Abstract
Purpose
SETD2 is one of the key epigenetic regulatory genes involved in histone modifications. Its alterations were potentially oncogenic and commonly found in cancers. Interestingly, SETD2 is one of the most frequent mutated genes found exclusively in phyllodes tumor of the breast (PT). However, little has been done to further characterize SETD2 alterations in PT.
Methods
In this study, we examined the alterations of SETD2 gene and protein expression in a large cohort of PTs. Their correlations with SETD2 downstream target, H3K36me3 expression, and clinicopathologic features in PT were also assessed.
Results
SETD2 mutation was found in 15.9% of our cases and was mostly predicted to be damaging mutations. Interestingly, SETD2 mutations were associated with lower H3K36me3 expression, particularly those with damaging mutations (p = .041). Neither SETD2 mutations nor H3K36me3 expression was associated with PT grading and other clinicopathological features. By contrast, the SETD2 protein expression cannot reflect its mutation status and showed a different trend of clinicopathological correlations from H3K36me3.
Conclusions
Our findings may suggest a potential involvement of epigenetic regulation via SETD2 alterations and downstream H3K36me3 on PT development. SETD2 mutations may occur early in the pathogenic process of PTs and its loss per se may not be sufficient for progression to malignancy. Exclusive alterations of SETD2 in PT can be used as markers for the diagnosis of fibroepithelial lesions. The association of H3K36me3 with SETD2 mutations may also indicate the value of evaluation of H3K36me3 expression in the diagnosis of fibroepithelial lesions.
Similar content being viewed by others
References
Tan J, Ong CK, Lim WK, Ng CC, Thike AA, Ng LM, Rajasegaran V, Myint SS, Nagarajan S, Thangaraju S, Dey S, Nasir ND, Wijaya GC, Lim JQ, Huang D, Li Z, Wong BH, Chan JY, McPherson JR, Cutcutache I, Poore G, Tay ST, Tan WJ, Putti TC, Ahmad BS, Iau P, Chan CW, Tang AP, Yong WS, Madhukumar P, Ho GH, Tan VK, Wong CY, Hartman M, Ong KW, Tan BK, Rozen SG, Tan P, Tan PH, Teh BT (2015) Genomic landscapes of breast fibroepithelial tumors. Nat Genet 47(11):1341–1345. https://doi.org/10.1038/ng.3409
Piscuoglio S, Ng CK, Murray M, Burke KA, Edelweiss M, Geyer FC, Macedo GS, Inagaki A, Papanastasiou AD, Martelotto LG, Marchio C, Lim RS, Ioris RA, Nahar PK, Bruijn ID, Smyth L, Akram M, Ross D, Petrini JH, Norton L, Solit DB, Baselga J, Brogi E, Ladanyi M, Weigelt B, Reis-Filho JS (2016) Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, and TERT promoter hotspot mutations and TERT gene amplification as likely drivers of progression. J Pathol 238(4):508–518. https://doi.org/10.1002/path.4672
Cani AK, Hovelson DH, McDaniel AS, Sadis S, Haller MJ, Yadati V, Amin AM, Bratley J, Bandla S, Williams PD, Rhodes K, Liu CJ, Quist MJ, Rhodes DR, Grasso CS, Kleer CG, Tomlins SA (2015) Next-gen sequencing exposes frequent MED12 mutations and actionable therapeutic targets in phyllodes tumors. Mol Cancer Res 13(4):613–619. https://doi.org/10.1158/1541-7786.MCR-14-0578
Garcia-Dios DA, Levi D, Shah V, Gillett C, Simpson MA, Hanby A, Tomlinson I, Sawyer EJ (2018) MED12, TERT promoter and RBM15 mutations in primary and recurrent phyllodes tumours. Br J Cancer 118(2):277–284. https://doi.org/10.1038/bjc.2017.450
Tsang JY, Go EM, Tse GM (2015) Identification of clinically relevant alterations in phyllodes tumor of the breast by amplicon-based next-generation sequencing. Breast Cancer Res Treat 151(3):717–719. https://doi.org/10.1007/s10549-015-3396-1
Tsang JYS, Hui YK, Lee MA, Lacambra M, Ni YB, Cheung SY, Wu C, Kwong A, Tse GMK (2018) Association of clinicopathological features and prognosis of TERT alterations in phyllodes tumor of breast. Sci Rep 8(1):3881. https://doi.org/10.1038/s41598-018-22232-w
Yoshida M, Ogawa R, Yoshida H, Maeshima A, Kanai Y, Kinoshita T, Hiraoka N, Sekine S (2015) TERT promoter mutations are frequent and show association with MED12 mutations in phyllodes tumors of the breast. Br J Cancer 113(8):1244–1248. https://doi.org/10.1038/bjc.2015.326
Fahey CC, Davis IJ (2017) SETting the stage for cancer development: SETD2 and the consequences of lost methylation. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a026468
Gu L, Wang Q, Sun QY (2010) Histone modifications during mammalian oocyte maturation: dynamics, regulation and functions. Cell Cycle 9(10):1942–1950. https://doi.org/10.4161/cc.9.10.11599
Chen R, Zhao WQ, Fang C, Yang X, Ji M (2020) Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers. J Cancer 11(11):3349–3356. https://doi.org/10.7150/jca.38391
Skucha A, Ebner J, Grebien F (2019) Roles of SETD2 in Leukemia-Transcription, DNA-Damage, and Beyond. Int J Mol Sci. https://doi.org/10.3390/ijms20051029
Cancer Genome Atlas Research N (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499(7456):43–49. https://doi.org/10.1038/nature12222
Simon JM, Hacker KE, Singh D, Brannon AR, Parker JS, Weiser M, Ho TH, Kuan PF, Jonasch E, Furey TS, Prins JF, Lieb JD, Rathmell WK, Davis IJ (2014) Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Genome Res 24(2):241–250. https://doi.org/10.1101/gr.158253.113
Grosso AR, Leite AP, Carvalho S, Matos MR, Martins FB, Vitor AC, Desterro JM, Carmo-Fonseca M, de Almeida SF (2015) Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma. Elife. https://doi.org/10.7554/eLife.09214
Kim JY, Yu JH, Nam SJ, Kim SW, Lee SK, Park WY, Noh DY, Nam DH, Park YH, Han W, Lee JE (2018) Genetic and clinical characteristics of phyllodes tumors of the breast. Transl Oncol 11(1):18–23. https://doi.org/10.1016/j.tranon.2017.10.002
Liu SY, Joseph NM, Ravindranathan A, Stohr BA, Greenland NY, Vohra P, Hosfield E, Yeh I, Talevich E, Onodera C, Van Ziffle JA, Grenert JP, Bastian BC, Chen YY, Krings G (2016) Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity. Mod Pathol 29(9):1012–1027. https://doi.org/10.1038/modpathol.2016.97
Md Nasir ND, Ng CCY, Rajasegaran V, Wong SF, Liu W, Ng GXP, Lee JY, Guan P, Lim JQ, Thike AA, Koh VCY, Loke BN, Chang KTE, Gudi MA, Lian DWQ, Madhukumar P, Tan BKT, Tan VKM, Wong CY, Yong WS, Ho GH, Ong KW, International Fibroepithelial C, Tan P, Teh BT, Tan PH (2019) Genomic characterisation of breast fibroepithelial lesions in an international cohort. J Pathol 249 (4):447–460. https://doi.org/https://doi.org/10.1002/path.5333
board Wcote, (ed) (2019) WHO classification of tumours of the Breast, 5th edn. IARC, Lyon
Chang HY, Koh VCY, Md Nasir ND, Ng CCY, Guan P, Thike AA, Teh BT, Tan PH (2020) MED12, TERT and RARA in fibroepithelial tumours of the breast. J Clin Pathol 73(1):51–56. https://doi.org/10.1136/jclinpath-2019-206208
Pareja F, Da Cruz PA, Murray MP, Hoang T, Gularte-Merida R, Brown D, da Silva EM, Sebastiao APM, Giri DD, Weigelt B, Reis-Filho JS, Brogi E (2019) Recurrent MED12 exon 2 mutations in benign breast fibroepithelial lesions in adolescents and young adults. J Clin Pathol 72(3):258–262. https://doi.org/10.1136/jclinpath-2018-205570
Yoon N, Bae GE, Kang SY, Choi MS, Hwang HW, Kim SW, Lee JE, Nam SJ, Gong G, Lee HJ, Bae YK, Lee A, Cho EY (2016) Frequency of MED12 mutations in phyllodes tumors: Inverse correlation with histologic grade. Genes Chromosomes Cancer 55(6):495–504. https://doi.org/10.1002/gcc.22351
Fontebasso AM, Schwartzentruber J, Khuong-Quang DA, Liu XY, Sturm D, Korshunov A, Jones DT, Witt H, Kool M, Albrecht S, Fleming A, Hadjadj D, Busche S, Lepage P, Montpetit A, Staffa A, Gerges N, Zakrzewska M, Zakrzewski K, Liberski PP, Hauser P, Garami M, Klekner A, Bognar L, Zadeh G, Faury D, Pfister SM, Jabado N, Majewski J (2013) Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol 125(5):659–669. https://doi.org/10.1007/s00401-013-1095-8
Chen YB, Xu J, Skanderup AJ, Dong Y, Brannon AR, Wang L, Won HH, Wang PI, Nanjangud GJ, Jungbluth AA, Li W, Ojeda V, Hakimi AA, Voss MH, Schultz N, Motzer RJ, Russo P, Cheng EH, Giancotti FG, Lee W, Berger MF, Tickoo SK, Reuter VE, Hsieh JJ (2016) Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat Commun 7:13131. https://doi.org/10.1038/ncomms13131
Huang KK, McPherson JR, Tay ST, Das K, Tan IB, Ng CC, Chia NY, Zhang SL, Myint SS, Hu L, Rajasegaran V, Huang D, Loh JL, Gan A, Sairi AN, Sam XX, Dominguez LT, Lee M, Soo KC, Ooi LL, Ong HS, Chung A, Chow PK, Wong WK, Selvarajan S, Ong CK, Lim KH, Nandi T, Rozen S, Teh BT, Quek R, Tan P (2016) SETD2 histone modifier loss in aggressive GI stromal tumours. Gut 65(12):1960–1972. https://doi.org/10.1136/gutjnl-2015-309482
Ho TH, Kapur P, Joseph RW, Serie DJ, Eckel-Passow JE, Tong P, Wang J, Castle EP, Stanton ML, Cheville JC, Jonasch E, Brugarolas J, Parker AS (2016) Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death. Mod Pathol 29(1):34–42. https://doi.org/10.1038/modpathol.2015.123
Walter DM, Venancio OS, Buza EL, Tobias JW, Deshpande C, Gudiel AA, Kim-Kiselak C, Cicchini M, Yates TJ, Feldser DM (2017) Systematic In Vivo Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma. Cancer Res 77(7):1719–1729. https://doi.org/10.1158/0008-5472.CAN-16-2159
Sim Y, Ng GXP, Ng CCY, Rajasegaran V, Wong SF, Liu W, Guan P, Nagarajan S, Ng WY, Thike AA, Lim JCT, Nasir N, Tan VKM, Madhukumar P, Yong WS, Wong CY, Tan BKT, Ong KW, Teh BT, Tan PH (2019) A novel genomic panel as an adjunctive diagnostic tool for the characterization and profiling of breast Fibroepithelial lesions. BMC Med Genomics 12(1):142. https://doi.org/10.1186/s12920-019-0588-2
Labbe RM, Holowatyj A, Yang ZQ (2013) Histone lysine demethylase (KDM) subfamily 4: structures, functions and therapeutic potential. Am J Transl Res 6(1):1–15
Karim RZ, Scolyer RA, Tse GM, Tan PH, Putti TC, Lee CS (2009) Pathogenic mechanisms in the initiation and progression of mammary phyllodes tumours. Pathology 41(2):105–117. https://doi.org/10.1080/00313020802579342
Chen Y, Fang R, Yue C, Chang G, Li P, Guo Q, Wang J, Zhou A, Zhang S, Fuller GN, Shi X, Huang S (2020) Wnt-Induced Stabilization of KDM4C Is Required for Wnt/beta-Catenin Target Gene Expression and Glioblastoma Tumorigenesis. Cancer Res 80(5):1049–1063. https://doi.org/10.1158/0008-5472.CAN-19-1229
Kim IK, McCutcheon JN, Rao G, Liu SV, Pommier Y, Skrzypski M, Zhang YW, Giaccone G (2019) Acquired SETD2 mutation and impaired CREB1 activation confer cisplatin resistance in metastatic non-small cell lung cancer. Oncogene 38(2):180–193. https://doi.org/10.1038/s41388-018-0429-3
Elgendy M, Fusco JP, Segura V, Lozano MD, Minucci S, Echeveste JI, Gurpide A, Andueza M, Melero I, Sanmamed MF, Ruiz MR, Calvo A, Pascual JI, Velis JM, Minana B, Valle RD, Pio R, Agorreta J, Abengozar M, Colecchia M, Brich S, Renne SL, Guruceaga E, Patino-Garcia A, Perez-Gracia JL (2019) Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer. Int J Cancer 145(7):1991–2001. https://doi.org/10.1002/ijc.32256
Pfister SX, Markkanen E, Jiang Y, Sarkar S, Woodcock M, Orlando G, Mavrommati I, Pai CC, Zalmas LP, Drobnitzky N, Dianov GL, Verrill C, Macaulay VM, Ying S, La Thangue NB, D’Angiolella V, Ryan AJ, Humphrey TC (2015) Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28(5):557–568. https://doi.org/10.1016/j.ccell.2015.09.015
Funding
The work was not supported by any funding agencies.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors declare that they have no conflicts of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
IRB approval was obtained for this study and a waiver of informed consent was obtained due to the retrospective nature of the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Tsang, J.Y., Lai, ST., Ni, YB. et al. SETD2 alterations and histone H3K36 trimethylation in phyllodes tumor of breast. Breast Cancer Res Treat 187, 339–347 (2021). https://doi.org/10.1007/s10549-021-06181-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-021-06181-z