Top

BMC Cancer

Published in:

Open Access 01-12-2018 | Research article

Genomic analysis of DNA repair genes and androgen signaling in prostate cancer

Authors: Kasey Jividen, Katarzyna Z Kedzierska, Chun-Song Yang, Karol Szlachta, Aakrosh Ratan, Bryce M Paschal

Published in: BMC Cancer | Issue 1/2018

Abstract

Background

The cellular effects of androgen are transduced through the androgen receptor, which controls the expression of genes that regulate biosynthetic processes, cell growth, and metabolism. Androgen signaling also impacts DNA damage signaling through mechanisms involving gene expression and transcription-associated DNA damaging events. Defining the contributions of androgen signaling to DNA repair is important for understanding androgen receptor function, and it also has translational implications.

Methods

We generated RNA-seq data from multiple prostate cancer lines and used bioinformatic analyses to characterize androgen-regulated gene expression. We compared the results from cell lines with gene expression data from prostate cancer xenografts, and patient samples, to query how androgen signaling and prostate cancer progression influences the expression of DNA repair genes. We performed whole genome sequencing to help characterize the status of the DNA repair machinery in widely used prostate cancer lines. Finally, we tested a DNA repair enzyme inhibitor for effects on androgen-dependent transcription.

Results

Our data indicates that androgen signaling regulates a subset of DNA repair genes that are largely specific to the respective model system and disease state. We identified deleterious mutations in the DNA repair genes RAD50 and CHEK2. We found that inhibition of the DNA repair enzyme MRE11 with the small molecule mirin inhibits androgen-dependent transcription and growth of prostate cancer cells.

Conclusions

Our data supports the view that crosstalk between androgen signaling and DNA repair occurs at multiple levels, and that DNA repair enzymes in addition to PARPs, could be actionable targets in prostate cancer.

Available only for authorised users

American Cancer Society. Cancer Facts & Figures 2016. Cancer facts fig 2016. 2016:1–9.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;67:7–30. https://doi.org/10.3322/caac.21387.CrossRef

Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24:1967–2000. https://doi.org/10.1101/gad.1965810.CrossRefPubMedPubMedCentral

Gioeli D. Signal transduction in prostate cancer progression. Clin Sci. 2005;108:293–308. https://doi.org/10.1042/CS20040329.CrossRef

Ferraldeschi R, Welti J, Luo J, Attard G, De Bono JS. Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene. 2014;34:1745–57.CrossRefPubMedCentralPubMed

Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and Olaparib in metastatic prostate Cancer. N Engl J Med. 2015;373:1697–708. https://doi.org/10.1056/NEJMoa1506859.CrossRefPubMedPubMedCentral

Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast Cancer in patients with a Germline BRCA mutation. N Engl J Med. 2017;377:523–33. https://doi.org/10.1056/NEJMoa1706450.CrossRefPubMed

Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34. https://doi.org/10.1056/NEJMoa0900212.CrossRefPubMed

Goodwin JF, Schiewer MJ, Dean JL, Schrecengost RS, de Leeuw R, Han S, et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 2013;3:1254–71. https://doi.org/10.1158/2159-8290.CD-13-0108.CrossRefPubMed

10.

Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997;337:295–300. https://doi.org/10.1056/NEJM199707313370502.CrossRefPubMed

11.

Jones CU, Hunt D, McGowan DG. Adding short-term androgen-deprivation therapy to radiotherapy improved survival in localized prostate cancer. Ann Intern Med. 2011;155:JC5-07.CrossRefPubMed

12.

Asim M, Tarish F, Zecchini HI, Sanjiv K, Gelali E, Massie CE, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;8:374.

13.

Benamar M, Guessous F, Du K, Corbett P, Obeid J, Gioeli D, et al. Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma. EBioMedicine. 2016;10:85–100.CrossRefPubMedCentralPubMed

14.

Dobin A, Gingeras TR. Optimizing RNA-seq mapping with STAR. Methods Mol Biol. 2016;1415:245–62.

15.

Anders S, Pyl PT, Huber W. HTSeq – a Python framework to work with high-throughput sequencing data HTSeq – a Python framework to work with high-throughput sequencing data. Bioinformatics 2014;31:0–5.

16.

Love MI, Anders S, Huber W. Differential analysis of count data - the DESeq2 package. 2014. doi:1https://doi.org/10.1186/s13059%2D014%2D0550-8.

17.

Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.CrossRefPubMedCentralPubMed

18.

Langfelder P, Horvath S. Fast R functions for robust correlations and hierarchical clustering. J Stat Softw. 2012;46:1–17.CrossRef

19.

Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database Hallmark gene set collection. Cell Syst. 2015;1:417–25.CrossRefPubMedCentralPubMed

20.

Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.CrossRefPubMed

21.

Pearl LH, Schierz AC, Ward SE, Al-Lazikani B, Pearl FMG. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer. 2015;15:166–80.CrossRefPubMed

22.

McClintick JN, Edenberg HJ. Effects of filtering by present call on analysis of microarray experiments. BMC Bioinformatics. 2006;7:49.CrossRefPubMedCentralPubMed

23.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.CrossRefPubMed

24.

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013:6(269):pl1.CrossRefPubMedCentralPubMed

25.

Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22. https://doi.org/10.1016/j.ccr.2010.05.026.CrossRefPubMedPubMedCentral

26.

Langmead B, Salzberg SL. Fast gapped-read alignment with bowtie 2. Nat Methods. 2012;9:357–9.CrossRefPubMedCentralPubMed

27.

Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008:9(9):R137.CrossRefPubMedCentralPubMed

28.

Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–2.CrossRefPubMedCentralPubMed

29.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL. Gene set enrichment analysis : A knowledge-based approach for interpreting genome-wide. PNAS. 2005;102:15545–50.CrossRefPubMedCentralPubMed

30.

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267–73.CrossRefPubMed

31.

Jay JJ, Brouwer C. Lollipops in the clinic: information dense mutation plots for precision medicine. PLoS One. 2016;11:e0160519.CrossRefPubMedCentralPubMed

32.

Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25:1754–60.CrossRefPubMedCentralPubMed

33.

Li H. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589–95.CrossRefPubMedCentralPubMed

34.

Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, del Angel G, Levy-Moonshine A, et al. From fastQ data to high-confidence variant calls: The genome analysis toolkit best practices pipeline. Curr Protoc Bioinforma. 2013;43:11.10.1-33.

35.

1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68–74. https://doi.org/10.1038/nature15393.CrossRef

36.

EVS. Exome Variant Server. NHLBI GO Exome Sequencing Project (ESP). 2014. doi:https://doi.org/10.1126/science.1219240.CrossRefPubMedCentralPubMed

37.

Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017;45:D777–83.CrossRefPubMed

38.

Cancer.sanger.ac.uk. COSMIC. cancer.sanger.ac.uk. Accessed 1 Dec 2017.

39.

National Center for Biotechnology Information (NCBI) [Internet]. https://www.ncbi.nlm.nih.gov/. Accessed 17 Mar 2018.

40.

Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.CrossRefPubMedCentralPubMed

41.

Gulko B, Hubisz MJ, Gronau I, Siepel A. A method for calculating probabilities of fitness consequences for point mutations across the human genome. Nat Genet. 2015;47:276–83.CrossRefPubMedCentralPubMed

42.

Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5. https://doi.org/10.1038/ng.2892.CrossRefPubMedPubMedCentral

43.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.CrossRefPubMedCentralPubMed

44.

Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, et al. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 2011;30:2719–33. https://doi.org/10.1038/emboj.2011.158.CrossRefPubMedPubMedCentral

45.

Lu J, Lonergan PE, Nacusi LP, Wang L, Schmidt LJ, Sun Z, et al. The Cistrome and gene signature of androgen receptor splice variants in castration resistant prostate Cancer cells. J Urol. 2015;193:690–8. https://doi.org/10.1016/j.juro.2014.08.043.CrossRefPubMed

46.

Paakinaho V, Makkonen H, Jääskeläinen T, Palvimo JJ. Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Mol Endocrinol. 2010;24:511–25.CrossRefPubMedCentralPubMed

47.

Roediger J, Hessenkemper W, Bartsch S, Manvelyan M, Huettner SS, Liehr T, et al. Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway. Mol Cancer. 2014;13:214.CrossRefPubMedCentralPubMed

48.

Tsihlias J, Zhang W, Bhattacharya N, Flanagan M, Klotz L, Slingerland J. Involvement of p27Kip1 in G1 arrest by high dose 5 alpha-dihydrotestosterone in LNCaP human prostate cancer cells. Oncogene. 2000;19:670–9.CrossRefPubMed

49.

Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40:179–204.CrossRefPubMedCentralPubMed

50.

Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3:1245–53. https://doi.org/10.1158/2159-8290.CD-13-0172.CrossRefPubMedPubMedCentral

51.

Gertz J, Savic D, Varley KE, Partridge EC, Safi A, Jain P, et al. Distinct properties of cell-type-specific and shared transcription factor binding sites. Mol Cell. 2013;52:25–36.CrossRefPubMed

52.

Hieronymus H, Lamb J, Ross KN, Peng XP, Clement C, Rodina A, et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006;10:321–30.CrossRefPubMed

53.

Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90–7.CrossRefPubMedCentralPubMed

54.

Mei S, Meyer CA, Zheng R, Qin Q, Wu Q, Jiang P, et al. Cistrome cancer: a web resource for integrative gene regulation modeling in cancer. Cancer Res. 2017;77:e19–22.CrossRefPubMedCentralPubMed

55.

Li L, Karanika S, Yang G, Wang J, Park S, Broom BM, et al. Androgen receptor inhibitor-induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal. 2017;10(480).CrossRefPubMedCentralPubMed

56.

Evans JR, Zhao SG, Chang SL, Tomlins SA, Erho N, Sboner A, et al. Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for high-risk prostate cancer. JAMA Oncol. 2016;2:471–80.CrossRefPubMedCentralPubMed

57.

Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016;22:369–78.CrossRefPubMedCentralPubMed

58.

Abeshouse A, Ahn J, Akbani R, Ally A, Amin S, Andry CD, et al. The molecular taxonomy of primary prostate Cancer. Cell. 2015;163:1011–25.CrossRef

59.

Lin C, Yang L, Tanasa B, Hutt K, B gun J, Ohgi K, et al. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in Cancer. Cell. 2009;139:1069–83.CrossRefPubMedCentralPubMed

60.

Haffner MC, Aryee MJ, Toubaji A, Esopi DM, Albadine R, Gurel B, et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet. 2010;42:668–75. https://doi.org/10.1038/ng.613.CrossRefPubMedPubMedCentral

61.

Flint M, Baum A, Chambers W, Jenkins F. Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones. Psychoneuroendocrinology. 2007;32:470–9.CrossRefPubMed

62.

Williamson LM, Lees-Miller SP. Estrogen receptor α-mediated transcription induces cell cycle-dependent DNA double-strand breaks. Carcinogenesis. 2011;32:279–85.CrossRefPubMed

63.

Ju BG, Lunyak VV, Perissi V, Garcia-Bassets I, Rose DW, Glass CK, et al. A topoisomerase IIβ-mediated dsDNA break required for regulated transcription. Science (80-). 2006;312:1798–802.CrossRef

64.

Goodwin JF, Kothari V, Drake JM, Zhao S, Dylgjeri E, Dean JL, et al. DNA-PKcs-mediated transcriptional regulation drives prostate Cancer progression and metastasis. Cancer Cell. 2015;28:97–113. https://doi.org/10.1016/j.ccell.2015.06.004.CrossRefPubMedPubMedCentral

65.

Puc J, Kozbial P, Li W, Tan Y, Liu Z, Suter T, et al. Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell. 2015;160:367–80. https://doi.org/10.1016/j.cell.2014.12.023.CrossRefPubMedPubMedCentral

66.

Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2:1134–49. https://doi.org/10.1158/2159-8290.CD-12-0120.CrossRefPubMedPubMedCentral

67.

Dupré A, Boyer-Chatenet L, Sattler RM, Modi AP, Lee JH, Nicolette ML, et al. A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol. 2008;4:119–25.CrossRefPubMedCentralPubMed

68.

Shibata A, Moiani D, Arvai AS, Perry J, Harding SM, Genois MM, et al. DNA double-Strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell. 2014;53:7–18.CrossRefPubMed

69.

Lee JH, Paull TT. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science (80-). 2005;308:551–4.CrossRef

70.

Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NMB, Orr AI, et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004;64:9152–9.CrossRefPubMed

71.

Reinhardt HC, Yaffe MB. Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Curr Opin Cell Biol. 2009;21:245–55.CrossRefPubMedCentralPubMed

72.

Ingvarsson S, Sigbjornsdottir BI, Huiping C, Hafsteinsdottir SH, Ragnarsson G, Barkardottir RB, et al. Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast Cancer Res. 2002;4(3):R4.

73.

Ta HQ, Ivey ML, Frierson HF, Conaway MR, Dziegielewski J, Larner JM, et al. Checkpoint kinase 2 negatively regulates androgen sensitivity and prostate cancer cell growth. Cancer Res. 2015;75:5093–105.CrossRefPubMedCentralPubMed

74.

Hopfner KP, Karcher A, Shin DS, Craig L, Arthur LM, Carney JP, et al. Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell. 2000;101:789–800.

75.

Luo G, Yao MS, Bender CF, Mills M, Bladl AR, Bradley A, et al. Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci U S A. 1999;96:7376–81. https://doi.org/10.1073/pnas.96.13.7376.CrossRefPubMedPubMedCentral

76.

Bender CF, Sikes ML, Sullivan R, Huye LE, Le Beau MM, Roth DB, et al. Cancer predisposition and hematopoietic failure in Rad50S/S mice. Genes Dev. 2002;16:2237–51.CrossRefPubMedCentralPubMed

77.

Heikkinen K. Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. J Med Genet. 2003;40:131e–131. https://doi.org/10.1136/jmg.40.12.e131.CrossRef

78.

Wang XG, Wang ZQ, Tong WM, Shen Y. PARP1 Val762Ala polymorphism reduces enzymatic activity. Biochem Biophys Res Commun. 2007;354:122–6.CrossRefPubMed

79.

Lockett KL, Hall MC, Xu J, Zheng S, Berwick M, Chuang SC, et al. The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function. Cancer Res. 2004;64:6344–8.CrossRefPubMed

80.

Dimova DK, Dyson NJ. The E2F transcriptional network: old acquaintances with new faces. Oncogene. 2005;24:2810–26.CrossRefPubMed

81.

Altintas DM, Shukla MS, Goutte-Gattat D, Angelov D, Rouault JP, Dimitrov S, et al. Direct cooperation between androgen receptor and E2F1 reveals a common regulation mechanism for androgen-responsive genes in prostate cells. Mol Endocrinol. 2012;26:1531–41. https://doi.org/10.1210/me.2012-1016.CrossRefPubMedPubMedCentral

82.

Sandberg R, Ernberg I. The molecular portrait of in vitro growth by meta-analysis of gene-expression profiles. Genome Biol. 2005;6:R65. https://doi.org/10.1186/gb-2005-6-8-r65.CrossRefPubMedPubMedCentral

83.

Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell. 2015;161:1592–605.CrossRefPubMedCentralPubMed

84.

Berte N, Piee-Staffa A, Piecha N, Wang M, Borgmann K, Kaina B, et al. Targeting homologous recombination by pharmacological inhibitors enhances the killing response of Glioblastoma cells treated with alkylating drugs. Mol Cancer Ther. 2016;15:2665–78. https://doi.org/10.1158/1535-7163.MCT-16-0176.CrossRefPubMed

85.

Kim YJ, Kim TW, Park SR, Kim HT, Ryu SY, Jung JY. Expression of the Mre11-Rad50-Nbs1 complex in cisplatin nephrotoxicity. Environ Toxicol Pharmacol. 2015;40:12–7.CrossRefPubMed

86.

Ying S, Hamdy FC, Helleday T. Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. Cancer Res. 2012;72:2814–21.CrossRefPubMed

87.

Herrero AB, Gutiérrez NC. Targeting ongoing DNA damage in multiple myeloma: effects of DNA damage response inhibitors on plasma cell survival. Front Oncol. 2017;7. https://doi.org/10.3389/fonc.2017.00098.

Title: Genomic analysis of DNA repair genes and androgen signaling in prostate cancer
Authors: Kasey Jividen
Katarzyna Z Kedzierska
Chun-Song Yang
Karol Szlachta
Aakrosh Ratan
Bryce M Paschal
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-018-4848-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Treatment of colon cancer in a patient with systemic lupus erythematosus: a case report

Efficacy and safety profile of drug-eluting beads transarterial chemoembolization by CalliSpheres® beads in Chinese hepatocellular carcinoma patients

The first case of SMARCB1 (INI1) - deficient squamous cell carcinoma of the pleura: a case report

RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis

A prospective cohort examination of haematological parameters in relation to cancer death and incidence: the Busselton Health Study

Testicular self examination among Bahir Dar University students: application of integrated behavioral model

Keynote webinar | Spotlight on antibody–drug conjugates in cancer