Table Info

Table 2.

TP53 exon 5 highly frequent new mutations detected in Moroccan prostate cancer patients with the corresponding effects according to Human Genome Variation Society (HGVS) nomenclature

Effect	CDS change	Genome location	Protein change	Frequency, N = 48
Deletion	c.534_536delCCA	Chr17:7675076	NA	1 (2%)
Frameshift	c.392delA	Chr17:7675220	NA	15 (31.25%)
Frameshift	c.383delC	Chr17:7675229	NA	6 (12.5%)
Frameshift	c.432delG	Chr17:7675180	NA	5 (10%)
Frameshift	c.396_397insT	Chr17:7675215	NA	4 (8%)
Frameshift	c.496_497insG	Chr17:7675115	NA	4 (8%)
Frameshift	c.388_389insC	Chr17:7675223	NA	3 (6.25%)
Frameshift	c.433delC	Chr17:7675179	NA	3 (6.25%)
Frameshift	c.379_380insT	Chr17:7675232	NA	2 (4%)
Frameshift	c.393delC	Chr17:7675219	NA	2 (4%)
Frameshift	c.413delinsTG	Chr17:7675199	NA	2 (4%)
Frameshift	c.428_429insT	Chr17:7675183	NA	2 (4%)
Frameshift	c.431_432delinsG	Chr17:7675180	NA	2 (4%)
Frameshift	c.532_533insC	Chr17:7675079	NA	2 (4%)
Frameshift	c.548_549insT	Chr17:7675063	NA	2 (4%)
Missense	c.502C>A	Chr17:7675110	p.His168Asn	11 (23%)
Missense	c.382C>T	Chr17:7675230	p.Pro128Ser	6 (12.5%)
Missense	c.398T>G	Chr17:7675214	p.Met133Arg	4 (8%)
Missense	c.413C>G	Chr17:7675199	p.Ala138Gly	4 (8%)
Missense	c.457C>G	Chr17:7675155	p.Pro153Ala	3 (6.25%)
Missense	c.550G>C	Chr17:7675062	p.Asp184His	2 (4%)
Missense	c.376_377delinsCT	Chr17:7675235	p.Tyr126Arg	1 (2%)
Missense	c.427G>C	Chr17:7675185	p.Val143Leu	1 (2%)
Missense	c.428_429delinsG	Chr17:7675183	p.Val143Ala	1 (2%)
Missense	c.428T>A	Chr17:7675184	p.Val143Glu	1 (2%)
Missense	c.431_432delinsGG	Chr17:7675180	p.Gln144Pro	1 (2%)
Missense	c.432_433delinsCA	Chr17:7675179	p.Gln144His	1 (2%)
Missense	c.443A>T	Chr17:7675169	p.Asp148Val	1 (2%)
Missense	c.454C>A	Chr17:7675158	p.Pro152Thr	1 (2%)
Missense	c.461_462delinsAT	Chr17:7675150	p.Gly154Asp	1 (2%)
Missense	c.476C>A	Chr17:7675136	p.Ala159Asp	1 (2%)
Missense	c.490A>C	Chr17:7675122	p.Lys164Gln	1 (2%)
Missense	c.496T>G	Chr17:7675116	p.Ser166Ala	1 (2%)
NA	c.559+13_559+12delinsAG	Chr17:7675040	NA	12 (25%)
NA	c.376-2delA	Chr17:7675238	NA	10 (21%)
NA	c.559+35G>A	Chr17:7675018	NA	8 (17%)
NA	c.376-6delC	Chr17:7675242	NA	7 (15%)
NA	c.376-12delC	Chr17:7675248	NA	6 (12.5%)
NA	c.376-3delC	Chr17:7675239	NA	5 (10%)
NA	c.376-6C>G	Chr17:7675242	NA	5 (10%)
NA	c.376-11T>C	Chr17:7675247	NA	3 (6.25%)
NA	c.376-36_376-35insC	Chr17:7675271	NA	2 (4%)
NA	c.376-4A>C	Chr17:7675240	NA	2 (4%)
NA	c.376-8delT	Chr17:7675244	NA	2 (4%)
Nonsense	c.378C>A	Chr17:7675234	p.Tyr126Ter	1 (2%)
Synonymous	c.441T>G	Chr17:7675171	p.Val147=	3 (6.25%)
Synonymous	c.375_376delinsCT	Chr17:7675236	p.Thr125=	1 (2%)
Synonymous	c.387C>T	Chr17:7675225	p.Ala129=	1 (2%)
Synonymous	c.390C>G	Chr17:7675222	p.Leu130=	1 (2%)
Synonymous	c.453C>A	Chr17:7675159	p.Pro151=	1 (2%)
Synonymous	c.492_493delinsTT	Chr17:7675119	p.Lys164=	1 (2%)
Synonymous	c.531C>A	Chr17:7675081	p.Pro177=	1 (2%)

CDS: coding DNA sequences

Declarations

Acknowledgments

Authors would like to thank the University Hassan II of Casablanca and the faculty of Sciences for all their efforts to support us during all the stages of this research. Thanks as well go to the team members of Laboratory: Virology, Oncology, Biosciences, Environment, and New BioEnergies of the FSTM. Many thanks to Mohammed V hospital in Rabat, Morocco for their help during sample collection.

Author contributions

KA: Conceptualization, Methodology, Formal analysis, Investigation, Project administration, Writing—original draft, Writing—review & editing. AL, RT, and KE: Resources. MME: Project administration, Validation, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

The study protocol was approved by the Ethics Committee for Biomedical Research of the Faculty of Medicine and Pharmacy of Casablanca, Morocco (No. 3/2018/April 30/2018).

Consent to participate

The informed consent to participate in the study was obtained from all participants.

Consent to publication

Not applicable.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

Not applicable.

Copyright

References

Compérat E, Wasinger G, Oszwald A, Kain R, Cancel-Tassin G, Cussenot O. The Genetic Complexity of Prostate Cancer. Genes (Basel). 2020;11:1396. [DOI] [PubMed] [PMC]

Boutros PC, Fraser M, Harding NJ, de Borja R, Trudel D, Lalonde E, et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat Genet. 2015;47:736–45. [DOI] [PubMed]

Paller CJ, Antonarakis ES. Management of biochemically recurrent prostate cancer after local therapy: evolving standards of care and new directions. Clin Adv Hematol Oncol. 2013;11:14–23. [PubMed] [PMC]

Vibishan B, Watve MG. Context-dependent selection as the keystone in the somatic evolution of cancer. Sci Rep. 2020;10:4223. [DOI] [PubMed] [PMC]

Dahran N, Szewczyk-Bieda M, Wei C, Vinnicombe S, Nabi G. Normalized periprostatic fat MRI measurements can predict prostate cancer aggressiveness in men undergoing radical prostatectomy for clinically localised disease. Sci Rep. 2017;7:4630. [DOI] [PubMed] [PMC]

Vidal AC, Oyekunle T, Howard LE, Hoedt AMD, Kane CJ, Terris MK, et al. Obesity, race, and long-term prostate cancer outcomes. Cancer. 2020;126:3733–41. [DOI] [PubMed]

Liotti A, Civita EL, Cennamo M, Crocetto F, Ferro M, Guadagno E, et al. Periprostatic adipose tissue promotes prostate cancer resistance to docetaxel by paracrine IGF-1 upregulation of TUBB2B beta-tubulin isoform. Prostate. 2021;81:407–17. [DOI] [PubMed] [PMC]

Mateo J, Boysen G, Barbieri CE, Bryant HE, Castro E, Nelson PS, et al. DNA Repair in Prostate Cancer: Biology and Clinical Implications. Eur Urol. 2017;71:417–25. [DOI] [PubMed]

Crocetto F, Barone B, Caputo VF, Fontana M, Cobelli Od, Ferro M. BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored. Diagnostics (Basel). 2021;11:908. [DOI] [PubMed] [PMC]

10.

Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31:1748–57. [DOI] [PubMed] [PMC]

11.

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. [DOI] [PubMed] [PMC]

12.

Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018;25:104–13. [DOI] [PubMed] [PMC]

13.

Reinhardt HC, Schumacher B. The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 2012;28:128–36. [DOI] [PubMed] [PMC]

14.

Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63:6643–50. [PubMed]

15.

Navone NM, Troncoso P, Pisters LL, Goodrow TL, Palmer JL, Nichols WW, et al. p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst. 1993;85:1657–69. [DOI] [PubMed]

16.

Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, Allred DC. p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res. 1993;53:3369–73. [PubMed]

17.

Nientiedt C, Endris V, Jenzer M, Mansour J, Sedehi NTP, Pecqueux C, et al. High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer-Results from a prospective pilot study using a 37 gene panel. Urol Oncol. 2020;38:637.e17–27. [DOI] [PubMed]

18.

Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, Reznik E, et al.; PCF/SU2C International Prostate Cancer Dream Team. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50:645–51. [DOI] [PubMed] [PMC]

19.

Mateo J, Seed G, Bertan C, Rescigno P, Dolling D, Figueiredo I, et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin Invest. 2020;130:1743–51. [DOI] [PubMed] [PMC]

20.

Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. J Clin Invest. 2013;123:4918–22. [DOI] [PubMed] [PMC]

21.

Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X, et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 2022;13:974. [DOI] [PubMed] [PMC]

22.

Lhousni S, Belmokhtar KY, Belmokhtar I, Errahhali ME, Errahhali ME, Boulouiz R, et al. Morocco's First Biobank: Establishment, Ethical Issues, Biomedical Research Opportunities, and Challenges. Biomed Res Int. 2020;2020:8812609. [DOI] [PubMed] [PMC]

23.

Zoubi MSA, Otoum R, Alorjani MS, Bashir SA, Trad BA, Abualrja MI, et al. TP53, SPOP and PIK3CA Genes Status in Prostate Cancer. Asian Pac J Cancer Prev. 2020;21:3365–71. [DOI] [PubMed] [PMC]

24.

Hijikata A, Raju R, Keerthikumar S, Ramabadran S, Balakrishnan L, Ramadoss SK, et al. Mutation@A Glance: an integrative web application for analysing mutations from human genetic diseases. DNA Res. 2010;17:197–208. [DOI] [PubMed] [PMC]

25.

Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81. [DOI] [PubMed]

26.

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. [DOI] [PubMed] [PMC]

27.

Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–58. [DOI] [PubMed] [PMC]

28.

Peller S, Rotter V. TP53 in hematological cancer: low incidence of mutations with significant clinical relevance. Hum Mutat. 2003;21:277–84. [DOI] [PubMed]

29.

Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol. 2010;221:49–56. [DOI] [PubMed] [PMC]

30.

Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250:1233–8. [DOI] [PubMed]

31.

Jordan JJ, Inga A, Conway K, Edmiston S, Carey LA, Wu L, et al. Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. Mol Cancer Res. 2010;8:701–16. [DOI] [PubMed] [PMC]

32.

Agarwalla PK, Dunn IF, Turner CD, Ligon KL, Schneider KA, Smith ER. A novel TP53 germline mutation in a family with a history of multiple malignancies: case report and review of the literature. Pediatr Neurosurg. 2008;44:501–8. [DOI] [PubMed]

33.

Bougeard G, Limacher JM, Martin C, Charbonnier F, Killian A, Delattre O, et al. Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. J Med Genet. 2001;38:253–7. [DOI] [PubMed] [PMC]

34.

Soussi T, Wiman KG. TP53: an oncogene in disguise. Cell Death Differ. 2015;22:1239–49. [DOI] [PubMed] [PMC]

35.

Morgan JE, Carr IM, Sheridan E, Chu CE, Hayward B, Camm N, et al. Genetic diagnosis of familial breast cancer using clonal sequencing. Hum Mutat. 2010;31:484–91. [DOI] [PubMed]

36.

Parrales A, Iwakuma T. Targeting Oncogenic Mutant p53 for Cancer Therapy. Front Oncol. 2015;5:288. [DOI] [PubMed] [PMC]

37.

Bullock AN, Fersht AR. Rescuing the function of mutant p53. Nat Rev Cancer. 2001;1:68–76. [DOI] [PubMed]

38.

Amadou A, Achatz MIW, Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. Curr Opin Oncol. 2018;30:23–29. [DOI] [PubMed]

39.

Spees CK, Kelleher KJ, Abaza R, Clinton SK. Prostate Cancer and Li-Fraumeni Syndrome: Implications for Screening and Therapy. Urol Case Rep. 2015;3:21–3. [DOI] [PubMed] [PMC]

40.

Maxwell KN, Cheng HH, Powers J, Gulati R, Ledet EM, Morrison C, et al. Inherited TP53 Variants and Risk of Prostate Cancer. Eur Urol. 2022;81:243–50. [DOI] [PubMed] [PMC]

41.

Dridi W, Fetni R, Lavoie J, Poupon M, Drouin R. The dominant-negative effect of p53 mutants and p21 induction in tetraploid G1 arrest depends on the type of p53 mutation and the nature of the stimulus. Cancer Genet Cytogenet. 2003;143:39–49. [DOI] [PubMed]

42.

Forrester K, Lupold SE, Ott VL, Chay CH, Band V, Wang XW, et al. Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent. Oncogene. 1995;10:2103–11. [PubMed]

43.

Korkmaz CG, Korkmaz KS, Kurys P, Elbi C, Wang L, Klokk TI, et al. Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer. Oncogene. 2005;24:4934–45. [DOI] [PubMed]

44.

Tamura T, Chiba J. STEAP4 regulates focal adhesion kinase activation and CpG motifs within STEAP4 promoter region are frequently methylated in DU145, human androgen-independent prostate cancer cells. Int J Mol Med. 2009;24:599–604. [DOI] [PubMed]

45.

Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015;163:1011–25. [DOI] [PubMed] [PMC]

46.

Hamid AA, Gray KP, Shaw G, MacConaill LE, Evan C, Bernard B, et al. Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer. Eur Urol. 2019;76:89–97. [DOI] [PubMed]

47.

Liu W, Xie CC, Thomas CY, Kim S, Lindberg J, Egevad L, et al. Genetic markers associated with early cancer-specific mortality following prostatectomy. Cancer. 2013;119:2405–12. [DOI] [PubMed] [PMC]

48.

Li S, Kang Y, Zeng Y. Targeting tumor and bone microenvironment: Novel therapeutic opportunities for castration-resistant prostate cancer patients with bone metastasis. Biochim Biophys Acta Rev Cancer. 2024;1879:189033. [DOI] [PubMed]

49.

Nicolosi P, Ledet E, Yang S, Michalski S, Freschi B, O'Leary E, et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol. 2019;5:523–8. [DOI] [PubMed] [PMC]

50.

Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:162–74. [DOI] [PubMed] [PMC]

51.

Pearson HB, Li J, Meniel VS, Fennell CM, Waring P, Montgomery KG, et al. Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth. Cancer Discov. 2018;8:764–79. [DOI] [PubMed]

52.

Guo X, Gao C, Yang D, Li S. Exosomal circular RNAs: A chief culprit in cancer chemotherapy resistance. Drug Resist Updat. 2023;67:100937. [DOI] [PubMed]

53.

Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, et al. The Landscape of Circular RNA in Cancer. Cell. 2019;176:869–81.e13. [DOI] [PubMed] [PMC]

54.

Chao F, Wang S, Zhang C, Han D, Ma Z, Chen G. Circular RNA circSMARCA5 is a prognostic biomarker in patients with malignant tumor: a meta-analysis. BMC Cancer. 2021;21:600. [DOI] [PubMed] [PMC]

55.

Cao S, Ma T, Ungerleider N, Roberts C, Kobelski M, Jin L, et al. Circular RNAs add diversity to androgen receptor isoform repertoire in castration-resistant prostate cancer. Oncogene. 2019;38:7060–72. [DOI] [PubMed] [PMC]

56.

Greene J, Baird A, Casey O, Brady L, Blackshields G, Lim M, et al. Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide. Sci Rep. 2019;9:10739. [DOI] [PubMed] [PMC]

57.

Shen Z, Zhou L, Zhang C, Xu J. Reduction of circular RNA Foxo3 promotes prostate cancer progression and chemoresistance to docetaxel. Cancer Lett. 2020;468:88–101. [DOI] [PubMed]

58.

Reale A, Khong T, Spencer A. Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment. J Clin Med. 2022;11:6892. [DOI] [PubMed] [PMC]

59.

Testa U, Castelli G, Pelosi E. Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications. Medicines (Basel). 2019;6:82. [DOI] [PubMed] [PMC]