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Journal of Cancer Research and Clinical Oncology

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01.11.2010 | Original Paper

Alterations in p53, BRCA1, ATM, PIK3CA, and HER2 genes and their effect in modifying clinicopathological characteristics and overall survival of Bulgarian patients with breast cancer

verfasst von: Stefan S. Bozhanov, Svetla G. Angelova, Maria E. Krasteva, Tsanko L. Markov, Svetlana L. Christova, Ivan G. Gavrilov, Elena I. Georgieva

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 11/2010

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Abstract

Purpose

Though p53, BRCA1, ATM, PIK3CA, and HER2 genes are shown to be involved in various aspects of breast carcinogenesis, their functional relationship and clinical value are still disputable. We investigated the genetic status or expression profile of these genes to further elucidate their clinical significance.

Methods

PCR-SSCP-Sequencing of p53, BRCA1, ATM, and PIK3CA was performed in 145 Bulgarian patients with sporadic breast cancer. Expression profiles of HER2 were determined by ICH and CISH. Relationship between mutations and clinicopathological characteristics was evaluated by Chi-squared and Fisher’s exact tests. Multivariate Cox proportional hazard test and Kaplan–Meier analysis were used to evaluate differences in overall survival between groups.

Results

The frequency of p53 (22.07%), BRCA1 (0.69%), ATM (7.59%), and PIK3CA (31.25%) alterations and HER2 (21.21%) overexpression was estimated. Mutated p53 was associated with tumor size (P = 0.033) and grade of malignancy (P = 0.001), ATM—with grade of malignancy (P = 0.032), and PIK3CA—with PR-positive tumors (P = 0.047). HER2 overexpression correlated with age of diagnosis (P = 0.009), tumor size (P = 0.0004), and ER expression (P = 0.011). Univariate survival analysis showed that mutated p53 is an indicator for worse outcome (P = 0.041). Combination of two genetic abnormalities did not correlate with more aggressive carcinogenesis and worse overall survival.

Conclusions

Our data indicated that p53, BRCA1, ATM, PIK3CA, and HER2 alterations specifically correlate with clinicopathological characteristics of Bulgarian patients with breast cancer. Of these genes, only mutated p53 showed significant, though not independent, negative effect on overall survival.

Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775CrossRefPubMed

Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103:1475–1479. doi:10.1073/pnas.0510857103 CrossRefPubMed

Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A (2007) Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:6064–6069. doi:10.1158/1078-0432.CCR-07-0266 CrossRefPubMed

Bartkova J, Horvejsv Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland MJ, Lukas C, Orntoft T, Lukas J, Bartek J (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864–870CrossRefPubMed

Borresen-Dale AL (2003) TP53 and breast cancer. Hum Mutat 21:292–300. doi:10.1002/humu.10174 CrossRefPubMed

Bull SB, Ozcelik H, Pinnaduwage D, Blackstein ME, Sutherland DA, Pritchard KI, Tzontcheva AT, Sidlofsky S, Hanna WM, Qizilbash AH, Tweeddale ME, Fine S, McCready DR, Andrulis IL (2004) The combination of p53 mutation and neu/erbB-2 amplification is associated with poor survival in node-negative breast cancer. J Clin Oncol 22:86–96. doi:10.1200/JCO.2004.09.128 CrossRefPubMed

Buzin CH, Tang SH, Cunningham JM, Shibata A, Ross RK, Hartmann A, Blaszyk H, Kovach JS (2001) Low frequency of p53 gene mutations in breast cancers of Japanese-American women. Nutr Cancer 39:72–77CrossRefPubMed

Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681CrossRefPubMed

Carr JA, Havstad S, Zarbo RJ, Divine G, Mackowiak P, Velanovich V (2000) The association of HER-2/neu amplification with breast cancer recurrence. Arch Surg 135:1469–1474CrossRefPubMed

Danon Sh, Valerianova Zdr, Ivanova Tzv (2006) Bulgarian National Cancer Registry. Cancer incidence in Bulgaria 2003. Bulgarian Publishing House, Sofia

Dork T, Bendix R, Bremer M, Rades D, Klopper K, Nicke M, Skawran B, Hector A, Yamini P, Steinmann D, Weise S, Stuhrmann M, Karstens JH (2001) Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61:7608–7615PubMed

Easton DF (1994) Cancer risks in A–T heterozygotes. Int J Radiat Biol 66:177–182CrossRef

Elledge RM, Fuqua SAW, Clark GM, Pujol P, Allred DC, Mcguire WL (1993) Prognostic significance of p53 gene alterations in nodenegative breast cancer. Breast Cancer Res Treat 26:225–235CrossRefPubMed

Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92(Suppl 7):564–569CrossRefPubMed

Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BAJ, Gayther SA, Birch JM, Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Hamann U et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689CrossRefPubMed

Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE, King MC (1994) Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet 8:399–404CrossRefPubMed

Gatti RA, Tward A, Concannon P (1999) Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 68:419–423. doi:10.1006/mgme.1999.2942 CrossRefPubMed

Georgieva M, Krasteva M, Angelova E, Ralchev K, Dimitrov V, Bozhimirov S, Georgieva E, Berger MR (2008) Analysis of the K-ras/B-raf/Erk signal cascade, p53 and CMAP as markers for tumor progression in colorectal cancer patients. Oncol Rep 20(Suppl 1):3–11PubMed

González-Hormazábal P, Bravo T, Blanco R, Valenzuela YC, Gómez F, Waugh E, Peralta O, Ortuzar W, Reyes JM, Jara L (2008) Association of common ATM variants with familial breast cancer in a South American population. BMC Cancer 8:117. doi:10.1186/1471-2407-8-117 CrossRefPubMed

Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Nieminen P, Winqvist R (2005) Association of common ATM polymorphism with bilateral breast cancer. Int J Cancer 116:69–72. doi:10.1002/ijc.20996 CrossRefPubMed

Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y, Imamura J, Ohta M, Jazag A, Guleng B, Tateishi K, Asaoka Y, Matsumura M, Kawabe T, Omata M (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567CrossRefPubMed

Izatt L, Greenman J, Hodgson S, Ellis D, Watts S, Scott G, Jacobs C, Liebmann R, Zvelebil MJ, Mathew C, Solomon E (2000) Identification of germline missense mutations and rare allelic variants in the ATM gene in early-onset breast cancer. Genes Chromosomes Cancer 26:286–294CrossRef

Khanna KK, Chenevix-Trench G (2004) ATM and genome maintenance: defining its role in breast cancer susceptibility. J Mammary Gland Biol Neoplasia 9:247–262. doi:10.1023/B:JOMG.0000048772.92326.a1 CrossRefPubMed

Khanna KK, Lavin MF, Jackson SP, Mulhern TD (2001) ATM, a central controller of cellular responses to DNA damage. Cell Death Differ 8:1052–1065CrossRefPubMed

Krasteva ME, Georgieva EI (2006) Germline p53 single-base changes associated with Balkan endemic nephropathy. Biochem Biophys Res Commun 342:562–567. doi:10.1016/j.bbrc.2006.02.004 CrossRefPubMed

Krasteva ME, Garanina Z, Georgieva EI (2003) Optimized polymerase chain reaction-based single-strand conformation polymorphism analysis of p53 gene applied to Bulgarian patients with invasive breast cancer. Clin Exp Med 3:173–180. doi:10.1007/s10238-003-0022-z CrossRefPubMed

Lacroix M, Toillon RA, Leclercq G (2006) p53 and breast cancer, an update. Endocr Relat Cancer 13:293–325. doi:10.1677/erc.1.01172 CrossRefPubMed

Langerød A, Zhao H, Borgan Ø, Nesland JM, Bukholm IR, Ikdahl T, Kåresen R, Børresen-Dale AL, Jeffrey SS (2007) TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 9(Suppl 3):30. doi:10.1186/bcr1675 CrossRef

Li SY, Rong M, Grieu F, Iacopetta B (2006) PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 96:91–95. doi:10.1007/s10549-005-9048-0 CrossRefPubMed

Liedtke C, Cardone L, Tordai A, Yan K, Gomez HL, Figureoa LB, Hubbard RE, Valero V, Souchon EA, Symmans WF, Hortobagyi GN, Bardelli A, Pusztai L (2008) PIK3CA-activating mutations and chemotherapy sensitivity in stage II–III breast cancer. Breast Cancer Res 10(Suppl 2):27. doi:10.1186/bcr1984 CrossRef

Maillet P, Chappuis PO, Vaudan G, Dobbie Z, Muller H, Hutter P, Sappino AP (2000) A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer. Int J Cancer 88:928–931. doi:10.1002/1097-0215(20001215)88:6<928:AID-IJC14>3.0.CO;2-P CrossRefPubMed

Markoff A, Sormbroen H, Bogdanova N, Preisler-Adams S, Ganev V, Dworniczak B, Horst J (1998) Comparison of conformation-sensitive gel electrophoresis and single-strand conformation polymorphism analysis for detection of mutations in the BRCA1 gene using optimized conformation analysis protocols. Eur J Hum Genet 6:145–150CrossRefPubMed

Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S (2007) Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res 15:408–414CrossRef

Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I, Varley J, Bignon Y, Uhrhammer N, Winqvist R, Jukkola-Vuorinen A, Niederacher D, Kato S, Ishioka C, Hainaut P, Borresen-Dale AL (2006) The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167. doi:10.1158/1078-0432.CCR-05-1029 CrossRefPubMed

Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26:2157–2165. doi:10.1038/sj.onc.1210302 CrossRefPubMed

Rahko E, Blanco G, Soini Y, Bloigu R, Jukkola A (2003) A mutant TP53 gene status is associated with a poor prognosis and anthracycline-resistance in breast cancer patients. Eur J Cancer 39:447–453CrossRefPubMed

Rosen PP, Lesser ML, Arroyo CD, Cranor M, Borgen P, Norton L (1995) p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis. J Clin Oncol 13:821–830PubMed

Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ (2003) The Her-2/neu gene and protein in breast cancer: biomarker and target of therapy. Oncologist 8:307–325CrossRefPubMed

Rudolph P, Olsson H, Bonatz G, Ratjen V, Bolte H, Baldetorp B, Fernö M, Parwaresch R, Alm P (1999) Correlation between p53, c-erbB-2, and topoisomerase II alpha expression, DNA ploidy, hormonal receptor status and proliferation in 356 node-negative breast carcinomas: prognostic implications. J Pathol 187:207–216. doi:10.1002/(SICI)1096-9896(199901)187:2<207:AID-PATH223>3.0.CO;2-U CrossRefPubMed

Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559CrossRefPubMed

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554. doi:10.1126/science.1096502 CrossRefPubMed

Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573CrossRefPubMed

Sansal I, Sellers WR (2004) The biology, clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22:2954–2963. doi:10.1200/JCO.2004.02.141 CrossRefPubMed

Sawaki M, Ito Y, Akiyama F, Tokudome N, Horii R, Mizunuma N, Takahashi S, Horikoshi N, Imai T, Nakao A, Kasumi F, Sakamoto G, Hatake K (2006) High prevalence of HER-2/neu and p53 overexpression in inflammatory breast cancer. Breast Cancer 13:172–178. doi:10.2325/jbcs.13.172 CrossRefPubMed

Singh B, Reddy PG, Goberdhan A, Walsh C, Dao S, Ngai I, Chou TC, O-charoenrat P, Levine AJ, Rao PH, Stoffel A (2002) p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. Genes Dev 16:984–993. doi:10.1101/gad.973602 CrossRefPubMed

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182CrossRefPubMed

Swift M, Morrell D, Massey RB, Chase CL (1991) Incidence of cancer in 161 families affected by ataxiatelangiectasia. N Engl J Med 325:1831–1836CrossRefPubMed

Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, Byrd P, Taylor M, Easton DF (2005) Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97:813–822. doi:10.1093/jnci/dji141 CrossRefPubMed

Tommiska J, Jansen L, Kilpivaara O, Edvardsen H, Kristensen V, Tamminen A, Aittomaki K, Blomqvist C, Borresen-Dale AL, Nevanlinna H (2006) ATM variants and cancer risk in breast cancer patients from Southern Finland. BMC Cancer 6:209. doi:10.1186/1471-2407-6-209 CrossRefPubMed

Tuma RS (2005) Trastuzumab trials steal show at ASCO meeting. J Natl Cancer Inst 97:870–871. doi:10.1093/jnci/97.12.870 CrossRefPubMed

Vogt PK, Kang S, Elsliger MA, Gymnopoulos M (2007) Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem Sci 32:342–349. doi:10.1016/j.tibs.2007.05.005 CrossRefPubMed

Whyte DB, Holbeck SL (2006) Correlation of PIK3CA mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem Biophys Res Commun 340:469–475. doi:10.1016/j.bbrc.2005.12.025 CrossRefPubMed

Yamashita H, Nishio M, Toyama T, Sugiura H, Zhang Z, Kobayashi S, Iwase H (2004) Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer. Breast Cancer Res 6(Suppl 1):24–30. doi:10.1186/bcr738 CrossRef

Yamashita H, Nishio M, Kobayashi S, Ando A, Sugiura H, Zhang Z, Hamaguchi M, Mita K, Fujii Y, Iwase H (2005) Phosphorylation of estrogen receptor a serine167 is predictive of response to endocrine therapy and increases post relapse survival in metastatic breast cancer. Breast Cancer Res 7:753–764. doi:10.1186/bcr1536 CrossRef

Titel: Alterations in p53, BRCA1, ATM, PIK3CA, and HER2 genes and their effect in modifying clinicopathological characteristics and overall survival of Bulgarian patients with breast cancer
verfasst von: Stefan S. Bozhanov
Svetla G. Angelova
Maria E. Krasteva
Tsanko L. Markov
Svetlana L. Christova
Ivan G. Gavrilov
Elena I. Georgieva
Publikationsdatum: 01.11.2010
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 11/2010
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-010-0824-9

Springer Medizin

Alterations in p53, BRCA1, ATM, PIK3CA, and HER2 genes and their effect in modifying clinicopathological characteristics and overall survival of Bulgarian patients with breast cancer