Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1996 Feb;87(2):134–140. doi: 10.1111/j.1349-7006.1996.tb03150.x

p16/CDKN2 Gene and p53 Gene Alterations in Japanese Non‐smoking Female Lung Adenocarcinoma

Yukio Takeshima 1, Takashi Nishisaka 1, Ryoji Kawano 1, Kentaro Kishizuchi 1, Satoshi Fujii 1, Souichi Kitaguchi 1, Kouki Inai 1,✉
PMCID: PMC5921066  PMID: 8609061

Abstract

Primary lung adenocarcinomas in non‐smoking females are increasing in the USA and Japan. Environmental factors such as passive smoking, asbestos, domestic radon, and hormonal effects have been implicated, but the etiology is still uncertain. We therefore analyzed point mutations of p16 gene, a newly characterized tumor suppressor gene, and compared the results with alterations of p53 gene in 28 primary lung adenocarcinomas in non‐smoking Japanese females. There were no cases with somatic point mutation of p16 gene, except for one case with two germline mutations (silent mutations). In contrast, six out of 16 informative cases showed loss of heterozygosity of p53 gene using a TP53 microsatellite marker and 19 out of 28 cases showed expression of oncoprotein using DO‐7 immunohistochemistry. These findings suggest that p16 gene alteration is a rare event in primary lung adenocarcinomas in Japanese non‐smoking females, compared with alterations of the p53 gene.

Keywords: p16/CDKN2, p53, Non‐smoker, Lung adenocarcinoma, PCR‐SSCP

Full Text

The Full Text of this article is available as a PDF (435.8 KB).

REFERENCES

  • 1).Stockwell , H. G. , Goldman , A. L. , Luman , G. H. , Noss , C. I. , Armstrong , A. W. , Pinkham , P. A. , Candelora , E. C. and Brusa , M. R.Environmental tobacco smoke and lung cancer risk in nonsmoking women . J. Natl. Cancer Inst. 84 , 1417 – 1422 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 2).Churg , A. and Greene , F. H. “ Pathology of Occupational Lung Disease ,” pp . 279 – 325 ( 1988. ). Igaku‐Shoin; , New York . [Google Scholar]
  • 3).Radford , E. P. and St. Clair Renrd , K. G.Lung cancer in Swedish iron miners exposed to low doses of radon daughters . N. Engl. J. Med. 310 , 1485 – 1494 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 4).Taioli , E. and Wynder , E. L.Endocrine factors and adenocarcinoma of the lung in women . J. Natl. Cancer Inst. 86 , 869 – 870 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 5).Wynder , E. L. and Hoffmann , D.Smoking and lung cancer: scientific challenges and opportunities . Cancer Res. 54 , 5284 – 5295 ( 1994. ). [PubMed] [Google Scholar]
  • 6).Fujiuchi , S. , Akiba , Y. , Osanai , S. , Yamazaki , Y. , Nakano , H. , Ohsaki , Y. and Kikuchi , K.A clinical analysis of lung cancer in women . Lung Cancer 35 , 43 – 48 ( 1995. ) ( in Japanese ). [Google Scholar]
  • 7).Hollstein , M. , Sidransky , D. , Vogestein , B. and Harris , C. C.p53 mutations in human cancers . Science 253 , 49 – 53 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 8).Harris , C. C.p53: at the crossroads of molecular carcinogenesis and risk assessment . Science 262 , 1980 – 1981 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 9).Greenblatt , M. S. , Bennett , W. P. , Hollstein , M. and Harris , C. C.Mutations in the p53 tumor suppressor gene: clue to cancer etiology and molecular pathogenesis . Cancer Res. 54 , 4855 – 4878 ( 1994. ). [PubMed] [Google Scholar]
  • 10).Takeshima , Y. , Seyama , T. , Bennett , W. P. , Akiyama , M. , Tokuoka , S. , Inai , K. , Mabuchi , K. , Land , C. E. and Harris , C. C.p53 mutations in lung cancers from nonsmoking atomic‐bomb survivors . Lancet 342 , 1520 – 1521 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 11).Suzuki , H. , Takahashi , T. , Kuroishi , T. , Suyama , M. , Ariyoshi , Y. , Takahashi , T. and Ueda , R.p53 mutations in non‐small cell lung cancer in Japan: association between mutations and smoking . Cancer Res. 52 , 734 – 736 ( 1992. ). [PubMed] [Google Scholar]
  • 12).Serrano , M. , Hannon , G. J. and Beach , D.A new regulatory motif in cell‐cycle control causing specific inhibition of cyclin D/CDK4 . Nature 366 , 704 – 707 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 13).Kamb , A. , Gruis , N. A. , Weaver‐Feldhaus , J. , Liu , Q. , Harshman , K. , Tavtigian , S. V. , Stockert , E. , Day , R. S. , Johnson , B. E. and Skolnick , M. H.A cell cycle regulator potentially involved in genesis of many tumor types . Science 264 , 436 – 440 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 14).Nobori , T. , Miura , K. , Wu , D. J. , Lois , A. , Takabayashi , K. and Carson , D. A.Deletions of the cyclin‐dependent kinase‐4 inhibitor gene in multiple human cancers . Nature 368 , 753 – 756 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 15).Okamoto , A. , Demetrick , D. J. , Spillare , E. A. , Hagiwara , K. , Hussan , S. P. , Bennett , W. P. , Forrester , K. , Gerwin , B. , Serrano , M. , Beach , D. H. and Harris , C. C.Mutations and altered expression of p16INK4 in human cancer . Proc. Natl. Acad. Sci. USA 91 , 11045 – 11049 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16).Shapiro , G. I. , Edwards , C. D. , Kobzik , L. , Godleski , J. , Richards , W. , Sugarbaker , D. J. and Rollins , B. J.Reciprocal Rb inaetivation and p16INK4 expression in primary lung cancers and cell lines . Cancer Res. 55 , 505 – 509 ( 1995. ). [PubMed] [Google Scholar]
  • 17).Moulton , T. , Samara , G. , Chung , W.‐Y. , Yuan , L. , Desai , R. , Sisti , M. , Bruce , J. and Tycho , B.MTS1/p16/CDKN2 lesions in primary glioblastoma multiforme . Am. J. Pathol. 146 , 613 – 619 ( 1995. ). [PMC free article] [PubMed] [Google Scholar]
  • 18).He , J. , Allen , J. R. , Collins , P. , Allalunis‐Turner , M. J. , Godbout , R. , Day , R. S. , III and James , C. D.CDK4 amplification is an alternative mechanism of p16 gene homozygous deletion in glioma cell lines . Cancer Res. 54 , 5804 – 5807 ( 1994. ). [PubMed] [Google Scholar]
  • 19).Schmidt , E. E. , Ichimura , K. , Reifebberger , G. and Collins , V. P.CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas . Cancer Res. 54 , 6321 – 6324 ( 1994. ). [PubMed] [Google Scholar]
  • 20).Giani , C. and Finocchiaro , G.Mutation rate of the CDKN2 gene in malignant gliomas . Cancer Res. 54 , 6338 – 6339 ( 1994. ). [PubMed] [Google Scholar]
  • 21).Jen , J. , Harper , J. W. , Binger , S. H. , Binger , D. D. , Papadopoulos , N. , Markowitz , S. , Willson , J. K. V. , Kinzler , K. W. and Vogelstein , B.Deletion of p16 and p15 genes in brain tumors . Cancer Res. 54 , 6353 – 6358 ( 1994. ). [PubMed] [Google Scholar]
  • 22).Walker , D. G. , Duan , W. , Popovic , E. A. , Kaye , A. H. , Tomlinson , F. H. and Lavin , M.Homozygous deletions of the multiple tumor suppressor gene 1 in the progression of human astrocytomas . Cancer Res. 55 , 20 – 23 ( 1995. ). [PubMed] [Google Scholar]
  • 23).Mori , T. , Miura , K. , Aoki , T. , Nishihira , T. , Mori , S. and Nakamura , Y.Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin‐dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma . Cancer Res. 54 , 3396 – 3397 ( 1994. ). [PubMed] [Google Scholar]
  • 24).Liu , Q. , Yan , Y.‐X. , McClure , M. , Nakagawa , H. , Fujimura , F. and Rustgi , A. K.MTS‐1 (CDKN2) tumor suppressor gene deletions are a frequent event in esophagus squamous cancer and pancreatic adenocarcinoma cell lines . Oncogene 10 , 619 – 622 ( 1995. ). [PubMed] [Google Scholar]
  • 25).Zhou , X. , Tarmin , L. , Yin , J. , Jiang , H.‐Y. , Suzuki , H. , Rhyu , M.‐G. , Abraham , J. M. and Meltzer , S.The MTS1 gene is frequently mutated in primary human esophageal tumors . Oncogene 9 , 3737 – 3741 ( 1994. ). [PubMed] [Google Scholar]
  • 26).Caldas , C. , Hahn , S. A. , da Costa , L. T. , Redston , M. S. , Shutte , M. , Syemour , A. B. , Weinstein , C. L. , Hruban , R. H. , Yeo , C. J. and Kern , S. E.Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma . Nat. Genet. 8 , 27 – 32 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 27).Cheng , J. Q. , Jhanwar , S. C. , Klein , W. M. , Bell , D. W. , Lee , W. C. , Altomare , D. A. , Nobori , T. , Olopade , O. I. , Buckler , A. J. and Testa , J. R.p16 alterations and deletion mapping of 9p21‐p22 in malignant mesothelioma . Cancer Res. 54 , 5547 – 5551 ( 1994. ). [PubMed] [Google Scholar]
  • 28).Zhang , S.‐Y. , Klein‐Szanto , A. J. P. , Sauter , E. R. , Shafarenko , M. , Mitsunaga , S. , Nobori , T. , Carson , D. A. , Ridge , J. A. and Goodrow , T. L.Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck . Cancer Res. 54 , 5050 – 5053 ( 1994. ). [PubMed] [Google Scholar]
  • 29).Hussussian , C. J. , Struewing , J. P. , Goldstein , A. M. , Higgins , P. A. T. , Ally , D. S. , Sheahan , M. D. , Clark , W. H. , Jr. , Tucker , M. A. and Dracopoli , N. C.Germline p16 mutations in familial melanoma . Nat. Genet. 8 , 15 – 21 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 30).Xu , L. , Sgroi , D. , Sterner , C. J. , Beauchanp , R. L. , Pinney , D. M. , Suzanne , K. , Ueki , K. , Rutter , J. L. , Buckler , A. J. , Louis , D. N. , Gusella , J. F. and Ramesh , V.Mutation analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas . Cancer Res. 54 , 5262 – 5264 ( 1994. ). [PubMed] [Google Scholar]
  • 31).Otsuki , T. , Clark , H. M. , Wellmann , A. , Jaffe , E. S. and Raffeld , M.Involvement of CDKN2 (p16INK4A/MTS1) and p15INK4B/MTS2 in human leukemias and lymphomas . Cancer Res. 55 , 1436 – 1440 ( 1995. ). [PubMed] [Google Scholar]
  • 32).Hayashi , N. , Sugimoto , Y. , Tsuchiya , E. , Ogawa , M. and Nakamura , Y.Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4I (cyclin‐dependent kinase‐4 inhibitor) gene in human primary non‐small cell lung carcinomas . Biochem. Biophys. Res. Commun. 202 , 1426 – 1430 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 33).Washimi , O. , Nagatake , M. , Osada , H. , Ueda , R. , Koshikawa , T. , Seki , T. , Takahashi , T. and Takahashi , T.In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non‐small cell lung carcinoma . Cancer Res. 55 , 514 – 517 ( 1995. ). [PubMed] [Google Scholar]
  • 34).Okamoto , A. , Hussain , S. P. , Hagiwara , K. , Spillare , E. A. , Rusin , M. R. , Demetrick , D. J. , Serrano , M. , Hannon , G. J. , Shiseki , M. , Zariwala , M. , Xiong , Y. , Beach , D. H. , Yokota , J. and Harris , C. C.Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer . Cancer Res. 55 , 1448 – 1451 ( 1995. ). [PubMed] [Google Scholar]
  • 35).Cairns , P. , Mao , L. , Merlo , A. , Lee , D. J. , Schwab , D. , Eby , Y. , Tokino , K. , van der Riet , P. , Blaugrund , J. E. and Sidransky , D.Rates of p16 (MTS1) mutations in primary tumors with 9p loss . Science 265 , 415 – 417 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 36).Spruck , C. H. , III , Gonzalez‐Zulueta , M. , Shibata , A. , Simoneau , A. R. , Lin , M.‐F. , Gonzarez , F. , Tsai , Y. C. and Jones , P. A.p16 gene in uncultured tumors . Science 370 , 183 – 185 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 37).The Japan Lung Cancer Society . “ General Rule for Clinical and Pathological Record of Lung Cancer ,” pp . 88 – 117 ( 1987. ). Kanahara Co. , Tokyo . [Google Scholar]
  • 38).Goelz , S. E. , Hamilton , S. R. and Vogelstein , B.Purification of DNA from formaldehyde fixed and paraffin embedded human tissue . Biochem. Biophys. Res. Commun. 130 , 118 – 126 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 39).Takeshima , Y. , Inai , K. , Bennett , W. P. , Metcalf , R. A. , Welsh , J. A. , Yonehara , S. , Hayashi , Y. , Fujihara , M. , Yamakido , M. , Akiyama , M. , Tokuoka , S. , Land , C. E. and Harris , C. C.p53 mutations in lung cancers from Japanese mustard gas workers . Carcinogenesis 15 , 2075 – 2079 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 40).Orita , M. , Suzuki , Y. , Sekiya , T. and Hayashi , K.Rapid and sensitive detection of point mutation and DNA polymorphisms using the polymerase chain reaction . Genomics 5 , 874 – 879 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 41).Jones , M. H. and Nakamura , Y.Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism . Genes Chromosome Cancer 5 , 89 – 90 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 42).Cannon‐Albright , L. A. , Goldgar , D. E. , Meye , L. J. , Lewis , C. M. , Anderson , D. E. , Fountain , J. W. , Hegi , M. E. , Wiseman , R. W. , Petty , E. M. , Bale , A. E. , Olopade , O. I. , Diaz , M. O. , Kwiatkowski , D. J. , Piepkorn , M. W. , Zone , J. J. and Skolnick , M. H.Assignment of a locus for familial melanoma, MLM, to chromosome 9p13‐p22 . Science 258 , 1148 – 1152 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 43).Weissenbach , J. , Gyapay , G. , Dib , C. , Vignal , A. , Morissette , J. , Millasseau , P. , Vaysseix , G. and Lathrop , M.A second‐generation linkage map of the human genome . Nature 359 , 794 – 801 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 44).Loughran , O. , Edington , K. G. , Bery , I. J. , Clark , L. J. and Parkinson , E. K.Loss of heterozygosity of chromosome 9p21 is associated with the immortal phenotype of neoplastic human head and neck keratinocytes . Cancer Res. 54 , 5045 – 5049 ( 1994. ). [PubMed] [Google Scholar]
  • 45).Merlo , A. , Gabrielson , E. , Askin , F. and Sidransky , D.Frequent loss of chromosome 9 in human primary non‐small cell lung cancer . Cancer Res. 54 , 640 – 642 ( 1994. ). [PubMed] [Google Scholar]
  • 46).van den Berg , F. M. , Baas , I. O. , Polak , M. M. and Offeraus , J. A.Detection of p53 overexpression in routinely paraffin‐embedded tissue of human carcinomas using a novel target unmasking fluid . Am. J. Pathol. 142 , 381 – 385 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]
  • 47).Westra , W. H. , Johan , A. G. , Offerhaus , J. A. , Goodman , S. N. , Slebos , R. J. C. , Polak , M. , Baas , I. O. , Rodenhuis , S. and Hruban , R. H.Overexpression of the p53 tumor suppressor gene product in primary lung adenocarcinoma is associated with cigarette smoking . Am. J. Surg. Pathol. 17 , 213 – 220 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 48).Dosaka‐Akita , H. , Shidoh , M. , Fujino , M. , Kinoshita , I. , Akie , K. , Katoh , M. and Kawakami , Y.Abnormal p53 expression in human lung cancer is associated with histological subtypes and patient smoking history . Am. J. clin. Pathol. 102 , 660 – 664 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 49).Bennett , W. P. , Hollstein , M. C. , He , A. , Zhu , S. M. , Resau , J. , Trump , B. F. , Metcalf , R. A. , Welsh , J. A. , Gannon , J. V. , Lane , D. P. and Harris , C. C.Archival analysis of p53 genetic and protein alterations in Chinese esophageal cancer . Oncogene 6 , 1779 – 1784 ( 1991. ). [PubMed] [Google Scholar]
  • 50).Hall , R. A. , McKee , P. H. , Menge , H. P. , Dover , R. and Lane , D. P.High levels of p53 protein in UV‐irradiated normal human skin . Oncogene 8 , 203 – 207 ( 1993. ). [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES