Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Sep;89(9):916–922. doi: 10.1111/j.1349-7006.1998.tb00649.x

Allelic Loss on Chromosome 9q Is Associated with Lymph Node Metastasis of Primary Breast Cancer

Kaori Minobe 1,2, Masahiko Onda 2, Aritoshi Iida 1, Fujio Kasumi 3, Goi Sakamoto 4, Yusuke Nakamura 5, Mitsuru Emi 1,
PMCID: PMC5921944  PMID: 9818027

Abstract

Frequent allelic losses on chromosome 9 are seen in a wide variety of human tumors; moreover, two genes (P16 and PTC) whose mutant alleles confer predispositions to some inherited cancer syndromes have been identified on this chromosome. Using 15 highly polymorphic microsatellite markers distributed on both arms of chromosome 9, we tested 96 primary breast carcinomas for allelic loss in order to define the locations of genes that might be involved in this type of tumor. Allelic loss was observed in 37 of the tumors (39%) and detailed deletion mapping identified target regions at 9p21, 9q22.3 and 9q33. Losses at 9q22.3 and 9q33 were correlated with the presence of lymph node metastasis, and allelic loss at 9q22.3 was observed more frequently in scirrhous tumors than in less aggressive histologic types. Therefore, inactivation of tumor suppressor genes in 9q22.3 and 9q33 regions might play a role in progression of breast cancers, especially in metastasis to lymph nodes and in development of scirrhous tumors.

Keywords: key words, Breast cancer, Loss of heterozygosity, Tumor suppressor gene, Chromosome 9

Full Text

The Full Text of this article is available as a PDF (183.4 KB).

REFERENCES

  • 1. ) Emi , M. , Miki , Y. and Nakamura , Y.Genetic alterations and diagnosis in human breast cancer . Jpn. J. Hum. Genet. , 42 , 34 – 35 ( 1997. ). [Google Scholar]
  • 2. ) Nakamura , Y.Multi‐step carcinogenesis of colorectal cancer . Jpn. J. Hum. Genet , 38 , 23 – 24 ( 1993. ). [Google Scholar]
  • 3. ) Nakamura , Y.Application of DNA markers to clinical genetics . Jpn. J. Hum. Genet. , 41 , 1 – 14 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Yanase , T.Human genetics: past, present, and future . Jpn. J. Hum. Genet. , 42 , 265 – 316 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Tsukamoto , K. , Ito , N. , Yoshimoto , M. , Kasumi , F. , Akiyama , F. , Sakamoto , G. , Nakamura , Y. and Emi , M.Allelic loss on chromosome 1p is associated with progression and lymph node metastasis of primary breast carcinoma . Cancer , 82 , 317 – 322 ( 1998. ). [PubMed] [Google Scholar]
  • 6. ) Matsumoto , S. , Kasumi , F. , Sakamoto , G. , Onda , M. , Nakamura , Y. and Emi , M.Detailed deletion mapping of chromosome 3p in breast cancers: a 2‐cM region on 3p14.3‐21.1 and a 5‐cM region on 3p24.3‐25.1 commonly deleted in tumors . Genes Chromosom. Cancer , 20 , 268 – 274 ( 1997. ). [PubMed] [Google Scholar]
  • 7. ) Kurose , K. , lida , A. , Araki , T. , Sakamoto , G. , Kasumi , F. , Nakamura , Y. and Emi , M.Frequent allelic loss at 7p14‐15 associated with aggressive histologic types of breast cancer . Jpn. J. Cancer Res. , 89 , 533 – 538 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. ) Nakata , T. , Yoshimoto , M. , Kasumi , F. , Akiyama , F. , Sakamoto , G. , Nakamura , Y. and Emi , M.Identification of a new commonly deleted region within a 2‐cM interval of 11p11 in breast cancers . Eur. J. Cancer , 34 , 417 – 421 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Tsukamoto , K. , Ito , N. , Yoshimoto , M. , Iwase , T. , Tada , T. , Kasumi , F. , Nakamura , Y. and Emi , M.Two distinct commonly deleted regions on chromosome 13q suggest involvement of BRCA2 and retinoblastoma genes in sporadic breast carcinomas . Cancer , 78 , 1929 – 1934 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Iida , A. , Isobe , R. , Yoshimoto , M. , Kasumi , F. , Nakamura , Y. and Emi , M.Localization of a breast cancer tumour‐suppressor gene to a 3‐cM interval within chromosomal region 16q22 . Br. J. Cancer , 75 , 264 – 267 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. ) Takita , K. , Sato , T. , Miyagi , M. , Watatani , M. , Akiyama , F. , Sakamoto , G. , Kasumi , F. , Abe , R. and Nakamura , Y.Correlation of loss of alleles on the short arms of chromosomes 11 and 17 with metastasis of primary breast cancer to lymph nodes . Cancer Res. , 52 , 3914 – 3917 ( 1992. ). [PubMed] [Google Scholar]
  • 12. ) Ito , I. , Yoshimoto , M. , Iwase , T. , Watanabe , S. , Katagiri , T. , Harada , Y. , Kasumi , F. , Yasuda , S. , Mitomi , T. , Emi , M. and Nakamura , Y.Association of genetic alterations on chromosome 17 and loss of hormone receptors in breast cancer . Br. J. Cancer , 71 , 438 – 441 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Emi , M. and Nakamura , Y.Positional cloning of breast cancer‐related gene . Jpn. J. Hum. Genet. , 39 , 30 – 31 ( 1994. ). [Google Scholar]
  • 14. ) Yokota , T. , Matsumoto , S. , Yoshimoto , M. , Kasumi , F. , Akiyama , F. , Sakamoto , G. , Nakamura , Y. and Emi , M.Mapping of a breast cancer tumor suppressor gene locus to a 4‐cM interval on chromosome 18q21 . Jpn. J. Cancer Res. , 88 , 959 – 964 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Iida , A. , Kurose , K. , Isobe , R. , Akiyama , F. , Sakamoto , G. , Yoshimoto , M. , Kasumi , F. , Nakamura , Y. and Emi , M.Mapping of a new target region of allelic loss to a 2‐cM interval at 22q13.1 in primary breast cancer . Genes Chromosom. Cancer , 21 , 108 – 112 ( 1998. ). [PubMed] [Google Scholar]
  • 16. ) Castellano , M. C. , Pollock , P. M. , Walters , M. K. , Sparrow , L. E. , Down , L. M. , Gabrielli , B. G. , Parsons , P. G. and Hayward , N. K.CDKN2A/P16 is inactivated in most melanoma cell lines . Cancer Res. , 57 , 4868 – 4875 ( 1997. ). [PubMed] [Google Scholar]
  • 17. ) Kamb , A. , Gruis , N. A. , Weaver‐Feldhaus , J. , Liu , Q. , Harshman , K. , Tavtigian , S. V. , Stockert , E. , Day , R. S. , III, 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]
  • 18. ) Nobori , T. , Miura , K. , Wu , D. J. , Lois , A. , Takabayashi , K. and Carson , D. A.Deletions of the cyclin‐dependent kinese‐4 inhibitor gene in multiple human cancers . Nature , 368 , 753 – 756 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Mori , T. , Miura , K. , Aoki , T. , Nishihira , T. , Mori , S. and Nakamura , Y.Frequent somatic mutation of the MTS1/CDK41 (multiple tumor suppressor/cyclin‐dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma . Cancer Res. , 54 , 3396 – 3397 ( 1994. ). [PubMed] [Google Scholar]
  • 20. ) Caldas , C. , Hahn , S. A. , da Costa , L. T. , Redston , M. S. , Schutte , M. , Seymour , A. B. , Weinstein , C. L. , Hruban , R. H. , Yeo , C. J. and Kern , S. E.Frequent somatic mutations and homozygous deletions of the p16 (MST1) gene in pancreatic adenocarcinoma . Nat. Genet. , 8 , 27 – 32 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Gonzalez‐Zulueta , M. , Shibata , A. , Ohneseit , P. F. , Spruck , C. H. , III , Busch , C. , Shamaa , M. , Elbaz , M. , Nichols , P. W. , Gonzalgo , M. L. , Malmastrom , P.‐U. and Jones , P. A.High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder . J. Natl. Cancer Inst. , 87 , 1383 – 1393 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Hahn , H. , Wicking , C. , Zaphiropoulos , P. G. , Gailani , M. R. , Shanley , S. , Chidambaram , A. , Vorechovsky , I. , Holmberg , E. , Unden , A. B. , Gillies , S. , Negus , K. , Smyth , I. , Pressman , C. , Leffell , D. J. , Gerrard , B. , Goldstein , A. M. , Dean , M. , Toftgard , R. , Chenevix‐Trench , G. , Wainwright , B. and Bale , A. E.Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome . Cell , 85 , 841 – 851 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Xie , J. , Johnson , R. I. , Zhang , X. , Bare , J. W. , Waldman , F. M. , Cogen , P. H. , Menon , A. G. , Warren , R. S. , Chen , L.‐C. , Scott , M. P. and Epstein , F. H. , Jr.Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors . Cancer Res. , 57 , 2369 – 2372 ( 1997. ). [PubMed] [Google Scholar]
  • 24. ) Habuchi , T. , Yoshida , O. and Knowles , M. A.A novel candidate tumour suppressor locus at 9q32‐33 in bladder cancer: localization of the candidate region within a single 840 kb YAC . Hum. Mol. Genet. , 6 , 913 – 919 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Japanese Breast Cancer Society . The general rules for clinical and pathological recording of breast cancer . Jpn. J. Surg. , 19 , 612 – 632 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Sato , T. , Tanigami , A. , Yamakawa , K. , Akiyama , F. , Kasumi , F. , Sakamoto , G. and Nakamura , Y.Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer . Cancer Res. , 50 , 7184 – 7189 ( 1990. ). [PubMed] [Google Scholar]
  • 27. ) Vogelstein , B. , Fearon , E. R. , Hamilton , S. R. , Kern , S. E. , Preisinger , A. C. , Leppert , M. , Nakamura , Y. , White , R. , Smits , A. and Bos , J. L.Genetic alterations during colorectal‐tumor development . N. Engl. J. Med. , 319 , 525 – 532 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Kinzler , K. W. , Nilbert , M. C. , Su , L. K. , Vogelstein , B. , Bryan , T. M. , Levy , D. B. , Smith , K. J. , Preisinger , A. C. , Hedge , P. , McKechnie , D. , Finniear , R. , Markham , A. , Groffen , J. , Boguski , M. S. , Altschul , S. F. , Horii , A. , Ando , H. , Miyoshi , Y. , Miki , Y. , Nishisho , I. and Nakamura , Y.Identification of FAP locus genes from chromosome 5q21 . Science , 253 , 661 – 665 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Baker , S. J. , Fearon , E. R. , Nigro , J. M. , van Tuinen , P. , Ledbetter , D. H. , Baker , D. F. , Nakamura , Y. , White , R. and Vogelstein , B.Chromosome 17 deletions and P53 gene mutations in colorectal carcinomas . Science , 244 , 217 – 221 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Brenner , A. J. and Aldaz , C. M.Chromosome 9q allelic loss and p16/CDKN2 in breast cancer and evidence of p16 inactivation in immortal breast epithelial cells . Cancer Res. , 55 , 2892 – 2895 ( 1995. ). [PubMed] [Google Scholar]
  • 31. ) Eiriksdottir , G. , Sigurdsson , A. , Jonasson , J. G. , Agnarsson , B. A. , Sigurdsson , H. , Gudmundsson , J. , Bergthorsson , J. T. , Barkardottir , R. B. , Egilsson , V. and Ingvarsson , S.Loss of heterozygosity on chromosome 9 in human breast cancer: association with clinical variables and genetic changes at other chromosome regions . Int. J. Cancer , 64 , 378 – 382 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) An , H.‐X. , Niederacher , D. , Picard , F. , van Roeyen , C. , Bender , H. G. and Beckmann , M. W.Frequent allele loss on 9p21‐22 defines a smallest common region in vicinity of the CDKN2 gene in sporadic breast cancer . Genes Chromosom. Cancer , 17 , 14 – 20 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Wu , Y. , Barnabas , N. , Russo , I. H. , Yang , X. and Russo , J.Microsatellite instability and loss of heterozygosity in chromosomes 9 and 16 in human breast epithelial cells transformed by chemical carcinogens . Carcinogenesis , 18 , 1069 – 1074 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Heung , D. P. , Lo , K.‐W. , van Hasselt , C. A. , Woo , J. K. S. , Choi , P. H. K. , Leung , S.‐F. , Cheung , S.‐T. , Cairns , P. , Sidransky , D. and Lee , J. C. K.A region of homozygous deletion on chromosome 9p21‐22 in primary nasopharyngeal carcinoma . Cancer Res. , 54 , 4003 – 4006 ( 1994. ). [PubMed] [Google Scholar]
  • 35. ) Bjorkqvist , A.‐M. , Tammilehto , L. , Anttili , S. , Mattson , K. and Knuutila , S.Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma . Br. J. Cancer , 75 , 523 – 527 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. ) Williamson , M. P. , Elder , A. P. , Shaw , M. E. , Devlin , J. and Knowles , M. A.P16 (CDKN2) is a major deletion target at 9p21 in bladder cancer . Hum. Mol. Genet. , 4 , 1569 – 1577 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Cairns , P. , Tokino , K. , Eby , Y. and Sidransky , D.Localization of tumor suppressor loci on chromosome 9 in primary human renal cell carcinomas . Cancer Res. , 55 , 224 – 227 ( 1995. ). [PubMed] [Google Scholar]
  • 38. ) Merlo , A. , Gabrielson , E. , Askin , F. and Sidransky , D.Frequent loss of chromosome 9p in human primary non‐small cell lung cancer . Cancer Res. , 54 , 640 – 642 ( 1994. ). [PubMed] [Google Scholar]
  • 39. ) van der Reit , P. , Nawroz , H. , Hruban , R. H. , Corio , R. , Tokino , K. , Koch , W. and Sidransky , D.Frequent loss of chromosome 9p21‐22 early in head and neck cancer progression . Cancer Res. , 54 , 1156 – 1158 ( 1994. ). [PubMed] [Google Scholar]
  • 40. ) Rush , E. B. , Abouezzi , Z. , Borgen , P. I. and Anelli , A.Analysis of MTS1/CDK4 in female breast carcinomas . Cancer Lett. , 89 , 223 – 226 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 41. ) Horwitz , K. B.Mechanism of hormone resistance in breast cancer . Breast Cancer Res. Treat. , 26 , 119 – 130 ( 1993. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES