A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

BMC Cancer

Laura Maria Pradella⁵  Cecilia Evangelisti³  Claudia Ligorio¹  Claudio Ceccarelli⁴  Iria Neri²  Roberta Zuntini⁵  Laura Benedetta Amato⁵  Simona Ferrari³  Alberto Maria Martelli³  Giuseppe Gasparre⁵  Daniela Turchetti⁵ 

[1] Section of Anatomic Pathology “M. Malpighi”, University of Bologna, Bellaria Hospital, Bologna, Italy

[2] Department of Experimental, Diagnostic and Specialty Medicine, Unit of Dermatology, University of Bologna, Bologna, Italy

[3] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

[4] Department of Experimental, Diagnostic and Specialty Medicine, Unit of Pathology, University of Bologna, Bologna, Italy

[5] Department of Medical and Surgical Sciences, Unit of Medical Genetics, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy

关键词: PI3K/Akt/mTOR pathway;    Cowden syndrome;    PTEN;    Hereditary breast cancer;   

Others  :  859087
DOI  :  10.1186/1471-2407-14-70

 received in 2013-08-23, accepted in 2014-02-04,  发布年份 2014

【 摘 要 】

Background

An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted.

Case presentation

We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one.

Conclusion

This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN-associated carcinogenesis.

【 授权许可】

   
2014 Pradella et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Turchetti D, Cortesi L, Federico M, Bertoni C, Mangone L, Ferrari S, Silingardi V: BRCA1 mutations and clinicopathological features in a sample of Italian women with early-onset breast cancer. Eur J Cancer 2000, 36(16):2083-2089.
• [2]Musolino A, Bella MA, Bortesi B, Michiara M, Naldi N, Zanelli P, Capelletti M, Pezzuolo D, Camisa R, Savi M, Neri TM, Ardizzoni A: BRCA mutations, molecular markers, and clinical variables in early-onset breast cancer: a population-based study. Breast 2007, 16(3):280-292.
• [3]Malone KE, Daling JR, Thompson JD, O’Brien CA, Francisco LV, Ostrander EA: BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 1998, 279(12):922-929.
• [4]Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR: Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999, 91(11):943-949.
• [5]Loizidou M, Marcou Y, Anastasiadou V, Newbold R, Hadjisavvas A, Kyriacou K: Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus. Clin Genet 2007, 71(2):165-170.
• [6]Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R: Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene 1998, 17(1):123-127.
• [7]Feilotter HE, Coulon V, McVeigh JL, Boag AH, Dorion-Bonnet F, Duboue B, Latham WC, Eng C, Mulligan LM, Longy M: Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer 1999, 79(5–6):718-723.
• [8]Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C: Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012, 18(2):400-407.
• [9]Vega A, Torres J, Torres M, Cameselle-Teijeiro J, Macia M, Carracedo A, Pulido R: A novel loss-of-function mutation (N48K) in the PTEN gene in a Spanish patient with Cowden disease. J Invest Dermatol 2003, 121(6):1356-1359.
• [10]Zielke A, Tezelman S, Jossart GH, Wong M, Siperstein AE, Duh QY, Clark OH: Establishment of a highly differentiated thyroid cancer cell line of Hürthle cell origin. Thyroid 1998, 8(6):475-483.
• [11]Graeser MK, Engel C, Rhiem K, Gadzicki D, Bick U, Kast K, Froster UG, Schlehe B, Bechtold A, Arnold N, Preisler-Adams S, Nestle-Kraemling C, Zaino M, Loeffler M, Kiechle M, Meindl A, Varga D, Schmutzler RK: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009, 27(35):5887-5892.
• [12]Bubien V, Bonnet F, Brouste V, Hoppe S, Barouk-Simonet E, David A, Edery P, Bottani A, Layet V, Caron O, Gilbert-Dussardier B, Delnatte C, Dugast C, Fricker JP, Bonneau D, Sevenet N, Longy M, Caux F, French Cowden Disease Network: High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet 2013, 50(4):255-263.
• [13]Riegert-Johnson DL, Gleeson FC, Roberts M, Tholen K, Youngborg L, Bullock M, Boardman LA: Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pratc 2010, 8(1):6. BioMed Central Full Text
• [14]Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 2013, 105(21):1607-1616.
• [15]Celebi JT, Tsou HC, Chen FF, Zhang H, Ping XL, Lebwohl MG, Kezis J, Peacocke M: Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN. J Med Genet 1999, 36(5):360-364.
• [16]Melbārde-Gorkuša I, Irmejs A, Bērziņa D, Strumfa I, Aboliņš A, Gardovskis A, Subatniece S, Trofimovičs G, Gardovskis J, Miklaševičs E: Challenges in the management of a patient with Cowden syndrome: case report and literature review. Hered Cancer Clin Pract 2012, 10:5. BioMed Central Full Text
• [17]Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP: Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005, 436:725-730.
• [18]Banneau G, Guedj M, MacGrogan G, De Mascarel I, Velasco V, Schiappa R, Bonadona V, David A, Dugast C, Gilbert-Dussardier B, Ingster O, Vabres P, Caux F, De Reynies A, Iggo R, Sevenet N, Bonnet F, Longy M: Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations. Breast Cancer Res 2010, 12(4):R63. BioMed Central Full Text
• [19]Berger AH, Knudson AG, Pandolfi PP: A continuum model for tumour suppression. Nature 2011, 476(7359):163-169.
• [20]Pradella LM, Zuntini R, Magini P, Ceccarelli C, Neri I, Cerasoli S, Graziano C, Gasparre G, Turchetti D: Two distinct thyroid tumours in a patient with Cowden syndrome carrying both a 10q23 and a mitochondrial DNA germline deletion. J Med Genet 2011, 48(11):779-782.
• [21]Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, Mackay A, Reis-Filho JS, Seri M, Turchetti D, Gasparre G: Where Birt-Hogg-Dube meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. Eur J Hum Genet 2013, 21(10):1169-1172.