the InternationalUnion @ 21q, P < 0.05, test). In squamous cell carcinomas, the frequency of Against Cancer (23). Information about each patient's smoking habits was obtained during preoperative interviews. Clinicopathological data are summa allelic loss on chromosome 9q (67%) fell between the frequencies ofloss on rized in Table 1. chromosomes 3p (82%) or l7p (88%) and chromosome 13q (60%). On the Southern Blotting Analysis. Extraction of DNA from the tissues and other hand, in adenocarcinomas frequent loss of heterozygosity was ob hybridizations were carried out according to methods described previously served on chromosomes Sq (32%), 9p (36%), 3p (40%), and lip (51%). (24). All probes used in this study are listed in Table 2. @ Furthermore, allelic losses on chromosomes 9p, 9q, and 13q tended to Statistical Analysis. The Yates-corrected test and Fisher's exact test correlate with smoking. These results suggest that more genetic changes were used for statisticalanalysisof the results. accumulate during tumorigenesis in squamous cell carcinomas than in adenocarcinomas and that unidentified tumor suppressor genes exist on chromosome 9q for squamous cell carcinoma and on chromosome Sq for RESULTS adenocardnoma of the lung. These differences may be related to differ ences in tumorigenic mechanisms, such as etiological factors, operating in Representative Southern blots with markers on chromosomes 3p, the separate histologies. 8q, 9q, and l'7p are shown in Fig. 1. In each case, loss or significant decrease of signal intensity was observed for one of the DNA restric tion fragments in the tumor lane, indicating loss of heterozygosity. A INTRODUCTION summary ofthe LOH observations is shown in Table 2. Frequent LOH was observed on chromosomes Vip (62 of 104 informative cases, The incidence of lung cancer has been increasing in recent years, 60%), 3p (56 of 113 informative cases, 50%), and 9p (27 of 64 and the disease may soon become the leading cause of death from informative cases, 42%). Relatively frequent LOH was also observed cancer in Japan. It is necessary to clarify the genetic mechanism in on chromosomes lq (29%), 8q (34%), 9q (29%), lOq (27%), 13q order to expand opportunities for early diagnosis, more effective (28%), and 21q (28%). therapy, and ultimately prevention. LOH frequencies were compared between squamous cell carci Many genetic alterations associated with lung cancer have been noma and adenocarcinoma (Fig. 2). On the majority of chromosomal reported. Changes in oncogenes include activation of genes in the myc arms tested (28 of 36), allelic losses were observed more frequently in and ras families (1â€”7)and inactivation of tumor suppressor genes squamous cell carcinomas than in adenocarcinomas; on nine chromo such as the retinoblastoma gene and p53 (8â€”13).Genes on chromo somal arms in particular (3p, 3q, 4q, 7p, 9q, 13q, 16q, l'7p, and 21q), some 3p, as yet unidentified, may also be related to lung cancers. Most the difference was statistically significant (3p, 3q, 4q, 9q, 13q, and of these analyses, however, have been performed in small cell lung l'7p, P < 0.01; â€˜lp,16q, and 21q, P < 0.05, f test) (Table 3). No cancer (14â€”19);only a few have been reported for non-small cell lung chromosomal arms sustained a significantly higher frequency of LOH cancer (18â€”21).Squamous cell carcinoma and adenocarcinoma are in adenocarcinomas than in squamous cell carcinomas. Fig. 2 also the major histological types of non-small cell lung cancer. Because shows that in squamous cell carcinomas the frequency of allelic loss they differ on the basis of histopathological and clinical characteristics was >30% on 16 chromosomal arms; of these, five (3p, 9p, 9q, 13q, and their relationship with smoking, their etiologies may be different; and l'7p) showed a markedly high frequency of LOH (82%, 55%, for example, a different tumor suppressor gene may be related to the 67%, 60%, and 88%, respectively). On the other hand, in adenocar genesis of each histology. To investigate this hypothesis, we have cinomas allelic losses of >25% were observed on 3p (40%), 8q (32%), examined LOH3 on all chromosomal arms, except 5p, 8p, and the 9p (36%), and l7p (51%). short arms of acrocentric chromosomes, in 160 non-small cell lung On chromosome 9q, we tested another DNA marker, MCTJJ2, carcinomas. which had been mapped on 9q13â€”q21.1(a more proximal region than EKZ19.3); the frequency of LOH in these two regions was compared. Received 3/31/94; accepted 8/29/94. The MCT112 locus showed allelic loss in only 3 of 10 informative The costs of publication of this article were defrayed in part by the payment of page squamous cell carcinomas, whereas a high frequency of loss (12 charges. This article must therefore be hereby marked advertisement in accordance with cases, 67%) was detected at the EKZ19.3 locus (T'able 4). Only 3 of 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by a Grant-in-Aid for Cancer Research from the Ministry these 12 tumors were informative for MCT1 12. Furthermore, of those of Education,Science, and Cultureand by the Smoking ResearchFoundation. 3, 1 retained heterozygosity and 2 showed LOH. In adenocarcinomas, 2 To whom requests for reprints should be addressed, at Department of Pathology, Cancer Institute, 1â€”37â€”1,Kami-ikebukuro,Toshima-ku, Tokyo 170, Japan. the frequency of allelic loss was <20% at both loci on chromosome 3 The abbreviation used is: LOH, loss of heterozygosity. 9q. Of the 10 adenocarcinomas which showed allelic loss at EKZ19.3, 5652

Table 1 Clinicopathologicalcharacteristics observed for any tested chromosomal arm in squamous cell carcino Squamous cell carcinoma Adenocarcinoma mas. In adenocarcinomas, however, the frequency of allelic loss on 3p (n = 41) (n = 119) was significantly higher in group 2 than in group 1 (P 0.0107, f StageI1561II69m1122N827Unclassified10GradeWell test) (Table 5); no correlation was observed for the other chromo somal arms. No association was observed between the grade of differentiation and LOH on any chromosomal arms in either histo logical type (data not shown). The relationship between LOH on six chromosomal arms (3p, 8q, 9p, 9q, 13q, and lip) and smoking status (smoker or nonsmoker) was differentiated344Moderately differentiated2952Poorly differentiated923Smoking 99 141 historySmoker3760Nonsmoker359Unknown10Table NT NT

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2 Lossofheterozygosityin non-small cell lung cancer No. of Allelic loss! cCl3-515 MCT128.2 @ airomosome patients informative (D3S685) (D8S39) arm Probe Locus Enzyme tested cases (%) â€˜p YNZ2Â° DJSS7 MspI 151 14/96 (15) 65 80 lq HHH1O6 D1S67 MspI 151 19/66 (29) NT NT 2p TBAB5.7a D2S47 PvuII 157 3/63 (5) @ 2q D2S44 TaqI 151 23/123(19) 3p cC13-515'@ D3S685 MspI 151 56/113(50) @ 3q EFD64.2a D3S46 MspI 151 18/95 (19) @..., @â€”2.9kb â€˜@ __ 2.8kb 4p YNH32a D4S125 MspI 68 1/34 (3) @ 4q EFD139â€• MspI 160 21/107(20) @-. 2.4kb 2.4kb 5q FB49 MspI 160 6/37 (16) 6p YNZ132â€• D6S40 MspI 160 16/82 (20) 6q Jc:z30a fJ5537 TaqI 149 11/75 (13) 7p RMU7-4 D7S370 MspI 160 12/56 (21) EKZ19 YNZ22 7q Jc267a D7S396 MspI 160 19/107(17) (D9S17) (D17S30) 8q MCf128.2' f@,5539 TaqI 157 18/53 (34) Fig. 1. Representative Southern blots demonstrating LOH of DNA from normal (N) 9p HHH22O D9S18 TaqI 157 27/64 (42) and tumor (T) tissues in patients with non-small cell carcinoma. The probes used are 9q EKZ19.3 D9S17 TaqI 158 22176(29) indicated below the blots. Patient numbers are shown above the blots. kb, kilobases. lOp TBQ7a D10S28 MspI 160 13/110(12) lOq @p@75a D1OS25 TaqI 149 20175 (27) lip cCIll-237Â° TaqI 157 9/49 (18) ilq SS6 INT2 TaqI 157 9/71 (13) i2p THH14 D12SJ6 MspI 160 6/63 (10) l2q YNH15 D12SJ7 MspI 160 17/95 (18) 13q MHZ47a Di3552 MspI 151 31/112 (28) 14q c@tr@iioi' Di4Si3 MspI 160 23/141 (16) 15q YNZ9O.1 D15S28 BamHI 156 8/65 (12) 16p CMM65G D16S84 TaqI 151 12/58 (21) 16q p79.2.23a D16S7 TaqI 151 23/111 (21) 17p YNZ22a D17S3O TaqI 160 621104(58) 17q CMM86a D17S74 Pvull 157 14/84 (17) i8p B74 D18S3 MspI 160 9/40 (23) 18q MCF1O8.2 D18S24 TaqI 158 5/25 (20) 19p [email protected] D19S2O Tag! 157 21/101 (21) 19q EFD4.2â€• D19522 TaqI 157 15 /61 (25) E 20p CMM6a D20S19 TaqI 158 18/120(15) 21q MCF15@ D2JS1J3 MspI 160 19/67 (28) 22q EW7.20 MspI 68 3/17 (20) E 0 a Vad&le number of tandem repeat markers. 0 E 0

(-) 2 were informative for MCT'112 and both retained heterozygosity at thislocus. The relationship between LOH and clinicopathological factors (pathological stage and grade of differentiation) was examined in each of the two histological types. Each histological type was divided into two groups according to stages (group 1, stage I; group 2, stages II and ifi) and into three grades of differentiation (well, moderately, and poorly differentiated). Stage IV was excluded from this investigation because all of the stage N cases were classified by intrapulmonary metastasis, which does not change the prognosis of the patients 0 10 20 30 40 50 60 70 80 90 significantly. Analyses were performed on the 16 chromosomes that % had shown alleic losses in >30% of the squamous cell carcinomas. Fig.2. Frequencyofalleliclosson individualchromosomalarmsinsquamouscell With respect to tumor stage, no significant correlation with LOH was carcinomaandadenocarcinoma.ELadenocarcinoma;,squamouscellcarcinoma. 5653

TabIc 3 FrequencytypesAllelic of LOH, by histological allelic loss on 9q has also been observed in squamous cell carcinomas (%)SquamousChromosomalcellarmcarcinomaloss/informative cases of the esophagus (25). Bronchus and esophagus are both derived from foregut; therefore, loss of a gene on 9q may play an important role in tumorigenesis within these developmentally related tissues. Total3pa Adenocarcinoma A tumor suppressor gene associated with bladder cancer is sus (81) 34/86 (40) 56/113 (50) pected to lie on chromosome 9q, and it appears to be located between 3qÂ° 10/26 (38) 8/69 (12) 18/95 (19) 4q0 13/25 (45) 8178 (10) 21/107(20) 9q12 and 9q34.1 (26â€”30).In our study of lung tumors, we observed 7@b22/27 (21)8q 7/18(39) 5/38(13) 12156 a much higher frequency of allelic loss with a DNA probe mapped (36) 10/31 (32) 18/53 (34) distal to 9q21.1 than we did with a more proximal probe. Moreover, 9p 11/20 (55) 16/44 (36) 27/64 (42) 9qa 12/18(67) 10/58(17) 22176(29) 1 tumor retained heterozygosity at MCTJJ2 although it showed l3qa 15/25(60) 16/87(18) 31/112(28) LOH at the distal locus. That is, putative tumor suppressor genes l@qâ€• 10/28(36) 13/83(16) 23/111 (21) 17pâ€• 21/24 (88) 41/80 (51) 62/104(60) associated with squamous cell carcinoma of the lung may be located (28)a 21qâ€•8/22 7/14 (50) 12/53 (23) 19/67 distal to 9q21.1. p < 0.01,x2test. With regard to 9p, the multiple tumor suppressor 1 gene, which bp < o.os.Table encodes cyclin-dependent kinase 4 inhibitor, has been recently iden tified in a region of 9p21 (31). Frequent allelic loss at the locus was 9qDNA 4 Allelic loss on chromosome reported in lung cancers (32, 33). We also found high frequencies of loss/informative cases (%) LOH not only in squamous cell carcinomas (55%) but also in Chromosome adenocarcinomas (36%). probe LocusAllelic AdenocarcinomaMCT1 location Squamous cell carcinoma Our previous study revealed a high frequency of allelic loss on (13)EKZ19.312 D9SiS9q13â€”q21.1 3/10 (30) 4/32 chromosome 8p, and there was no difference in frequency of LOH in D9Si79q34 12/18 (67) 10/58(17) adenocarcinomas and squamous cell carcinomas (34). LOH on 8p showed no significant correlation with clinicopathological stage or grade of differentiation. tested in both histologies. The majority of patients with squamous cell We observed high frequencies of allelic loss on chromosomes 9p, carcinomas (37 cases, 93%) were smokers; therefore, statistical anal 9q, and 13q in squamous cell carcinomas, the majority of which ysis was difficult. In adenocarcinomas (Table 6), smokers showed a were from smokers, and higher frequencies of allelic loss on these higher incidence of allelic loss on chromosomes 9p, 9q, and 13q than arms in adenocarcinomas from smokers than in those from nonsmok did nonsmokers (P = 0.076, 0.063, and 0.089, respectively, f test ers. These results suggest that smoking is correlated with deletions of and Fisher's exact test). chromosomes 9p, 9q, and 13q. In adenocarcinomas, we observed 32% allelic loss on chromosome DISCUSSION 8q. This genomic region sustained the fourth highest frequency of LOH, higher than that on chromosome 13q. This result implies the In this study of 160 non-small cell lung cancers, overall frequencies existence of a tumor suppressor gene on chromosome 8q that con of allelic loss of >30% were observed on four chromosomal arms (3p, tributes specifically to this histology. Allelic loss on chromosome 3p 8q, 9p, and l'7p); relatively frequent allelic loss was observed on was correlated with the stage of adenocarcinoma, a finding also chromosomes lq, 9q, lOq, 13q, and 21q. We have already reported reported by Yokoyama et a!. (21). These results suggest that the high frequencies of allelic loss on chromosomes lq, 3p, 8q, 13q, and putative tumor suppressor gene on 3p may be related to progression of l'7p and earlier suggested the existence of tumor suppressor genes on adenocarcinomas. these chromosomal arms (24). The present study provides additional evidence for the existence of tumor suppressor genes on 9p, 9q, lOq, and 21q. The majority of chromosomal arms showed a higher frequency of Table5 CorrelationbetweenWH chromosome 3p and pathological stages, loss in squamous cell carcinomas than in adenocarcinomas; nine histologiesHistologyAllelicbyon chromosomal arms showed statistically significant differences be (%)Stageloss /informative cases tween the two histologies. Although the proportion of advanced stages Ilâ€”IllSquamous I Stage was slightly larger among the squamous cell carcinomas than among cell carcinoma (67) 9/11 (82) the adenocarcinomas tested here, we found no difference with respect 16/26(62)aAdenocarcinomaâ€•8/12 13/43 (30) to tumor stage in the frequency of allelic loss on the 16 chromosomal p 0.0107, x2 test. arms which showed LOH in >30% of the squamous cell carcinomas. Weston et a!. (20) reported a higher tendency toward allelic losses on Table6 CorrelationbetweenLOll on six chromosomalarmsand smokingfor patients all arms (chromosomes 3, 11, 17, 18, and 20) examined in squamous with adenocarcinonias of the lung cell carcinoma than in adenocarcinoma. Therefore, the frequency of Allelic loss/informative cases (%) allelic loss on many chromosomal arms appears to be commonly Chromosomal higher in squamous cell carcinoma, regardless of stage. These results arm Smoker Nonsmoker suggest that more cumulative genetic changes are associated with 3p 17/51 (33) 15/32(47) 8q 7/21(33) 3/10(30) tumorigenesis in squamous cell carcinoma than contribute to Ã§@a 11/22 (50) 5/21 (24) adenocarcinoma, a pattern which may reflect a difference in the 9qa 7/27 (26) 2/28 (7) carcinogenic mechanisms responsible for the two histologies. 13q@' 11/49 (22) 3/34 (9) Vip 21/44 (48) 19/35(54) In squamous cell carcinomas, the higher frequency of allelic loss a p values for the difference between frequencies of LOH on chromosomes 9g, 9q, and (67%) on chromosome 9q than on 13q implies the existence of a 13q in smokers versus nonsmokers were 0.076, 0.063, and 0.089, respectively (y' test and tumor suppressor gene specific to this histological type. Frequent Fisher's exact test). 5654

ACKNOWLEDGMENTS 16. Naylor, S. L., Johnson, B. E., Minna, J. D., and Sakaguchi, A. Y. Loss of heterozy gosity of chromosome 3p markers in small-cell lung cancer. Nature (Land.), 329: We would like to thankDrs. K, Nakagawaand S. Tsuchiyafor providing 451â€”454,1987. 17. Mori, N., Yokota, J., Oshimura, M., Cavence, W. K., Mizoguchi, H., Noguchi, M., samples and Drs. H. Sugano and T. Kitagawa for helpful advice and discus Shimosato, Y., Sugimura, T., and Terada, M. Concordant deletions of chromosome 3p sions. The technical assistance of Dr. R. Futagami and N. Wada is also and loss of heterozygosityfor chromosome13 and 17 in small cell lung carcinoma. gratefully acknowledged. Cancer Res., 49: 5130â€”5135,1989. 18. Brauch, H., Johnson, B., Hovis, J., Yano, T., Gazdar, A., Pettengill, 0. S., Graziano, S., Sorenson, G. D., Poiesz, B. J., Minna, J., Linehan, M., and Thar, B. Molecular analysis of the short arm of chromosome 3 in small-cell and non-small-cell carcinoma REFERENCES of the lung. N. EngI. J. Med., 3i7: 1109â€”1113,1987. 19. Hibi, K., Takahashi, T., Yamakawa, K., Ueda, R., Sekido, Y., Ariyoshi, Y., Suyama, 1. Kurzrock,R., Gallick,0., andGutterman,J.Differentialexpressionof p21 ras gene M., Takagi,H., Nakamura,Y., andTakahashi,T. Threedistinctregions involved in productsamonghistologicalsubtypesoffreshprimaryhumanlungtumors.Cancer 3p deletion in human lung cancer. Oncogene, 7: 445â€”449,1992. Rca.,46: 1530â€”1534,1986. 20. Weston, A., Willey, J., Modali, R., Sugimurs, H., McDowell, E., Resau, J., Light, B., 2. ROdenhUis,S.,vande Wetering,M., Mooi, W., Evers,S., vanZandwijk,N., andBus, Haugen, A., Mann, D., Trump,B., and Harris,C. C. DifferentialDNA sequence J. Mutationalactivationof the K-ras oncogene:a possiblepathogenicfactorin deletions from chromosome 3, 11, 13, and 17 in squamous cell carcinoma, large cell adenocarcinoma of the lung. N. Engl. J. Med., 317: 929â€”935,1987. carcinoma, and adenocarcinoma of the human lung. Proc. NatI. Acad. Sci. USA, 86: 3. ROdenhUis,S.,Slebos,R.,Ajm,G.,Evers,S.,Mooi,W.,Wagenaar,S.,Bodegom,P., 5099â€”5103,1989. andBos,J. IncidenceandpossibleclinicalsignificanceofK-rasoncogeneactivation 21. Yokoyama, S., Yamakawa, K., Tsuchiya, E., Murata, M., Sakiyama, S., and Naka in adenocarcinoma of the human lung. Cancer Res., 48: 5738â€”5741, 1988. mura, Y. Deletion mapping on the short arm of chromosome 3 in squamous cell 4. Johnson,B., Makuch,R., Simmons,A., Gazdar,A., Burch,D., andCashell,A. myc carcinoma and adenocarcinoma. Cancer Res., 52: 873â€”877,1992. family DNA amplification in small cell lung cancer patient tumors and corresponding 22. World Health Organization. Histological Typing of Lung Tumors. Intemational cell lines. Cancer Res., 48: 5163-5166, 1988. Histological Classification of Tumors, Ed. 2, Vol. 1. Geneva: World Health Organi 5. Gemma, A., Nakajima, T., Shiraish, M., Noguchi, M., Gotoh, M., Sekiya, T., Niitani, ration,1981. H., and Shimosato,Y. myc family gene abnormalityin lung cancersand its relation 23. International Union Against Cancer. ThM Classification of Malignant Tumours, Ed. to xcnotransplantabiity.CancerRes.,48: 6025-6028,1988. 4, Revision 2, Berlin: Springer-Verlag, 1992. 6. Yokota,J., Wads, M., Yoshida,T., Noguchi,M., Terasaki,T., Shimosato,Y., 24. Tsuchiya, E., Nakamura, Y., Weng, S-Y., Nakagawa, K., Tsuchiya, S., Sugano, H., Sugimura, T., and Terada, M. Heterogeneity of lung cancer cells with respect to the and Kitagawa, T. Allelotype of non-small cell carcinoma: comparison between loss of amplification and rearrangement of myc family oncogenes. Oncogene, 2: 607â€”611, heterozygosity in squamous cell carcinoma and adenocarcinoma. Cancer Res., 52: 1988. 2478â€”2481,1992. 7. Sekido, Y., Obata, Y., Hida, T., Suyama, M., Shimokata, K., Ariyoshi, Y., and 25.Aoki,T.,Mori,T.,XiQun,D.,Nisihira,T.,Matsubara,T.,andNakamura, Takahashi, T. Preferential expression of c-kit protooncogene transcripts in small cell Allelotypestudy of esophagealcarcinoma.Genes ChromosomesCancer,10: lungcancer.CancerRes.,51: 2416-2419,1991. 177â€”182,1994. 8. Takahashi,T.,Nau,M.,Chiba,I., Birrer,M.,Rosenberg,R.,Vinocour,M.,Levitt, 26. Olumi, A. F., Tsai, Y. C., Nichols, P. W., Skinner, D. 0., Cain, D. R., Bender, L L, M.,Pass,H.,Gazdar,A.,andMinna,J.p53:a frequenttargetforgeneticabnormal and Jones, P. A. Alleic loss of chromosome lip distinguishes high grade from low ities in lung cancer. Science (Washington DC), 246: 491â€”494,1989. grade transitional cell carcinomas of the bladder. Cancer Rca., 50: 7081â€”7083,1990. 9. Iggo, R_,Gatter,K., Bartek,J., Lane, D., and Harris,A. Increasedexpression of 27. Tsai, Y. C., Nichols, P. W., Hiti, A. L., Wiliams, Z., Skinner, D. G., and Jones, P. A. mutantformsof p53 oncogenein primarylung cancer.Lancet,335: 675â€”679, Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer. Cancer Res., 1990. SO: 44â€”47,1990. 10. Chiba,I., Takahashi,T., Nau, M., D'Amico, D., Curiel,D., Mitsudomi,T., Buchha 28. Cairns, P., Shaw, M. E., and Knowles, M. A. Initiation of bladder cancer may involve gen, D., Carbone, D., Piantadosi, S., Koga, H., Reissman, P., Slamon, D., Holmes, deletion of a tumor-suppressor gene on chromosome 9. Oncogene, 8: 1083â€”1085, B.C.,andMinna,J.Mutationsinthep5.3genearefrequentinprimary,resected1993. non-small cell lung cancer. Oncogene, 5: 1603â€”1611,1990. 29. Cairns, P., Shaw, M. E., and Knowles, M. A. Preliminary mapping of the deleted 11. Sameshima,Y.,Matsuno,Y.,Hirohashi,S.,Shimosato,Y.,Mizoguchi,H.,Sugimura, region of chromosome 9 in bladder cancer. Cancer Rca., 53: 1230â€”1232,1993. T., Terada,M.,andYokota,J.Alterationsofthep53 genearecommonandcritical 30. Kwiatkowski, D. J., Armour, J., Bale, A. E., Fountain, J. W., Goudie, D., Haines, events for the maintenance of malignant phenotypes in small-cell lung carcinoma. J. L, Knowles, M. A., Pilz, A., Slaugenhaupt, S., and Povey, S. Report of the Second Oncogene,7:451â€”457,1992. International Workshop on Human Chromosome 9. Cytogenet. Cell Genet., 64: 12. Harbour, J. W., Lai, S-L, Whang-Peng, J., Gazdar, A. F., Minna, J. D., and Kaye, 93â€”121,1993. F. J. Abnormalitiesin structuresandexpressionof the humanretinoblastomagenein 31. Kamb, A., Gruis, N. A., Weaver-Feldhaus,J., Liu, 0., Harshman, K., Tavtigian, S. V., SCLC.Science(WashingtonDC),241:353â€”357,1988. Stockert, E., Day, R. S., III, Johnson, B. E., and Skolnick, M. H. A cell cycle regulator 13. Yokota,J., Akiyama,T., Fung,Y-K., Benedict,W., Namba,Y., Hanaoka,M., Wada, potentially involved in genesis of many tumor types. Science (Washington DC), 264: M., Terasaki, T., Shimosato, Y., Sugimura, T., and Terada, M. Altered expression of 436â€”440,1994. the retinoblastoma (RB) gene in small-cell carcinoma of the lung. Oncogene, 3: 32. Olopade, 0. I., Buchhagen, D. L., Malik, K., Sherman, J., Nobori, T., Bader, S., Nau, 471â€”475,1988. M. M., Gazdar,A. F., Minna,J. D., andDiaz, M. 0. Homozygousloss of interferon 14. Whang-Peng,J., Kao-Shan,C. S., and Lee, E. C. Specificchromosomedefect genes defines the critical region on 9p that is deleted in lung cancers. Cancer Res., 53: associated with human small-cell lung cancer: deletion 3p (14â€”23).Science (Wash 2410â€”2415,1993. ington DC), 215: 181â€”182,1982. 33. Merlo, A., Gabrielson, E., Askin, F., and Sidransky, D. Frequent loss of chromosome 15. Yokota, 3., Wade, M., Shimosato, Y., Terada, M., and Sugimura, T. Loss of het 9 in human primary non-small cell lung cancer. Cancer Res., 54: 640â€”642,1994. erozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromo 34. Ohata, H., Emi, M., Fujiwara, Y., Higashino, K., Nakagawa, K., Futagami, R., some 3 in adenocarcinoma of the lung. Proc. Nail. Acad. Sci. USA, 84: 9252-9256, Tsuchiya, E., and Nakamura, Y. Deletion mapping of short arm of chromosome 8 in 1987. non-small cell lung carcinoma. Genes Chromosomes Cancer, 7: 85â€”88,1993.

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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1994 American Association for Cancer Research. Difference of Allelotype between Squamous Cell Carcinoma and Adenocarcinoma of the Lung

Shuji Sato, Yusuke Nakamura and Eiju Tsuchiya

Cancer Res 1994;54:5652-5655.

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