Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1997 Apr;88(4):407–413. doi: 10.1111/j.1349-7006.1997.tb00397.x

Mutational Analysis of BRCA1 Gene in Ovarian and Breast‐ovarian Cancer Families in Japan

Masashi Takano 1, Hiroshi Aida 1, Ikunosuke Tsuneki 1, Koichi Takakuwa 1, Isao Hasegawa 1, Hajime Tanaka 2, Masaaki Saito 2, Shoji Tsuji 2, Takahiko Sonoda 3, Masayuki Hatae 4, Jui‐Tung Chen 5, Katsuyuki Takahashi 6, Kazuo Hasegawa 7, Nagayasu Toyoda 8, Noriyasu Saito 9, Michiaki Yakushiji 10, Tsutomu Araki 11, Kenichi Tanaka 1,✉
PMCID: PMC5921420  PMID: 9197534

Abstract

We analyzed the alteration of BRCAI in DNA obtained from 83 individuals of 13 Japanese site‐specific ovarian cancer families and 6 breast‐ovarian cancer families. Six germline mutations were detected in 7 families, which consisted of 4 breast‐ovarian cancer and 3 site‐specific ovarian cancer families, by single‐strand conformation polymorphism analysis, followed by direct sequence determination. The mutations included three framcshifts, two nonsense mutations, and one missense mutation causing loss of a zinc‐binding motif. The frequency of loss of heterozygosity at the microsatellite markers on the BRCAI gene was 57% (8 of 14 cases) in site‐specific ovarian cancer families, and 100% (6 of 6 cases) in breast‐ovarian cancer families. All tumors of the patients carrying a mutation of BRCAI showed deletion of wild‐type alleles, implicating BRCAI as a tumor suppressor gene. Tbese results suggest tbat germline mutations of the BRCAI gene play an important role in the carcinogen‐esis of breast and/or ovarian cancer in a majority of breast‐ovarian cancer families and in some site‐specific ovarian cancer families.

Keywords: BRCAI, Mutation, Ovarian cancer, Breast, ovarian cancer, Japanese

Full Text

The Full Text of this article is available as a PDF (403.7 KB).

REFERENCES

  • 1. ) Aoki , Y. , Takakuwa , K. , Kodama , S. , Tanaka , K. , Takahashi , M. , Tokunaga , A. and Takahashi , T.Use of adoptive transfer of tumor‐infiltrating lymphocyte alone or in combination with cisplatin‐containing chemotherapy in patients with epithelial ovarian cancer . Cancer Res. , 51 , 1934 – 1939 ( 1991. ). [PubMed] [Google Scholar]
  • 2. ) Hall , J. M. , Lee , M. K. , Newman , B. , Morrow , J. E. , Anderson , L. A. , Huey , B. and King , M. C.Linkage of early‐onset familial breast cancer to chromosome 17q21 . Science , 250 , 1684 – 1689 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Miki , Y. , Swensen , J. , Shattuck‐Eidens , D. , Futreal , P. A. , Harshman , K. , Tavtigian , S. , Liu , Q. , Cochran , C. , Bennett , L. M. , Ding , W. , Bell , R. , Rosenthal , J. , Hussey , C. , Tran , T. , McClure , M. , Frye , C. , Hattier , T. , Phelps , R. , Haugen‐Strano , A. , Katcher , H. , Yakumo , K. , Gholami , Z. , Shaffer , D. , Stone , S. , Bayer , S. , Wray , C. , Bodgen , R. , Dayananth , P. , Ward , J. , Tonin , P. , Narod , S. , Bristow , P. P. , Norris , F. H. , Helvering , L. , Morrison , P. , Rosteck , P. , Lai , M. , Barrett , J. C. , Lewis , C. , Nauhausen . S. , Cannon‐Albright , L. , Goldgar , D. , Wiseman , R. , Kamb , A. and Skolnik , M. H.A strong candidate for the breast and ovarian cancer susceptibility gene BRCAI . Science , 266 , 66 – 71 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Easton , D. F. , Bishop , D. T. , Ford , D. , Crockford , G. P.and the Breast Cancer Linkage Consortium: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families . Am. J. Hum. Genet , 52 , 678 – 701 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Steichen‐Gersdorf , E. , Gallion , H. H. , Ford , D. , Girodet , C. , Easton , D. F. , DiCioccio , R. A. , Evans , G. , Pondrer , M. A. , Pye , C. , Mazoyer , S. , Noguchi , T. , Karengueven , F. , Sobol , H. , Hardouin , A. , Bignon , Y. J. , Fiver , M. S. , Smith , S. A. and Ponder , B. A.Familial site‐specific ovarian cancer is linked to BRCAI on 17ql2‐21 . Am, J. Hutu. Genet. , 55 , 870 – 875 ( 1994. ). [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Hosking , J. , Trowsdale , J. , Nicolai , H. , Solomon , E. , Foulkes , W. , Stamp , G. , Singer , E. and Jeffreys , A.A somatic BRCAI mutation in an ovarian tumour . Nat. Genet. , 9 , 343 – 344 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Merajver , S. D. , Pham , T. M. , Caduff , R. F. , Chen , M. , Poy , E. L. , Cooney , K. A. , Weber , B. L. , Collins , F. S. , Jonston , C. and Frank , T. S.Somatic mutations in the BRCAI gene in sporadic ovarian tumours , Nat. Genet. , 9 , 439 – 443 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Simard , J. , Tonin , P. , Durocher , F. , Morgan , K. , Rommens , J. , Gingras , S. , Samson , C. , Leblanc , J.F. , Belanger , C. , Dion , F. , Goldgar , Q. , Shattuck‐Eidens , D. , Labrie , F. and Narod , S. A.Common origins of BRCAI mutations in Canadian breast and ovarian cancer families . Nat. Genet. , 8 , 382 – 398 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Struewing , J. P. , Abeliovich , D. , Peretz , T. , Avishai , N. , Kaback , M. M. , Collins , F. S. and Brody , L. C.The carrier frequency of the SRCAI 185del AG is approximately 1 percent in Ashkenazi Jewish individuals . Nat. Genet. , 11 , 198 – 200 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Goldgar , D. E. and Reilly , P. R.A common BRCAI mutation in the Ashkanazim . Nat. Genet. , 11 , 113 – 114 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Inoue , R. , Fukutomi , T. , Ushijima , T. , Matsumoto , Y. , Sugimura , T. and Nagao , M.Linkage analysis of BRCAI in Japanese breast cancer families . Jpn. J. Cancer Res. , 85 , 1233 – 1239 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Inoue , R. , Fukutomi , T. , Ushijima , T. , Matsumoto , Y. , Sugimura , T. and Nagao , M.Germline mutation of BRCAI in Japanese breast cancer families . Cancer Res. , 55 , 3521 – 3524 ( 1995. ). [PubMed] [Google Scholar]
  • 13. ) Katagiri , T. , Emi , M. , Ito , I , Kobayashi , K. , Yoshimoto , M. , Iwase , T. , Kasumi , F. , Miki , Y. , Skolnick , M. H. and Nakamura , Y.Mutations in the BRCAI gene in Japanese breast cancer patients . Hum. Mutat. , 7 , 334 – 339 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Emi , M. , Matsushima , M. , Katagiri , T. , Yokota , T. , Nakata , T. , Kasumi , F. , Miki , Y. , Skolnick , M. H. and Nakamura , Y.Multiplex mutation screening of the BRCAI gene in 1000 Japanese breast cancers: 2‐3% of Japanese breast cancer is attributable to BRCAI mutations . Br. J, Cancer , in press ( 1996. ). [DOI] [PMC free article] [PubMed]
  • 15. ) Matsushima , M. , Kobayashi , K. , Emi , M. , Saito , H. , Saito , J. , Suzumori , K. and Nakamura , Y.Mutation analysis of BRCAI gene in 76 Japanese ovarian cancer patients, four germline mutations but no evidence of somatic mutation . Hum. Mol. Genet. , 4 , 1953 – 1956 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Sambrook , J. , Fritsch , E. F. and Maniatis , T.Isolation of high‐molecular‐weight DNA from mammalian cells . In “ Molecular Cloning ‐ A Laboratory Manual ,” pp. 9.14 – 9.23 ( 1989. ). Cold Spring Harbor Laboratory Press; , New York . [Google Scholar]
  • 17. ) Friedman , L. S. , Ostermeyer , E. A. , Szabo , C. I. , Dowd , P. , Lynch , E. D. , Rowell , S. E. and King , M. C.Confirmation of BRCAI by analysis of germline mutations linked to breast and ovarian cancer in ten families . Nat. Genet. , 8 , 399 – 404 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Neuhausen , S. L. , Swensen , J. , Miki , Y. , Liu , Q. , Tavtigian , S. , Shuttuck‐Eidens , D. , Kamb , A. , Hobbs , M. R. , Gingrich , J. , Shizuya , H. , Kim , U. J. , Cochran , C. , Futreal , P. A. , Wiseman , R. W. , Lynch , H. T. , Tonin , P. , Narod , S. , Cannon‐Albright , L. , Skolnick , M. H. and Goldgar , D. E.A P1‐based physical map of the region from D17S776 to D17S78 containing the breast cancer susceptibility gene BRCAI . Hum. Mol Genet. , 3 , 1919 – 1926 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Gayther , S. A. , Warren , W. , Mazoyer , S. , Russell , P. A. , Harrington , P. A. , Chiano , M. , Seal , S. , Hamoudi , R. , van Rensburg , E. J. , Dunning , A. M. , Love , R. , Evans , G. , Easton , D. , Clayton , D. , Stratton , M. R. and Ponder , B. A. J.Germline mutations of BRCAI gene in breast and ovarian cancer families provide evidence for a genotype‐phenotype correlation . Nat. Genet. , 11 , 428 – 433 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Langston , A. A. , Malone , K. E. , Thompson , J. D. , Daling , J. R. and Ostrander , E. A.BRCAI mutation in a population‐based sample of young women with breast cancers . N. Engl. J. Med. , 334 ( 3 ), 137 – 142 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Serova , O. , Montagna , M. , Torchard , D. , Narod , S. A. , Tonin , P. , Sylla , B. , Lynch , H. T. , Feunteun , J. and Lenoir , G. M.A high incidence of BRCAI mutations in 20 breast‐ovarian cancer families . Am. J. Hum. Genet , 58 , 42 – 51 ( 1996. ). [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Marajver , S. D. , Frank , T. S. , Xu , J. , Pham , T. M. , Calzone , K. A. , Bennet‐Baker , P. , Chamberlain , J. , Boyd , J. , Garbar , J. E. , Collins , F.S. , and Weber , B. L.Germline mutation and loss of the wild‐type ailele in tumors from families with early onset breast and ovarian cancer . Clin. Cancer Res. , 1 , 539 – 544 ( 1995. ). [PubMed] [Google Scholar]
  • 23. ) Johannsson , O. , Ostermeyer , E. A. , Hakansson , S. , Friedman , L. S. , Johansson , U. , Sellberg , G. , Brondum‐Nielsen , K. , Sele , V. , Olsson , H. , King , M. C. and Borg , A.Founding BRCAI mutations in hereditary breast and ovarian cancer in southern Sweden . Am. J. Hum. Genet. , 58 , 441 – 450 ( 1996. ). [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Takahashi , H. , Behbakht , K. , McGovern , P , Chiu , H. C. , Couch , F. J. , Weber , B. L. , Friedman , L. S. , King , M. C. , Furusato , M. , LiVolsi , V. A. , Menzin , A. W. , Liu , P. C. , Rubin , S. C. and Boyd , J.Mutation analysis of the BRCAI gene in ovarian cancers . Cancer Res. , 55 , 2998 – 3002 ( 1995. ). [PubMed] [Google Scholar]
  • 25. ) Collins , F. S.BRCAI ‐‐ Lots of mutations, lots of dilemmas . N. Engl. J. Med. , 334 , 186 – 188 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Anderson , T. I.Genetic heterogeneity in breast cancer susceptibility , Acta Oncolol , 35 , 407 – 410 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Michael , R. S.Recent advances in understanding of genetic susceptibility to breast cancer . Hum. Mol. Genet. , 5 , 1515 – 1519 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Teare , M. D. , Rohde , K. and Santibanez , M. F.The use of loss of constitutional heterozygosity data to ascertain the location of predisposing genes in cancer families . J. Med. Genet , 31 , 448 – 452 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Rebbeck , T. R. , Lustbader , E. D. and Beutow , K. H.Somatic ailele loss in genetic linkage analysis of cancer . Genet. Epidemiol , 11 , 419 – 429 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Kruglyak , L. and Lander , E. S.Complete multipoint sib‐pair analysis of qualitative and quantitative traits . Am, J. Hum. Genet. , 57 , 439 – 454 ( 1995. ). [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES