Advertisement

Breast Cancer Research and Treatment

, Volume 132, Issue 1, pp 29–39 | Cite as

Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes

  • Sandrine Boyault
  • Youenn Drouet
  • Claudine Navarro
  • Thomas Bachelot
  • Christine Lasset
  • Isabelle Treilleux
  • Eric Tabone
  • Alain Puisieux
  • Qing WangEmail author
Preclinical study

Abstract

Understanding how cancer genes are mutated in individual tumors is an important issue with potential clinical and therapeutic impact. This is especially relevant with recently developed targeted therapies since mutated genes can be targets and/or predictors. However, to date, gene mutation profiling in individual tumors is still underexplored. Breast cancer is composed of various subtypes. We presumed that this heterogeneity reflected the involvement of different molecular mechanisms including gene mutations that affect defined signaling pathways. Unlike the majority of published mutational studies, this study was aimed to draw a mutation profile in individual tumors by screening a panel of cancer genes in the same tumor. Thus, five genes frequently mutated in breast cancers: TP53, PIK3CA, PTEN, CDH1, and AKT1 were screened in each of 120 human primary breast tumors. Mutations in at least one of these genes were found in 62.5% of the tumors, of which the majority carried a single-gene mutation. Interestingly, a substantial proportion of tumors carried mutations either in TP53 or in genes of the PI3K pathway (PIK3CA or PTEN or AKT1). These two distinct mutation patterns were significantly associated to hormone receptor expression but independent of HER2 status.

Keywords

Breast cancer Mutation screening PI3K pathway TP53 mutation 

Notes

Acknowledgments

This study was supported partially by funds from the Ligue Départementale de l’Ain and from Institut National du Cancer. We thank Pr Jean Yves Blay for helpful discussion, Thérèse Gargi for clinical data collection and documentation and George Hinkal for assistance in manuscript writing.

Conflict of interest

None.

References

  1. 1.
    Perou CM, Sørlie T, Eisen MB et al (2000) Molecular portraits of human breast tumors. Nature 406:747–752PubMedCrossRefGoogle Scholar
  2. 2.
    Hugh J, Hanson J, Cheang MC et al (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 8:1168–1176CrossRefGoogle Scholar
  3. 3.
    Sjöblom T, Jones S, Wood LD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274PubMedCrossRefGoogle Scholar
  4. 4.
    Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113PubMedCrossRefGoogle Scholar
  5. 5.
    Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158PubMedCrossRefGoogle Scholar
  6. 6.
    Olivier M, Langerød A, Carrieri P et al (2006) The clinical value of TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167PubMedCrossRefGoogle Scholar
  7. 7.
    Langerød A, Zhao H, Borgan Ø et al (2007) TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 9:R30PubMedCrossRefGoogle Scholar
  8. 8.
    Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619PubMedCrossRefGoogle Scholar
  9. 9.
    Jiang BF, Liu LZ (2009) PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 102:19–65PubMedCrossRefGoogle Scholar
  10. 10.
    Miled N, Yan Y, Hon WC et al (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317:239–242PubMedCrossRefGoogle Scholar
  11. 11.
    Huang CH, Mandelker D, Schmidt-Kittler O et al (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744–1748PubMedCrossRefGoogle Scholar
  12. 12.
    Li SY, Rong M, Grieu F, Iacopetta B (2006) PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 96:91–95PubMedCrossRefGoogle Scholar
  13. 13.
    Saal LH, Holm K, Maurer M et al (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559PubMedCrossRefGoogle Scholar
  14. 14.
    Pérez-Tenorio G, Alkhori L, Olsson B et al (2007) PIK3CA mutations and PTEN loss correlated with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 13:3577–3584PubMedCrossRefGoogle Scholar
  15. 15.
    Kalinsky K, Jacks LM, Heguy A et al (2009) PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 15:5049–5059PubMedCrossRefGoogle Scholar
  16. 16.
    López-Knowles E, O’Toole SA, McNeil CM et al (2009) PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer 126:1121–1131Google Scholar
  17. 17.
    Carpten JD, Faber AL, Horn C, Donoho GP et al (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–445PubMedCrossRefGoogle Scholar
  18. 18.
    Yin Y, Shen WH (2008) PTEN: a new guardian of the genome. Oncogene 27:5443–5453PubMedCrossRefGoogle Scholar
  19. 19.
    Schrader KA, Masciari S, Boyd N et al (2008) Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer 7:73–82PubMedCrossRefGoogle Scholar
  20. 20.
    Bertucci F, Orsetti B, Nègre V et al (2008) Lobular and ductal carcinomas of the breast have distinct genomic and expression profiles. Oncogene 27:5359–5372PubMedCrossRefGoogle Scholar
  21. 21.
    Engelman JA (2009) Targeting PI3K signaling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562PubMedCrossRefGoogle Scholar
  22. 22.
    Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP (2009) Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9:862–873PubMedCrossRefGoogle Scholar
  23. 23.
    Mehta CR, Patel NR (1986) Algorithm 643. FEXACT: a Fortran subroutine for Fisher’s exact test on unordered r*c contingency tables. ACM Trans Math Softw 12:154–161CrossRefGoogle Scholar
  24. 24.
    Clarkson DB, Fan Y, Joe H (1993) A remark on algorithm 643: FEXACT: an algorithm for performing Fisher’s Exact Test in r x c contingency tables. ACM Trans Math Softw 19:484–488CrossRefGoogle Scholar
  25. 25.
    Berx G, Becker KF, Höfler H, van Roy F (1998) Mutations of the human E-cadherin (CDH1) gene. Hum Mutat 12:226–237PubMedCrossRefGoogle Scholar
  26. 26.
    Huiping C, Kristjansdottir S, Jonasson JG, Magnusson J, Egilsson V, Ingvarsson S (2001) Alterations of E-cadherin and beta-catenin in gastric cancer. BMC cancer 1:16PubMedCrossRefGoogle Scholar
  27. 27.
    Salahshor S, Haixin L, Huo H et al (2001) Low frequency of E-cadherin alterations in familial breast cancer. Breast Cancer Res 3:199–207PubMedCrossRefGoogle Scholar
  28. 28.
    Murugan AK, Hong NT, Fukui Y, Munirajan AK, Tsuchida N (2008) Oncogenic mutations of the PIK3CA gene in head and neck squamous cell carcinomas. Int J Oncol 32:101–111PubMedGoogle Scholar
  29. 29.
    Catasus L, Gallardo A, Cuatrecasas M, Prat J (2008) PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod Pathol 21:131–139PubMedGoogle Scholar
  30. 30.
    Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J (2009) High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res 69:3625–3633PubMedCrossRefGoogle Scholar
  31. 31.
    Manié E, Vincent-Salomon A, Lehmann-Che J et al (2009) High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal tumors. Cancer Res 69:663–671PubMedCrossRefGoogle Scholar
  32. 32.
    Baker L, Quinlan PR, Patten N et al (2010) p53 mutation, deprivation and poor prognosis in primary breast cancer. Br J Cancer 102:719–726PubMedCrossRefGoogle Scholar
  33. 33.
    Zhou W, Muggerud AA, Vu P et al (2009) Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution. Mol Oncol 3:214–219PubMedCrossRefGoogle Scholar
  34. 34.
    Offersen BV, Alsner J, Ege Olsen K et al (2008) A comparison among HER2, TP53, PAI-1, angiogenesis, and proliferation activity as prognostic variables in tumors from 408 patients diagnosed with early breast cancer. Acta Oncol 47:618–632PubMedCrossRefGoogle Scholar
  35. 35.
    Petitjean A, Mathe E, Kato S et al (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28:622–629PubMedCrossRefGoogle Scholar
  36. 36.
    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 57:3657–3659PubMedGoogle Scholar
  37. 37.
    Ueda K, Nishijima M, Inui H et al (1998) Infrequent mutations in the PTEN/MMAC1 gene among primary breast cancers. Jpn J Cancer Res 89:17–21PubMedCrossRefGoogle Scholar
  38. 38.
    Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091PubMedCrossRefGoogle Scholar
  39. 39.
    Marty B, Maire V, Gravier E et al (2008) Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res 10:R101PubMedCrossRefGoogle Scholar
  40. 40.
    Muggerud AA, Rønneberg JA, Wärnberg F et al (2010) Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer. Breast Cancer Res 12:R3PubMedCrossRefGoogle Scholar
  41. 41.
    Michelucci A, Di Cristofano C, Lami A et al (2009) PIK3CA in breast carcinoma: a mutational analysis of sporadic and hereditary cases. Diag Mol Pathol 18:200–205CrossRefGoogle Scholar
  42. 42.
    Righetti SC, Della Torre G, Pilotti S et al (1996) A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. Cancer Res 56:689–693PubMedGoogle Scholar
  43. 43.
    Di Cintio A, Di Gennaro E, Budillon A (2010) Restoring p53 function in cancer: novel therapeutic approaches for applying the brakes to tumorigenesis. Recent Pat Anticancer Drug Discov 5:1–13PubMedCrossRefGoogle Scholar
  44. 44.
    Ghayad S, Cohen PA (2010) Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. Recent Pat Anticancer Drug Discov 5:29–57PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Sandrine Boyault
    • 1
  • Youenn Drouet
    • 2
    • 9
  • Claudine Navarro
    • 1
  • Thomas Bachelot
    • 3
  • Christine Lasset
    • 2
    • 9
  • Isabelle Treilleux
    • 4
  • Eric Tabone
    • 5
  • Alain Puisieux
    • 6
    • 7
    • 8
  • Qing Wang
    • 1
    Email author
  1. 1.Laboratoire de Recherche TranslationnelleCentre Léon BérardLyon Cedex 08France
  2. 2.Département de Santé PubliqueCentre Léon BérardLyonFrance
  3. 3.Département de MédecineCentre Léon BérardLyonFrance
  4. 4.Département Anatomie et Cytologie PathologiqueCentre Léon BérardLyonFrance
  5. 5.Centre de Ressources BiologiquesCentre Léon BérardLyonFrance
  6. 6.Centre Léon BérardLyonFrance
  7. 7.InsermLyonFrance
  8. 8.Université de LyonLyon1France
  9. 9.Biométrie et Biologie évolutive, Université de LyonLyon 1France

Personalised recommendations