Abstract
Purpose
Very little is known about the genetic risk factors associated with triple-negative breast cancer (TNBC), an aggressive clinical subtype characterised by the absence of ER, PR and HER2. p53, the tumour suppressor gene, is essential for maintaining genomic stability in response to cellular stress. In breast cancer, the mutation rates of TP53 vary depending on the subtype, such that ER-negative tumours have a high rate, and in ER-positive tumours they are less common. Previous studies have implicated the intronic polymorphism in TP53 (rs17878362; or PIN3) with an increased risk of developing breast cancer, although little has been discerned on its prevalence in different subtypes. In this study, we investigated the prevalence of the PIN3 genotype in the blood of cohorts with ER-positive and the ER-negative subtype TNBC, and assessed its association with outcome.
Methods
We genotyped 656 TNBC and 648 ER-positive breast cancer patients, along with 436 controls, and compared the prevalence of polymorphism rs17878362 in these cohorts.
Results
We found there to be no differences in the prevalence of the PIN3 genotype between the ER-positive and TNBC cohorts. Furthermore, no statistically significant difference was observed in the outcome of patients in either cohort with respect to their PIN3 genotype.
Conclusions
Taken together, our results do not support an association of the PIN3 genotype with increased breast cancer risk, either in ER-positive or ER-negative patients.
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References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210
Carey L, Winer E, Viale G, Cameron D, Gianni L (2010) Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 7(12):683–692. https://doi.org/10.1038/nrclinonc.2010.154
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434. https://doi.org/10.1158/1078-0432.CCR-06-3045
Podo F, Buydens LM, Degani H, Hilhorst R, Klipp E, Gribbestad IS, Van Huffel S, van Laarhoven HW, Luts J, Monleon D, Postma GJ, Schneiderhan-Marra N, Santoro F, Wouters H, Russnes HG, Sorlie T, Tagliabue E, Borresen-Dale AL, Consortium F (2010) Triple-negative breast cancer: present challenges and new perspectives. Mol Oncol 4(3):209–229. https://doi.org/10.1016/j.molonc.2010.04.006
Aubrey BJ, Strasser A, Kelly GL (2016) Tumor-Suppressor Functions of the TP53 Pathway. Cold Spring Harb Perspect Med 6 (5). https://doi.org/10.1101/cshperspect.a026062
Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2(1):a001008. https://doi.org/10.1101/cshperspect.a001008
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(4):1157–1167. https://doi.org/10.1158/1078-0432.CCR-05-1029
Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. https://doi.org/10.1038/nature11412
Dumont P, Leu JIJ, Della Pietra AC, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33(3):357–365. https://doi.org/10.1038/ng1093
Lazar V, Hazard F, Bertin F, Janin N, Bellet D, Bressac B (1993) Simple sequence repeat polymorphism within the p53 gene. Oncogene 8(6):1703–1705
Hrstka R, Beranek M, Klocova K, Nenutil R, Vojtesek B (2009) Intronic polymorphisms in TP53 indicate lymph node metastasis in breast cancer. Oncol Rep 22(5):1205–1211
Morten BC, Wong-Brown MW, Scott RJ, Avery-Kiejda KA (2016) The presence of the intron 3 16 bp duplication polymorphism of p53 (rs17878362) in breast cancer is associated with a low Delta40p53:p53 ratio and better outcome. Carcinogenesis 37(1):81–86. https://doi.org/10.1093/carcin/bgv164
Sagne C, Marcel V, Amadou A, Hainaut P, Olivier M, Hall J (2013) A meta-analysis of cancer risk associated with the TP53 intron 3 duplication polymorphism (rs17878362): geographic and tumor-specific effects. Cell Death Dis 4(2):e492. https://doi.org/10.1038/cddis.2013.24
He X-F, Su J, Zhang Y, Huang X, Liu Y, Ding D-P, Wang W, Arparkorn K (2011) Association between the p53 polymorphisms and breast cancer risk: meta-analysis based on case–control study. Breast Cancer Res Treat 130(2):517–529. https://doi.org/10.1007/s10549-011-1583-2
Wu D, Zhang Z, Chu H, Xu M, Xue Y, Zhu H, Zhang Z (2013) Intron 3 Sixteen Base Pairs Duplication Polymorphism of P53 Contributes to Breast Cancer Susceptibility: Evidence from Meta-Analysis. PLOS ONE 8(4):e61662. https://doi.org/10.1371/journal.pone.0061662
Costa S, Pinto D, Pereira D, Rodrigues H, Cameselle-Teijeiro J, Medeiros R, Schmitt F (2008) Importance of TP53 codon 72 and intron 3 duplication 16 bp polymorphisms in prediction of susceptibility on breast cancer. BMC Cancer 8(1):32. https://doi.org/10.1186/1471-2407-8-32
De Vecchi G, Verderio P, Pizzamiglio S, Manoukian S, Bernard L, Pensotti V, Volorio S, Ravagnani F, Radice P, Peterlongo P (2008) The p53 Arg72Pro and Ins16bp polymorphisms and their haplotypes are not associated with breast cancer risk in BRCA-mutation negative familial cases. Cancer Detect Prev 32(2):140–143. https://doi.org/10.1016/j.cdp.2008.06.003
Wang-Gohrke S, Becher H, Kreienberg R, Runnebaum IB, Chang-Claude J (2002) Intron 3 16 bp duplication polymorphism of p53 is associated with an increased risk for breast cancer by the age of 50 years. Pharmacogenetics 12(3):269–272
Ashton KA, Proietto A, Otton G, Symonds I, McEvoy M, Attia J, Gilbert M, Hamann U, Scott RJ (2009) Polymorphisms in TP53 and MDM2 combined are associated with high grade endometrial cancer. Gynecol Oncol 113(1):109–114. https://doi.org/10.1016/j.ygyno.2008.12.036
Avery-Kiejda KA, Morten B, Wong-Brown MW, Mathe A, Scott RJ (2014) The relative mRNA expression of p53 isoforms in breast cancer is associated with clinical features and outcome. Carcinogenesis 35(3):586–596. https://doi.org/10.1093/carcin/bgt411
Rodrigues MS, Machado CA, Pagnoncelli D, Avvad E, Paixao JC, Gallo CV (2011) TP53 and XRCC1 polymorphisms and breast cancer prognosis: a case-case study. Clinics (Sao Paulo) 66(6):1097–1100
Acknowledgements
The authors would like to thank the Australian Breast Cancer Tissue Bank (ABCTB) for providing the DNA extracted from the blood of breast cancer patients.
Funding
This study was funded by the Hunter Medical Research Institute Bloomfield Group Foundation Grants (HMRI 13-02 (KAK), HMRI 12-08 (KAK)); the National Breast Cancer Foundation Collaborative Breast Cancer Research Program Grant (RJS); the Hunter Cancer Research Alliance; the Australian Postgraduate Award (BCM) and the Hunter Medical Research Institute MM Sawyer Scholarship (HMRI 11-39) (to BCM). The funding source had no role in study design; the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of all institutional and/or national research committees, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Online Resource 1, Supplementary Fig 1
: Representative image of the 4% agarose gel stained with GelGreen to identify PIN3 allele PCR products. Lanes 1-21 and 23 represent breast tumour samples, where lane 1 shows the 0/0 genotype, lane 5 represents the 0/16 heterozygous genotype, and lane 9 represents the 16/16 genotype. Lane 22 is a negative control, and 24 was a positive control representing the 0/0 genotype. M= 25kbp molecular weight marker. Online Resource 1, Supplementary Fig 2: Cumulative incidence plot of survivability in the different breast cancer subtypes between genotypes, adjusted for competing risk and noncancer-related deaths. (A) ER-positive (n= 648) (B) TNBC Australian cohort (n= 361) (C) combined breast tumour cohorts (Australian cohorts only; n= 1009) (PDF 307 KB)
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Morten, B.C., Chiu, S., Oldmeadow, C. et al. The intron 3 16 bp duplication polymorphism of p53 (rs17878362) is not associated with increased risk of developing triple-negative breast cancer. Breast Cancer Res Treat 173, 727–733 (2019). https://doi.org/10.1007/s10549-018-5039-9
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DOI: https://doi.org/10.1007/s10549-018-5039-9