Skip to main content
SpringerLink
Log in

Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in advanced gastric carcinomas

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

A novel tumor suppressor gene, PTEN/MMAC1, located on chromosome band 10q23.3, encodes a 403-amino acid, dual-specificity protein phosphatase. The defects in this gene are responsible for the development of some advanced cancers. Inactivating alterations, including mutations and deletions, in the PTEN/MMAC1 gene have been identified in several types of human cancers and cancer cell lines. To clarify the participation of the PTEN/MMAC1 gene in advanced gastric carcinogenesis, we screened their frequency of mutations in primary advanced gastric adenocarcinoma tissues. Cancer specimens and their corresponding normal tissues were obtained surgically from 60 patients with pathologically proven advanced gastric carcinoma at the Department of Surgery of Kaohsiung Medical University Hospital. All nine exons of the PTEN/MMAC1 gene were amplified using polymerase chain reaction and screened for mutations by single-strand conformation polymorphism analysis and followed by direct sequencing. After neutral polyacrylamide gel electrophoresis, 17 patients (28.3%) showed an apparent electrophoretic mobility shift between the cancer and its paired normal tissue. These results from direct sequencing indicated that mutations consisted of eight cases (47.1%) of missense mutation, five silent mutations (29.4%), two nonsense mutations (11.8%), a 12-bp deletion (5.9%), and a mutation within the splice donor site of intron 6 (5.9%). The mutation hot spots at codons 45, 66, 82 and 204 in advanced gastric cancer have not been observed previously. Based on the present analysis, our study implicated that the mutations of the PTEN/MMAC1 gene do not occur at a significant rate in human advanced gastric carcinoma, but the rare clustered mutation site (exons 2–6) perhaps suggested that PTEN/MMAC1 might contribute to the gastric carcinogenesis and its progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

Similar content being viewed by others

References

  1. Bose K, Crane A, Hibshoosh H, Manaukhani M, Sandweis L, Parsons R (2002) Reduced expression of PTEN correlates with breast cancer progression. Hum Pathol 33:405–409

    Article  CAS  PubMed  Google Scholar 

  2. Bostrom J, Cobbers JM, Wolter M, Tabatabai G, Weber RG, Lichter P, Collins VP, Reifenberger G (1998) Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res 58:29–33

    PubMed  Google Scholar 

  3. Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, Jen J, Isaacs WB, Bova GS, Sidransky D (1997) Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 57:4997–5000

    CAS  PubMed  Google Scholar 

  4. Chang JG, Chen YJ, Perng LI, Wang NM, Kao MC, Yang TY, Chang CP, Tsai CH (1999) Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur J Cancer 35:647-651

    Article  CAS  PubMed  Google Scholar 

  5. Dahia PL (2000) PTEN, a unique tumor suppressor gene. Endocr Relat Cancer 7:115–129

    CAS  PubMed  Google Scholar 

  6. Anonymous (1997) Department of Health and Vital Statistics, vol. I. Department of Health, Taipei, pp 71–85

  7. Depowski PL, Rosenthal SI, Ross JS (2001) Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol 14:672–676

    CAS  PubMed  Google Scholar 

  8. Dicuonzo G, Angeletti S, Garcia-Foncillas J, Brugarolas A, Okrouzhnov Y, Santini D, Tonini G, Lorino G, De Cesaris M, Baldi A (2001) Colorectal carcinomas and PTEN/MMAC1 gene mutations. Clin Cancer Res 7:4049–4053

    CAS  PubMed  Google Scholar 

  9. Dong JT, Li CL, Sipe TW, Frierson HF Jr (2001) Mutations of PTEN/MMAC1 in primary prostate cancers from Chinese patients. Clin Cancer Res 7:304–308

    CAS  PubMed  Google Scholar 

  10. Fei G, Ebert MP, Mawrin C, Leodolter A, Schmidt N, Dietzmann K, Malfertheiner P (2002) Reduced PTEN expression in gastric cancer and in the gastric mucosa of gastric cancer relatives. Eur J Gastroenterol Hepatol 14:297–303

    Article  CAS  PubMed  Google Scholar 

  11. Guldberg P, Thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J (1997) Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 57:3660–3663

    CAS  PubMed  Google Scholar 

  12. Harima Y, Sawada S, Nagata K, Sougawa M, Ostapenko V, Ohnishi T (2001) Mutation of the PTEN gene in advanced cervical cancer correlated with tumor progression and poor outcome after radiotherapy. Int J Oncol 18:493–497

    CAS  PubMed  Google Scholar 

  13. Hu YC, Lam KY, Tang JC, Srivastava G (1999) Mutational analysis of the PTEN/MMAC1 gene in primary oesophageal squamous cell carcinomas. Mol Pathol 52:353–356

    CAS  PubMed  Google Scholar 

  14. Japanese Research Society for Gastric Cancer (1995) The general rules for the gastric cancer study. Part I. Clinical, surgical, and conclusive findings. Part II. Histological findings. Kanehara and Co., Tokyo, pp 2–46

  15. Kang YH, Lee HS, Kim WH (2002) Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest 82:285–291

    CAS  PubMed  Google Scholar 

  16. Kondo K, Yao M, Kobayashi K, Ota S, Yoshida M, Kaneko S, Baba M, Sakai N, Kishida T, Kawakami S, Uemura H, Nagashima Y, Nakatani Y, Hosaka M (2001) PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int J Cancer 91:219–224

    Article  CAS  PubMed  Google Scholar 

  17. Kubo Y, Urano Y, Hida Y, Arase S (1999) Lack of somatic mutation in the PTEN gene in squamous cell carcinomas of human skin. J Dermatol Sci 19:199–201

    Article  CAS  PubMed  Google Scholar 

  18. Kurose K, Bando K, Fukino K, Sugisaki Y, Araki T, Emi M (1998) Somatic mutations of the PTEN/MMAC1 gene in fifteen Japanese endometrial cancers: evidence for inactivation of both alleles. Jpn J Cancer Res 89:842–848

    CAS  PubMed  Google Scholar 

  19. Li DM, Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124–2129

    CAS  PubMed  Google Scholar 

  20. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947

    CAS  PubMed  Google Scholar 

  21. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16:64–67

    CAS  PubMed  Google Scholar 

  22. Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, Eng C (1997) Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 16:333–334

    CAS  PubMed  Google Scholar 

  23. Maxwell GL, Risinger JI, Tong B, Shaw H, Barrett JC, Berchuck A, Futreal PA (1998) Mutation of the PTEN tumor suppressor gene is not a feature of ovarian cancers. Gynecol Oncol 70:13–16

    Article  CAS  PubMed  Google Scholar 

  24. Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NK (1997) P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A 94:9052–9057

    Google Scholar 

  25. Nakatsuru S, Yanagisawa A, Ichii S, Tahara E, Kato Y, Nakamura Y, Horii A (1992) Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Hum Mol Genet 1:559–563

    CAS  PubMed  Google Scholar 

  26. Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ, Campbell IG (1998) Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 58:2095–2097

    CAS  PubMed  Google Scholar 

  27. Okami K, Wu L, Riggins G, Cairns P, Goggins M, Evron E, Halachmi N, Ahrendt SA, Reed AL, Hilgers W, Kern SE, Koch WM, Sidransky D, Jen J (1998) Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res 58:509–511

    CAS  PubMed  Google Scholar 

  28. Poetsch M, Dittberner T, Woenckhaus C (2001) PTEN/MMAC1 in malignant melanoma and its importance for tumor progression. Cancer Genet Cytogenet 125:21–26

    Article  CAS  PubMed  Google Scholar 

  29. Rasheed BK, Stenzel TT, McLendon RE (1997) PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 57:4187–4190

    CAS  PubMed  Google Scholar 

  30. Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI, Boyd J (1997) Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res 57:3657–3959

    CAS  PubMed  Google Scholar 

  31. Risinger JI, Hayes AK, Berchuck A, Barrett JC (1997) PTEN/MMAC1 mutations in endometrial cancers. Cancer Res 57:4736–4738

    CAS  PubMed  Google Scholar 

  32. Sakurada A, Suzuki A, Sato M, Yamakawa H, Orikasa K, Uyeno S, Ono T, Ohuchi N, Fujimura S, Horii A (1997) Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney, and ovary. Jpn J Cancer Res 88:1025–1028

    CAS  PubMed  Google Scholar 

  33. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, New York, pp 6.22–6.34

    Google Scholar 

  34. Sato K, Tamura G, Tsuchiya T, Endoh Y, Sakata K, Motoyama T, Usuba O, Kimura W, Terashima M, Nishizuka S, Zou T, Meltzer SJ (2002) Analysis of genetic and epigenetic alterations of the PTEN gene in gastric cancer. Virchows Arch 440:160–165

    CAS  PubMed  Google Scholar 

  35. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362

    Google Scholar 

  36. Tahara E (1995) Molecular biology of gastric cancer. World J Surg 19:484–490

    CAS  PubMed  Google Scholar 

  37. Tahara E, Semba S, Tahara H (1996) Molecular biological observations in gastric cancer. Semin Oncol 23:307–315

    CAS  PubMed  Google Scholar 

  38. Tamura G, Kihana T, Nomura K, Terada M, Sugimura T, Hirohashi S (1991) Detection of frequent p53 gene mutations in primary gastric cancer by cell sorting and polymerase chain reaction single-strand conformation polymorphism analysis. Cancer Res 51:3056–3058

    CAS  PubMed  Google Scholar 

  39. Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R, Ellenson LH (1997) Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 57:3935–3940

    CAS  PubMed  Google Scholar 

  40. Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, El-Naggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills GB, Pershouse MA, Pollack RE, Tornos C, Troncoso P, Yung WK, Fujii G, Berson A, Steck PA (1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57:5221–5225

    CAS  PubMed  Google Scholar 

  41. Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R (1997) Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 57:4183–4186

    CAS  PubMed  Google Scholar 

  42. Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, Said JW, Isaacs WB, Sawyers CL (1998) Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A 95:5246–5250

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This research was supported by a grant from the National Science Council of the Republic of China (NSC89–2314-B-037–120).

Author information

Authors and Affiliations

  1. Department of Surgery, Kaohsiung Medical University and Hospital, Shih-Chuan 1st Road, No. 100, 807, Kaohsiung , Taiwan

    Jaw-Yuan Wang, Tsung-Jen Huang, Fang-Ming Chen, Ming-Feng Hou & Jan-Sing Hsieh

  2. MedicoGenomic Research Center, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan

    Shiu-Ru Lin

  3. Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Ming-Chia Hsieh

Authors
  1. Jaw-Yuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tsung-Jen Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang-Ming Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming-Chia Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shiu-Ru Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming-Feng Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jan-Sing Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan-Sing Hsieh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, JY., Huang, TJ., Chen, FM. et al. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in advanced gastric carcinomas. Virchows Arch 442, 437–443 (2003). https://doi.org/10.1007/s00428-003-0803-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-003-0803-5

Keywords

Search

Navigation