Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39

Abstract

Purpose

Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC.

Methods

Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes.

Results

Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case–control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035).

Conclusions

This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

Abbreviations

BC:

Breast cancer

WES:

Whole exome sequencing

HRM:

High resolution melting (HRM)

AS-PCR:

Allele-specific PCR

LOH:

Loss-of-heterozygosity

References

  1. 1.

    Siegel RL, Miller KD, Jemal CA (2018) Cancer statistics. CA Cancer J Clin 68(1):7–30. https://doi.org/10.3322/caac.21442

    Article  PubMed  Google Scholar 

  2. 2.

    Girard E, Eon-Marchais S, Olaso R, Renault AL, Damiola F, Dondon MG, Barjhoux L, Goidin D, Meyer V, Le Gal D, Beauvallet J, Mebirouk N, Lonjou C, Coignard J, Marcou M, Cavaciuti E, Baulard C, Bihoreau MT, Cohen-Haguenauer O, Leroux D, Penet C, Fert-Ferrer S, Colas C, Frebourg T, Eisinger F, Adenis C, Fajac A, Gladieff L, Tinat J, Floquet A, Chiesa J, Giraud S, Mortemousque I, Soubrier F, Audebert-Bellanger S, Limacher JM, Lasset C, Lejeune-Dumoulin S, Dreyfus H, Bignon YJ, Longy M, Pujol P, Venat-Bouvet L, Bonadona V, Berthet P, Luporsi E, Maugard CM, Noguès C, Delnatte C, Fricker JP, Gesta P, Faivre L, Lortholary A, Buecher B, Caron O, Gauthier-Villars M, Coupier I, Servant N, Boland A, Mazoyer S, Deleuze JF, Stoppa-Lyonnet D, Andrieu N, Lesueur F (2019) Familial breast cancer and DNA repair genes: insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int J Cancer 144(8):1962–1974. https://doi.org/10.1002/ijc.31921

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Hauke J, Horvath J, Groß E, Gehrig A, Honisch E, Hackmann K, Schmidt G, Arnold N, Faust U, Sutter C, Hentschel J, Wang-Gohrke S, Smogavec M, Weber BHF, Weber-Lassalle N, Weber-Lassalle K, Borde J, Ernst C, Altmüller J, Volk AE, Thiele H, Hübbel V, Nürnberg P, Keupp K, Versmold B, Pohl E, Kubisch C, Grill S, Paul V, Herold N, Lichey N, Rhiem K, Ditsch N, Ruckert C, Wappenschmidt B, Auber B, Rump A, Niederacher D, Haaf T, Ramser J, Dworniczak B, Engel C, Meindl A, Schmutzler RK, Hahnen E (2018) Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med 7(4):1349–1358. https://doi.org/10.1002/cam4.1376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    Hahnen E, Hauke J, Engel C, Neidhardt G, Rhiem K, Schmutzler RK (2017) Germline mutations in triple-negative breast cancer. Breast Care (Basel) 12(1):15–19. https://doi.org/10.1159/000455999

    Article  Google Scholar 

  5. 5.

    Neidhardt G, Hauke J, Ramser J, Groß E, Gehrig A, Müller CR, Kahlert AK, Hackmann K, Honisch E, Niederacher D, Heilmann-Heimbach S, Franke A, Lieb W, Thiele H, Altmüller J, Nürnberg P, Klaschik K, Ernst C, Ditsch N, Jessen F, Ramirez A, Wappenschmidt B, Engel C, Rhiem K, Meindl A, Schmutzler RK, Hahnen E (2017) Association between loss-of-function mutations within the FANCM gene and early-onset familial breast cancer. JAMA Oncol 3(9):1245–1248. https://doi.org/10.1001/jamaoncol.2016.5592

    Article  PubMed  Google Scholar 

  6. 6.

    Pelttari LM, Kiiski JI, Ranta S, Vilske S, Blomqvist C, Aittomaki K, Nevanlinna H (2015) RAD51, XRCC3, and XRCC2 mutation screening in Finnish breast cancer families. Springerplus 4:92. https://doi.org/10.1186/s40064-015-0880-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Gutiérrez-Enríquez S, Bonache S, de Garibay GR, Osorio A, Santamariña M, Ramón y Cajal T, Esteban-Cardeñosa E, Tenés A, Yanowsky K, Barroso A, Montalban G, Blanco A, Cornet M, Gadea N, Infante M, Caldés T, Díaz-Rubio E, Balmaña J, Lasa A, Vega A, Benítez J, de la Hoya M, Diez O (2014) About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants. Int J Cancer 134(9):2088–2097. https://doi.org/10.1002/ijc.28540

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Sokolenko AP, Iyevleva AG, Preobrazhenskaya EV, Mitiushkina NV, Abysheva SN, Suspitsin EN, Kuligina ESh, Gorodnova TV, Pfeifer W, Togo AV, Turkevich EA, Ivantsov AO, Voskresenskiy DV, Dolmatov GD, Bit-Sava EM, Matsko DE, Semiglazov VF, Fichtner I, Larionov AA, Kuznetsov SG, Antoniou AC, Imyanitov EN (2012) High prevalence and breast cancer predisposing role of the BLM c.1642 C > T (Q548X) mutation in Russia. Int J Cancer 130:2867–2873. https://doi.org/10.1002/ijc.26342

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39:165–167. https://doi.org/10.1038/ng1959

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71. https://doi.org/10.1126/science.7545954

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D, Fields P, Marshall G, Narod S, Lenoir GM, Lynch H, Feunteun J, Devilee P, Cornelisse CJ, Menko FH, Daly PA, Ormiston W, McManus R, Pye C, Lewis CM, Cannon-Albright LA, Peto J, Ponder BAJ, Skolnick MH, Easton DF, Goldgar DE, Stratton MR (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265:2088–2090. https://doi.org/10.1126/science.8091231

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238. https://doi.org/10.1126/science.1978757

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Wang YA, Jian JW, Hung CF, Peng HP, Yang CF, Cheng HS, Yang AS (2018) Germline breast cancer susceptibility gene mutations and breast cancer outcomes. BMC Cancer 18(1):315. https://doi.org/10.1186/s12885-018-4229-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. 14.

    Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, Hallberg E, Moore R, Thomas A, Lilyquist J, Feng B, McFarland R, Pesaran T, Huether R, LaDuca H, Chao EC, Goldgar DE, Dolinsky JS (2017) Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 3(9):1190–1196. https://doi.org/10.1001/jamaoncol.2017.0424

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Skol AD, Sasaki MM, Onel K (2016) The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance. Breast Cancer Res 18(1):99. https://doi.org/10.1186/s13058-016-0759-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Sokolenko AP, Suspitsin EN, Kuligina ESh, Bizin IV, Frishman D, Imyanitov EN (2015) Identification of novel hereditary cancer genes by whole exome sequencing. Cancer Lett 369(2):274–288. https://doi.org/10.1016/j.canlet.2015.09.014

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Hillemanns P, Dörk T (2010) High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet 78(4):364–372. https://doi.org/10.1111/j.1399-0004.2010.01473.x

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Sokolenko AP, Bogdanova N, Kluzniak W, Preobrazhenskaya EV, Kuligina ES, Iyevleva AG, Aleksakhina SN, Mitiushkina NV, Gorodnova TV, Bessonov AA, Togo AV, Lubiński J, Cybulski C, Jakubowska A, Dörk T, Imyanitov EN (2014) Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. Breast Cancer Res Treat 145(2):553–562. https://doi.org/10.1007/s10549-014-2971-1

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Dzhemileva LU, Barashkov NA, Posukh OL, Khusainova RI, Akhmetova VL, Kutuev IA, Gilyazova IR, Tadinova VN, Fedorova SA, Khidiyatova IM, Lobov SL, Khusnutdinova EK (2010) Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia. J Hum Genet 55(11):749–754. https://doi.org/10.1038/jhg.2010.101

    Article  Google Scholar 

  20. 20.

    Chekmariova EV, Sokolenko AP, Buslov KG, Iyevleva AG, Ulibina YM, Rozanov ME, Mitiushkina NV, Togo AV, Matsko DE, Voskresenskiy DA, Chagunava OL, Devilee P, Cornelisse C, Semiglazov VF, Imyanitov EN (2006) CHEK2 1100delC mutation is frequent among Russian breast cancer patients. Breast Cancer Res Treat 100(1):99–102. https://doi.org/10.1007/s10549-006-9227-7

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Prokofyeva D, Bogdanova N, Dubrowinskaja N, Bermisheva M, Takhirova Z, Antonenkova N, Turmanov N, Datsyuk I, Gantsev S, Christiansen H, Park-Simon TW, Hillemanns P, Khusnutdinova E, Dörk T (2013) Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom’s syndrome, is associated with breast cancer in Slavic populations. Breast Cancer Res Treat 137(2):533–539. https://doi.org/10.1007/s10549-012-2357-1

    Article  CAS  Google Scholar 

  22. 22.

    Suspitsin EN, Yanus GA, Sokolenko AP, Yatsuk OS, Zaitseva OA, Bessonov AA, Ivantsov AO, Heinstein VA, Klimashevskiy VF, Togo AV, Imyanitov EN (2014) Development of breast tumors in CHEK2, NBN/NBS1 and BLM mutation carriers does not commonly involve somatic inactivation of the wild-type allele. Med Oncol 31(2):828. https://doi.org/10.1007/s12032-013-0828-9

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Li Q, Wang K (2017) InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet 100(2):267–280. https://doi.org/10.1016/j.ajhg.2017.01.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. 24.

    Amendola LM, Jarvik GP, Leo MC, McLaughlin HM, Akkari Y, Amaral MD, Berg JS, Biswas S, Bowling KM, Conlin LK, Cooper GM, Dorschner MO, Dulik MC, Ghazani AA, Ghosh R, Green RC, Hart R, Horton C, Johnston JJ, Lebo MS, Milosavljevic A, Ou J, Pak CM, Patel RY, Punj S, Richards CS, Salama J, Strande NT, Yang Y, Plon SE, Biesecker LG, Rehm HL (2016) Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the clinical sequencing exploratory research consortium. Am J Hum Genet 98(6):1067–1076. https://doi.org/10.1016/j.ajhg.2016.03.024

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Kulandaisamy A, Binny Priya S, Sakthivel R, Tarnovskaya S, Bizin I, Hönigschmid P, Frishman D, Gromiha MM (2018) MutHTP: mutations in human transmembrane proteins. Bioinformatics 34(13):2325–2326. https://doi.org/10.1093/bioinformatics/bty054

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Karczewski KJ, Weisburd B, Thomas B, Solomonson M, Ruderfer DM, Kavanagh D, Hamamsy T, Lek M, Samocha KE, Cummings BB, Birnbaum D, The Exome Aggregation Consortium, Daly MJ, MacArthur DG (2017) The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 45(D1):D840–D845. https://doi.org/10.1093/nar/gkw971

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Sokolenko AP, Mitiushkina NV, Buslov KG, Bit-Sava EM, Iyevleva AG, Chekmariova EV, Kuligina ESh, Ulibina YM, Rozanov ME, Suspitsin EN, Matsko DE, Chagunava OL, Trofimov DY, Devilee P, Cornelisse C, Togo AV, Semiglazov VF, Imyanitov EN (2006) High frequency of BRCA1 5382insC mutation in Russian breast cancer patients. Eur J Cancer 42(10):1380–1384. https://doi.org/10.1016/j.ejca.2006.01.050

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Yuan X, Sun X, Shi X, Jiang C, Yu D, Zhang W, Guan W, Zhou J, Wu Y, Qiu Y, Ding Y (2015) USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo. Oncol Rep 34(2):823–832. https://doi.org/10.3892/or.2015.4065

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Wang H, Ji X, Liu X, Yao R, Chi J, Liu S, Wang Y, Cao W, Zhou Q (2013) Lentivirus-mediated inhibition of USP39 suppresses the growth of breast cancer cells in vitro. Oncol Rep 30(6):2871–2877. https://doi.org/10.3892/or.2013.2798

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Zhao F, Wang N, Yi Y, Lin P, Tang K, Wang A, Jin Y (2016) Knockdown of CREB3/Luman by shRNA in mouse granulosa cells results in decreased estradiol and progesterone synthesis and promotes cell proliferation. PLoS ONE 11(12):e0168246. https://doi.org/10.1371/journal.pone.0168246

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 31.

    Xing Z, Sun F, He W, Wang Z, Song X, Zhang F (2018) Downregulation of ubiquitin-specific peptidase 39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells. Oncol Lett 15(4):5443–5450. https://doi.org/10.3892/ol.2018.8061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 32.

    Xu Y, Zhu MR, Zhang JY, Si GM, Lv JJ (2018) Knockdown of ubiquitin–specific peptidase 39 inhibits the malignant progression of human renal cell carcinoma. Mol Med Rep 17(3):4729–4735. https://doi.org/10.3892/mmr.2018.8421

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Wu J, Chen Y, Geng G, Li L, Yin P, Nowsheen S, Li Y, Wu C, Liu J, Zhao F, Kim W, Zhou Q, Huang J, Guo G, Zhang C, Tu X, Gao X, Lou Z, Luo K, Qiao H, Yuan J (2019) USP39 regulates DNA damage response and chemo-radiation resistance by deubiquitinating and stabilizing CHK2. Cancer Lett 449:114–124. https://doi.org/10.1016/j.canlet.2019.02.015

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Wang LK, Hsiao TH, Hong TM, Chen HY, Kao SH, Wang WL, Yu SL, Lin CW, Yang PC (2014) MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma. PLoS ONE 9(5):e96765. https://doi.org/10.1371/journal.pone.0096765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    Fujiwara T, Katsuda T, Hagiwara K, Kosaka N, Yoshioka Y, Takahashi RU, Takeshita F, Kubota D, Kondo T, Ichikawa H, Yoshida A, Kobayashi E, Kawai A, Ozaki T, Ochiya T (2014) Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells. Stem Cells 32(4):959–973. https://doi.org/10.1002/stem.1618

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Cui W, Zhang S, Shan C, Zhou L, Zhou Z (2013) microRNA-133a regulates the cell cycle and proliferation of breast cancer cells by targeting epidermal growth factor receptor through the EGFR/Akt signaling pathway. FEBS J 280(16):3962–3974. https://doi.org/10.1111/febs.12398

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Dong X, Su H, Jiang F, Li H, Shi G, Fan L (2018) miR-133a, directly targeted USP39, suppresses cell proliferation and predicts prognosis of gastric cancer. Oncol Lett 15(6):8311–8318. https://doi.org/10.3892/ol.2018.8421

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Cai J, Liu T, Huang P, Yan W, Guo C, Xiong L, Liu A (2017) USP39, a direct target of microRNA-133a, promotes progression of pancreatic cancer via the AKT pathway. Biochem Biophys Res Commun 486(1):184–190. https://doi.org/10.1016/j.bbrc.2017.03.025

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Petersen CM (1993) Alpha 2-macroglobulin and pregnancy zone protein. Serum levels, alpha 2-macroglobulin receptors, cellular synthesis and aspects of function in relation to immunology. Dan Med Bull 40(4):409–446

    PubMed  CAS  Google Scholar 

  40. 40.

    Wyatt AR, Cater JH, Ranson M (2016) PZP and PAI-2: structurally-diverse, functionally similar pregnancy proteins? Int J Biochem Cell Biol 79:113–117. https://doi.org/10.1016/j.biocel.2016.08.018

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Zheng Y, Liu Y, Zhao S, Zheng Z, Shen C, An L, Yuan Y (2018) Large-scale analysis reveals a novel risk score to predict overall survival in hepatocellular carcinoma. Cancer Manag Res 10:6079–6096. https://doi.org/10.2147/CMAR.S181396

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Torrezan GT, de Almeida FGDSR, Figueiredo MCP, Barros BDF, de Paula CAA, Valieris R, de Souza JES, Ramalho RF, da Silva FCC, Ferreira EN, de Nóbrega AF, Felicio PS, Achatz MI, de Souza SJ, Palmero EI, Carraro DM (2018) Complex landscape of germline variants in Brazilian patients with hereditary and early onset breast cancer. Front Genet 9:161. https://doi.org/10.3389/fgene.2018.00161

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Thompson ER, Doyle MA, Ryland GL, Rowley SM, Choong DY, Tothill RW, Thorne H, kConFab, Barnes DR, Li J, Ellul J, Philip GK, Antill YC, James PA, Trainer AH, Mitchell G, Campbell IG (2012) Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet 8(9):e1002894. https://doi.org/10.1371/journal.pgen.1002894

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. 44.

    Wang J, Xu X, Liu Z, Wei X, Zhuang R, Lu D, Zhou L, Xie H, Zheng S (2013) LEPREL1 expression in human hepatocellular carcinoma and its suppressor role on cell proliferation. Gastroenterol Res Pract 2013:109759. https://doi.org/10.1155/2013/109759

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Shah R, Smith P, Purdie C, Quinlan P, Baker L, Aman P, Thompson AM, Crook T (2009) The prolyl 3-hydroxylases P3H2 and P3H3 are novel targets for epigenetic silencing in breast cancer. Br J Cancer 100(10):1687–1696. https://doi.org/10.1038/sj.bjc.6605042

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. 46.

    Zhang C, Guo H, Li B, Sui C, Zhang Y, Xia X, Qin Y, Ye L, Xie F, Wang H, Yuan M, Yuan L, Ye J (2015) Effects of Slit3 silencing on the invasive ability of lung carcinoma A549 cells. Oncol Rep 34(2):952–960. https://doi.org/10.3892/or.2015.4031

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Guan H, Wei G, Wu J, Fang D, Liao Z, Xiao H, Li M, Li Y (2013) Down-regulation of miR-218-2 and its host gene SLIT3 cooperate to promote invasion and progression of thyroid cancer. J Clin Endocrinol Metab 98(8):E1334–E1344. https://doi.org/10.1210/jc.2013-1053

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    Marlow R, Strickland P, Lee JS, Wu X, Pebenito M, Binnewies M, Le EK, Moran A, Macias H, Cardiff RD, Sukumar S, Hinck L (2008) SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium. Cancer Res 68(19):7819–7827. https://doi.org/10.1158/0008-5472.CAN-08-1357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. 49.

    Ng L, Chow AKM, Man JHW, Yau TCC, Wan TMH, Iyer DN, Kwan VHT, Poon RTP, Pang RWC, Law WL (2018) Suppression of Slit3 induces tumor proliferation and chemoresistance in hepatocellular carcinoma through activation of GSK3β/β-catenin pathway. BMC Cancer 18(1):621. https://doi.org/10.1186/s12885-018-4326-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 50.

    Howley BV, Link LA, Grelet S, El-Sabban M, Howe PH (2018) A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer. Oncogene 37(10):1308–1325. https://doi.org/10.1038/s41388-017-0023-0

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Jeong J, Park S, An HT, Kang M, Ko J (2017) Small leucine zipper protein functions as a negative regulator of estrogen receptor α in breast cancer. PLoS ONE 12(6):e0180197. https://doi.org/10.1371/journal.pone.0180197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. 52.

    Bertschmann J, Thalappilly S, Riabowol K (2019) The ING1a model of rapid cell senescence. Mech Ageing Dev 177:109–117. https://doi.org/10.1016/j.mad.2018.06.004

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Guérillon C, Bigot N, Pedeux R (2014) The ING tumor suppressor genes: status in human tumors. Cancer Lett 345(1):1–16. https://doi.org/10.1016/j.canlet.2013.11.016

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    Zhang R, Jin J, Shi J, Hou Y (2017) INGs are potential drug targets for cancer. J Cancer Res Clin Oncol 143(2):189–197. https://doi.org/10.1007/s00432-016-2219-z

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Thakur S, Singla AK, Chen J, Tran U, Yang Y, Salazar C, Magliocco A, Klimowicz A, Jirik F, Riabowol K (2014) Reduced ING1 levels in breast cancer promotes metastasis. Oncotarget 5(12):4244–4256. https://doi.org/10.18632/oncotarget.1988

  56. 56.

    Thakur S, Nabbi A, Klimowicz A, Riabowol K (2015) Stromal ING1 expression induces a secretory phenotype and correlates with breast cancer patient survival. Mol Cancer 14:164. https://doi.org/10.1186/s12943-015-0434-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. 57.

    Maxwell KN, Wubbenhorst B, Wenz BM, De Sloover D, Pluta J, Emery L, Barrett A, Kraya AA, Anastopoulos IN, Yu S, Jiang Y, Chen H, Zhang NR, Hackman N, D’Andrea K, Daber R, Morrissette JJD, Mitra N, Feldman M, Domchek SM, Nathanson KL (2017) BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nat Commun 8(1):319. https://doi.org/10.1038/s41467-017-00388-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. 58.

    Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, Scott AD, Krassowski M, Cherniack AD, Houlahan KE, Jayasinghe R, Wang LB, Zhou DC, Liu D, Cao S, Kim YW, Koire A, McMichael JF, Hucthagowder V, Kim TB, Hahn A, Wang C, McLellan MD, Al-Mulla F, Johnson KJ; Cancer Genome Atlas Research Network, Lichtarge O, Boutros PC, Raphael B, Lazar AJ, Zhang W, Wendl MC, Govindan R, Jain S, Wheeler D, Kulkarni S, Dipersio JF, Reimand J, Meric-Bernstam F, Chen K, Shmulevich I, Plon SE, Chen F, Ding L (2018) Pathogenic germline variants in 10,389 adult cancers. Cell 173(2):355–370.e14. https://doi.org/10.1016/j.cell.2018.03.039

    Article  CAS  Google Scholar 

  59. 59.

    Wendt C, Margolin S (2019) Identifying breast cancer susceptibility genes—a review of the genetic background in familial breast cancer. Acta Oncol 58(2):135–146. https://doi.org/10.1080/0284186X.2018.1529428

    Article  PubMed  CAS  Google Scholar 

  60. 60.

    Sheskin DJ (2004) Handbook of parametric and nonparametric statistical procedures, 3rd edn. Chapman & Hall/CRC, Boca Raton

    Book  Google Scholar 

Download references

Funding

Whole exome sequencing, bioinformatic analysis, and case–control validation studies have been supported by the Russian Science Foundation (Grant 19-15-00207), DST (Grant DST/INT/RUS/RSF/11), and the German Research Foundation (Grant Do761/10-1). The Hannover–Ufa Breast Cancer Study (HUBCS) was also supported by the Russian Foundation for Basic Research (Grants 17-44-020498, 17-29-06014 and 18-29-09129), the program for support of the bioresource collections (Grant N007-030164/2), and by the Ministry of Science and Higher Education of Russian Federation (Grant NAAAA-A16-116020350032-1).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ekaterina S. Kuligina.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study design was approved by the local Ethical Committee. All procedures performed in study were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kuligina, E.S., Sokolenko, A.P., Bizin, I.V. et al. Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39. Breast Cancer Res Treat 179, 731–742 (2020). https://doi.org/10.1007/s10549-019-05492-6

Download citation

Keywords

  • Hereditary breast cancer
  • Non-BRCA1/2
  • Germline mutations
  • Whole exome sequencing
  • Case–control study