Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Hereditary breast and ovarian cancer syndrome
Bakry D, Malkin D (2013) TP53 germline mutations: genetics of Li–Fraumeni syndrome. In: Hainaut P, Olivier M, Wiman KG (eds) p53 in the clinics. Springer, New York, pp 167–188
van der Groep P, van der Wall E, van Diest PJ (2011) Pathology of hereditary breast cancer. Cell Oncol (Dordr) 34(2):71–88. https://doi.org/10.1007/s13402-011-0010-3
Li FP, Fraumeni JJF (1969) Soft-TISSUE SARCOMAS, BREAST CANCER, AND OTHER NEOPLASMSA FAMILIAL SYNdrome? Ann Intern Med 71(4):747–752. https://doi.org/10.7326/0003-4819-71-4-747
Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, Han JH, Lowstuter K, Longmate J, Sommer SS, Weitzel JN (2009) Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27(8):1250–1256
Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg A, Trent J, Raffeld M, Yakhini Z, Ben-Dor A, Dougherty E, Kononen J, Bubendorf L, Fehrle W, Pittaluga S, Gruvberger S, Loman N, Johannsson O, Olsson H, Sauter G (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344(8):539–548. https://doi.org/10.1056/NEJM200102223440801
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100(14):8418–8423. https://doi.org/10.1073/pnas.0932692100
Hu C, Polley EC, Yadav S, Lilyquist J, Shimelis H, Na J, Hart SN, Goldgar DE, Shah S, Pesaran T, Dolinsky JS, LaDuca H, Couch FJ (2020) The contribution of germline predisposition gene mutations to clinical subtypes of invasive breast cancer from a clinical genetic testing cohort. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djaa023
Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J, Gruber SB, Ford JM, Euhus D, Lebensohn A, Telli M, Pochebit SM, Lypas G, Garber JE (2012) Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat 133(3):1125–1130. https://doi.org/10.1007/s10549-012-1993-9
Rath MG, Masciari S, Gelman R, Miron A, Miron P, Foley K, Richardson AL, Krop IE, Verselis SJ, Dillon DA, Garber JE (2013) Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat 139(1):193–198. https://doi.org/10.1007/s10549-012-2375-z
Lee DS, Yoon SY, Looi LM, Kang P, Kang IN, Sivanandan K, Ariffin H, Thong MK, Chin KF, Mohd Taib NA, Yip CH, Teo SH (2012) Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res 14(2):R66. https://doi.org/10.1186/bcr3172
Melhem-Bertrandt A, Bojadzieva J, Ready KJ, Obeid E, Liu DD, Gutierrez-Barrera AM, Litton JK, Olopade OI, Hortobagyi GN, Strong LC, Arun BK (2012) Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 118(4):908–913. https://doi.org/10.1002/cncr.26377
Wilson JR, Bateman AC, Hanson H, An Q, Evans G, Rahman N, Jones JL, Eccles DM (2010) A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47(11):771–774. https://doi.org/10.1136/jmg.2010.078113
Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, Easton DF (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318. https://doi.org/10.1200/JCO.2002.09.023
Packwood K, Martland G, Sommerlad M, Shaw E, Moutasim K, Thomas G, Bateman AC, Jones L, Haywood L, Evans DG, Birch JM, Alsalmi OA, Henderson A, Poplawski N, Eccles DM (2019) Breast cancer in patients with germline TP53 pathogenic variants have typical tumour characteristics: the Cohort study of TP53 carrier early onset breast cancer (COPE study). J Pathol Clin Res 5(3):189–198. https://doi.org/10.1002/cjp2.133
Fortuno C, Mester J, Pesaran T, Weitzel JN, Dolinsky J, Yussuf A, McGoldrick K, Garber JE, Savage SA, Khincha PP, Gareth Evans D, Achatz MI, Nichols KE, Maxwell KN, Schiffman JD, Sandoval R, James PA, Spurdle AB, Consortium L-FEL (2020) Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines. Hum Mutat 41(9):1555–1562. https://doi.org/10.1002/humu.24060
den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, Roux AF, Smith T, Antonarakis SE, Taschner PE (2016) HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat 37(6):564–569. https://doi.org/10.1002/humu.22981
Paulo P, Pinto P, Peixoto A, Santos C, Pinto C, Rocha P, Veiga I, Soares G, Machado C, Ramos F, Teixeira MR (2017) Validation of a next-generation sequencing pipeline for the molecular diagnosis of multiple inherited cancer predisposing syndromes. J Mol Diagn 19(4):502–513. https://doi.org/10.1016/j.jmoldx.2017.05.001
Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526(7571):68–74. https://doi.org/10.1038/nature15393
Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, Tsimberidou AM, Vnencak-Jones CL, Wolff DJ, Younes A, Nikiforova MN (2017) Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, american society of clinical oncology, and college of american pathologists. J Mol Diagn 19(1):4–23. https://doi.org/10.1016/j.jmoldx.2016.10.002
Silva MP, Barros-Silva JD, Vieira J, Lisboa S, Torres L, Correia C, Vieira-Coimbra M, Martins AT, Jeronimo C, Henrique R, Paulo P, Teixeira MR (2016) NCOA2 is a candidate target gene of 8q gain associated with clinically aggressive prostate cancer. Genes Chromosomes Cancer 55(4):365–374. https://doi.org/10.1002/gcc.22340
Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 142(11):1364–1382. https://doi.org/10.5858/arpa.2018-0902-SA
Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev 26(12):1268–1286. https://doi.org/10.1101/gad.190678.112
Kakudo Y, Shibata H, Otsuka K, Kato S, Ishioka C (2005) Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s. Cancer Res 65(6):2108–2114. https://doi.org/10.1158/0008-5472.CAN-04-2935
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013. https://doi.org/10.1200/JCO.2013.50.9984
McBride KA, Ballinger ML, Killick E, Kirk J, Tattersall MH, Eeles RA, Thomas DM, Mitchell G (2014) Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nature Rev Clin Oncol 11(5):260–271. https://doi.org/10.1038/nrclinonc.2014.41
Eccles DM, Li N, Handwerker R, Maishman T, Copson ER, Durcan LT, Gerty SM, Jones L, Evans DG, Haywood L, Campbell I (2016) Genetic testing in a cohort of young patients with HER2-amplified breast cancer. Ann Oncol 27(3):467–473. https://doi.org/10.1093/annonc/mdv592
Sorrell AD, Espenschied CR, Culver JO, Weitzel JN (2013) Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome: current status of clinical applications and future directions. Mol Diagn Ther 17(1):31–47. https://doi.org/10.1007/s40291-013-0020-0
Schon K, Tischkowitz M (2018) Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat 167(2):417–423. https://doi.org/10.1007/s10549-017-4531-y
Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugieres L, Caron O, Benusiglio PR, Bressac-de Paillerets B, Bonadona V, Bonaiti-Pellie C, Tinat J, Baert-Desurmont S, Frebourg T (2015) Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 33(21):2345–2352. https://doi.org/10.1200/JCO.2014.59.5728
Li VD, Li KH, Li JT (2019) TP53 mutations as potential prognostic markers for specific cancers: analysis of data from The Cancer Genome Atlas and the International Agency for Research on Cancer TP53 Database. J Cancer Res Clin Oncol 145(3):625–636. https://doi.org/10.1007/s00432-018-2817-z
Horio Y, Suzuki H, Ueda R, Koshikawa T, Sugiura T, Ariyoshi Y, Shimokata K, Takahashi T, Takahashi T (1994) Predominantly tumor-limited expression of a mutant allele in a Japanese family carrying a germline p53 mutation. Oncogene 9(4):1231–1235
Pinto C, Veiga I, Pinheiro M, Peixoto A, Pinto A, Lopes JM, Reis RM, Oliveira C, Baptista M, Roque L, Regateiro F, Cirnes L, Hofstra RM, Seruca R, Castedo S, Teixeira MR (2009) TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset. Fam Cancer 8(4):383–390. https://doi.org/10.1007/s10689-009-9251-y
Varley JM (2003) Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat 21(3):313–320. https://doi.org/10.1002/humu.10185
Masciari S, Dewanwala A, Stoffel EM, Lauwers GY, Zheng H, Achatz MI, Riegert-Johnson D, Foretova L, Silva EM, Digianni L, Verselis SJ, Schneider K, Li FP, Fraumeni J, Garber JE, Syngal S (2011) Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med 13(7):651–657. https://doi.org/10.1097/GIM.0b013e31821628b6
Ariffin H, Chan AS, Oh L, Abd-Ghafar S, Ong GB, Mohamed M, Razali H, Juraida E, Teo SH, Karsa M, Shamsani J, Hainaut P (2015) Frequent occurrence of gastric cancer in Asian kindreds with Li-Fraumeni syndrome. Clin Genet 88(5):450–455. https://doi.org/10.1111/cge.12525
McCuaig JM, Armel SR, Novokmet A, Ginsburg OM, Demsky R, Narod SA, Malkin D (2012) Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer 11(4):607–613. https://doi.org/10.1007/s10689-012-9557-z
This work was funded by IPO-Porto Research Center. MP is a Post-Doctoral fellow from Fundação para a Ciência e a Tecnologia (FCT: SFRH/BPD/113014/2015). PP is a Post-Doctoral fellow supported by FCT and the Research Center of IPO-Porto (UID/DTP/00776/POCI-01-0145-FEDER-006868). JG is a PhD student fellow from Fundação para a Ciência e a Tecnologia (FCT: SFRH/BD/138670/2018). The funding bodies did not have a role in the design of the study; collection, analysis, and interpretation of data; and in writing the manuscript.
Conflicts of interest
The authors declare that they have no conflict of interest.
All procedures performed in this were in accordance with the ethical standards of Comissão de Ética para a Saúde do IPO-Porto (committee’s reference number: CES219-019) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
The consent obtained from study participants was written.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Escudeiro, C., Pinto, C., Vieira, J. et al. The role of TP53 pathogenic variants in early-onset HER2-positive breast cancer. Familial Cancer (2020). https://doi.org/10.1007/s10689-020-00212-2
- HER2-positive breast cancer
- TP53 germline variants
- Li-fraumeni syndrome
- Next-generation sequencing