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. 1999 Sep;90(9):934–941. doi: 10.1111/j.1349-7006.1999.tb00838.x

Rare‐type Mutations of MMAC1 Tumor Suppressor Gene in Human Glioma Cell Lines and Their Tumors of Origin

Shu‐Jing Zhang 1, Sumio Endo 1, Tomio Ichikawa 1, Junichi Yoshimura 2, Kiyoshi Onda 2, Ryuichi Tanaka 2, Kazuo Washiyama 1, Toshiro Kumanishi 1,✉
PMCID: PMC5926156  PMID: 10551321

Abstract

A total of 10 glioma cell lines were examined to evaluate the status of the MMAC1 gene, a candidate tumor suppressor gene. Six cell lines showed mutations with presumed loss of heterozygosity and 1 cell line showed no mRNA expression. The 6 mutations consisted of 3 3‐bp deletions (codons 17, 101 or 199), 1 missense mutation (codon 252) and 2 truncation mutations (1 nonsense mutation at codon 233 and 1 2‐bp insertion at codon 241). Among them, the 3‐bp deletions, which are a rare type of mutation in MMAC1 gene, were located in the N‐terminal half (codons 1–212) of the coding region, which is considered important in MMAC1 function. The missense mutation was located unusually in the C‐terminal half (codons 212–403), but it was in a small region in which some other reported missense mutations are clustered. Thus, these 4 mutations were suggested to have functional effects on the MMAC1 activity, like the other 2 mutations with predicted protein truncations. By sequence analysis of cDNA clones, we confirmed that all the mutations including these 4 rare ones were in the MMAC1 gene, not in the PTH2 pseudogene. In 2 cases, we also examined the primary glioma tissues from which the cell lines had been derived and found the same mutations as in the cell lines in both cases. This suggested that the mutations in these cell lines were derived from the primary glioma tissues, but not from artifacts arising during long‐term in vitro cultivation.

Keywords: MMAC1, PTEN, Tumor suppressor gene, Pseudogene, Glioma

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REFERENCES

  • 1).Steck , P. A. , Pershouse , M. A. , Jasser , S. A. , Yung , W. K. A. , Lin , H. , Ligon , A. H. , Langford , L. A. , Baumgard , M. L. , Hattier , T. , Davis , T. , Frye , C. , Hu , R. , Swedlund , B. , Teng , D. H. F. and Tavtigian , S. V.Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers . Nat. Genet. , 15 , 356 – 362 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 2).Li , J. , Yen , C. , Liaw , D. , Podsypanina , K. , Bose , S. , Wang , S. I. , Puc , J. , Miliaresis , C. , Rodgers , L. , McCombie , R. , Bigner , S. H. , Giovanella , B. C. , Ittmann , M. , Tycko , B. , Hibshoosh , H. , Wigler , M. H. and Parsons , R.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer . Science , 275 , 1943 – 1947 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 3).Li , D.‐M. and Sun , H.TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor β . Cancer Res. , 57 , 2124 – 2129 ( 1997. ). [PubMed] [Google Scholar]
  • 4).Myers , M. P. , Stolarov , J. P. , Eng , C. , Li , J. , Wang , S. I. , Wigler , M. H. , Parsons , R. and Tonks , N. K.P‐TEN, the tumor suppressor from human chromosome 10q23, is a dual‐specificity phosphatase . Proc. Natl. Acad. Sci. USA , 94 , 9052 – 9057 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5).Maehama , T. and Dixon , J. E.The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5‐trisphosphate . J. Biol. Chem. , 273 , 13375 – 13378 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 6).Furnari , F. B. , Huang , H.‐J. S. and Cavenee , W. K.The phosphoinositol phosphatase activity of PTEN mediates a serum‐sensitive G1 growth arrest in glioma cells . Cancer Res. , 58 , 5002 – 5008 ( 1998. ). [PubMed] [Google Scholar]
  • 7).Wang , S. I. , Puc , J. , Li , J. , Bruce , J. N. , Cairns , P. , Sidransky , D. and Parsons , R.Somatic mutations of PTEN in glioblastoma multiforme . Cancer Res. , 57 , 4183 – 4186 ( 1997. ). [PubMed] [Google Scholar]
  • 8).Liu , W. , James , C. D. , Frederick , L. , Alderete , B. E. and Jenkins , R. B.PTEN/MMAC1 mutations and EGFR amplification in glioblastomas . Cancer Res. , 57 , 5254 – 5257 ( 1997. ). [PubMed] [Google Scholar]
  • 9).Chiariello , E. , Roz , L. , Albarosa , R. , Magnani , I. and Finocchiaro , G.PTEN/MMAC1 mutations in primary glioblastomas and short‐term cultures of malignant gliomas . Oncogene , 16 , 541 – 545 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 10).Rasheed , B. K. A. , Stenzel , T. T. , McLendon , R. E. , Parsons , R. , Friedman , A. H. , Friedman , H. S. , Bigner , D. D. and Bigner , S. H.PTEN gene mutations are seen in high‐grade but not in low‐grade gliomas . Cancer Res. , 57 , 4187 – 4190 ( 1997. ). [PubMed] [Google Scholar]
  • 11).Duerr , E.‐M. , Rollbrocker , B. , Hayashi , Y. , Peters , N. , Meyer‐Puttlitz , B. , Louis , D. N. , Schramm , J. , Wiestler , O. D. , Parsons , R. , Eng , C. and von Deimling , A.PTEN mutations in gliomas and glioneuronal tumors . Oncogene , 16 , 2259 – 2264 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 12).Maier , D. , Zhang , Z. , Taylor , E. , Hamou , M.‐F. , Gratzl , O. , van Meir , E. G. , Scott , R. J. and Merlo , A.Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25–26 region as the primary target in low‐grade and high‐grade gliomas . Oncogene , 16 , 3331 – 3335 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 13).Furnari , F. B. , Lin , H. , Huang , H.‐J. S. and Cavenee , W. K.Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain . Proc. Natl. Acad. Sci. USA , 94 , 12479 – 12484 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14).Teng , D. H.‐F. , Hu , R. , Lin , H. , Davis , T. , Iliev , D. , Frye , C. , Swedlund , B. , Hansen , K. L. , Vinson , V. L. , Gumpper , K. L. , Ellis , L. , El‐Naggar , A. , Frazier , M. , Jasser , S. , Langford , L. A. , Lee , J. , Mills , G. B. , Pershouse , M. A. , Pollack , R. E. , Tornos , C. , Troncoso , P. , Yung , W. K. A. , Fujii , G. , Berson , A. , Bookstein , R. , Bolen , J. B. , Tavtigian , S. V. and Steck , P. A.MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines . Cancer Res. , 57 , 5221 – 5225 ( 1997. ). [PubMed] [Google Scholar]
  • 15).Cairns , P. , Okami , K. , Halachmi , S. , Halachmi , N. , Esteller , M. , Herman , J. G. , Jen , J. , Isaacs , W. B. , Bova , G. S. and Sidransky , D.Frequent inactivation of PTEN/MMAC1 in primary prostate cancer . Cancer Res. , 57 , 4997 – 5000 ( 1997. ). [PubMed] [Google Scholar]
  • 16).Suzuki , H. , Freije , D. , Nusskern , D. R. , Okami , K. , Cairns , P. , Sidransky , D. , Isaacs , W. B. and Bova , G. S.Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues . Cancer Res. , 58 , 204 – 209 ( 1998. ). [PubMed] [Google Scholar]
  • 17).Kong , D. , Suzuki , A. , Zou , T.‐T. , Sakurada , A. , Kemp , L. W. , Wakatsuki , S. , Yokoyama , T. , Yamakawa , H. , Furukawa , T. , Sato , M. , Ohuchi , N. , Sato , S. , Yin , J. , Wang , S. , Abraham , J. M. , Souza , R. F. , Smolinski , K. N. , Meltzer , S. J. and Horii , A.PTEN1 is frequently mutated in primary endometrial carcinomas . Nat. Genet. , 17 , 143 – 144 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 18).Risinger , J. I. , Hayes , A. K. , Berchuck , A. and Barrett , J. C.PTEN/MMAC1 mutations in endometrial cancers . Cancer Res. , 57 , 4736 – 4738 ( 1997. ). [PubMed] [Google Scholar]
  • 19).Tashiro , H. , Blazes , M. S. , Wu , R. , Cho , K. R. , Bose , S. , Wang , S. I. , Li , J. , Parsons , R. and Ellenson , L. H.Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies . Cancer Res. , 57 , 3935 – 3940 ( 1997. ). [PubMed] [Google Scholar]
  • 20).James , C. D. , Carlbom , E. , Dumanski , J. P. , Hansen , M. , Nordenskjold , M. , Collins , V. P. and Cavenee , W. K.Clonal genomic alterations in glioma malignancy stages . Cancer Res. , 48 , 5546 – 5551 ( 1988. ). [PubMed] [Google Scholar]
  • 21).Fults , D. , Pedone , C. A. , Thomas , G. A. and White , R.Allelotype of human malignant astrocytoma . Cancer Res. , 50 , 5784 – 5789 ( 1990. ). [PubMed] [Google Scholar]
  • 22).Rasheed , B. K. A. , McLendon , R. E. , Friedman , H. S. , Friedman , A. H. , Fuchs , H. E. , Bigner , D. D. and Bigner , S. H.Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25 . Oncogene , 10 , 2243 – 2246 ( 1995. ). [PubMed] [Google Scholar]
  • 23).Kim , S. K. , Su , L.‐K. , Oh , Y. , Kemp , B. L. , Hong , W. K. and Mao , L.Alterations of PTEN/MMAC1, a candidate tumour suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines . Oncogene , 16 , 89 – 93 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 24).Dahia , P. L. M. , FitzGerald , M. G. , Zhang , X. , Marsh , D. J. , Zheng , Z. , Pietsch , T. , von Deimling , A. , Haluska , F. G. , Haber , D. A. and Eng , C.A highly conserved processed PTEN pseudogene is located on chromosome band 9p21 . Oncogene , 16 , 2403 – 2406 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 25).Zhang , S.‐J. , Endo , S. , Koga , H. , Ichikawa , T. , Feng , X.‐L. , Onda , K. , Washiyama , K. and Kumanishi , T.A comparative study of glioma cell lines for p16, p15, p53 and p21 gene alterations . Jpn. J. Cancer Res. , 87 , 900 – 907 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26).Onda , K. , Tanaka , R. , Washiyama , K. , Takeda , N. and Kumanishi , T.Correlation of DNA ploidy and morphological features of human glioma cell cultures with the establishment of cell lines . Acta Neuropathol. , 76 , 433 – 440 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 27).Onda , K. , Washiyama , K. , Tanaka , R. , Nishiyama , A. , Usui , H. and Kumanishi , T.Establishment of human glioma cell lines with stable and unstable GFAP expression . Biomed. Res. , 13 , 327 – 334 ( 1992. ). [Google Scholar]
  • 28).Yamazaki , K.Tumorigenicity of established human glioma cell lines in lasat and nude mice . Neuropathology , 3 , 29 – 38 ( 1982. ) ( in Japanese ). [Google Scholar]
  • 29).Bigner , D. D. , Bigner , S. H. , Ponten , J. , Westermark , B. , Mahaley , M. S. , Jr. , Ruoslahti , E. , Herschman , H. , Eng , L. F. and Wikstrand , C. J.Heterogeneity of genotypic and phenotypic characteristics of fifteen permanent cell lines derived from human gliomas . J. Neuropathol. Exp. Neurol. 40 , 201 – 229 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 30).Chomczynski , P. and Sacchi , N.Single‐step method of RNA isolation by acid guanidinium thiocyanate‐phenol‐chloroform extraction . Anal. Biochem. , 162 , 156 – 159 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 31).Liaw , D. , Marsh , D. J. , Li , J. , Dahia , P. L. M. , Wang , S. I. , Zheng , Z. , Bose , S. , Call , K. M. , Tsou , H. C. , Peacocke , M. , Eng , C. and Parsons , R.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome . Nat. Genet. , 16 , 64 – 67 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 32).Lynch , E. D. , Ostermeyer , E. A. , Lee , M. K. , Arena , J. F. , Ji , H. , Dann , J. , Swisshelm , K. , Suchard , D. , MacLeod , P. M. , Kvinnsland , S. , Gjertsen , B. T. , Heimdal , K. , Lubs , H. , Moller , P. and King , M.‐C.Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis . Am. J. Hum. Genet. , 61 , 1254 – 1260 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33).Kohno , T. , Takahashi , M. , Manda , R. and Yokota , J.Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers . Genes Chromosom. Cancer , 22 , 152 – 156 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 34).Gronbaek , K. , Zeuthen , J. , Guldberg , P. , Ralfkiaer , E. and Hou‐Jensen , K.Alterations of the MMAC1/PTEN gene in lymphoid malignancies . Blood , 19 , 4388 – 4390 ( 1998. ). [PubMed] [Google Scholar]
  • 35).FitzGerald , M. G. , Marsh , D. J. , Wahrer , D. , Bell , D. , Caron , S. , Shannon , K. E. , Ishioka , C. , Isselbacher , K. J. , Garber , J. E. , Eng , C. and Haber , D. A.Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer . Oncogene , 17 , 727 – 731 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 36).Guldberg , P. , thor Straten , P. , Birck , A. , Ahrenkiel , V. , Kirkin , A. F. and Zeuthen , J.Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma . Cancer Res. , 57 , 3660 – 3663 ( 1997. ). [PubMed] [Google Scholar]

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