A Prognostic Hypoxia Gene Signature with Low Heterogeneity Within the Dominant Tumour Lesion in Prostate Cancer Patients

Overview

Journal Br J Cancer

Specialty Oncology

Date 2022 Mar 25

PMID 35332267

Authors

Unn Beate Salberg

Vilde Eide Skingen

Christina Saeten Fjeldbo

Tord Hompland

Harald Bull Ragnum

Ljiljana Vlatkovic

Knut Hakon Hole

Therese Seierstad

Heidi Lyng

Affiliations

Soon will be listed here.

Abstract

Background: Gene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer.

Methods: The 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels was applied in the analyses. Hypoxic fraction from pimonidazole immunostained whole-mount and biopsy sections was used as reference standard for hypoxia.

Results: The gene score was correlated with pimonidazole-defined hypoxic fraction in whole-mount sections, and the two parameters showed almost equal association with clinical markers of tumour aggressiveness. Based on the gene score, incorrect classification according to hypoxic fraction in whole-mount sections was seen in one third of the patients. The incorrect classifications were apparently not due to intra-tumour heterogeneity, since the score had low heterogeneity compared to pimonidazole-defined hypoxic fraction in biopsies. The score showed prognostic significance in uni-and multivariate analysis in independent cohorts.

Conclusions: Our signature from the index lesion reflects tumour hypoxia and predicts prognosis in prostate cancer, independent of intra-tumour heterogeneity in pimonidazole-defined hypoxia.

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References

Fraser M, Berlin A, Bristow R, van der Kwast T . Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urol Oncol. 2014; 33(2):85-94. DOI: 10.1016/j.urolonc.2013.10.020. View

Milosevic M, Warde P, Menard C, Chung P, Toi A, Ishkanian A . Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res. 2012; 18(7):2108-14. DOI: 10.1158/1078-0432.CCR-11-2711. View

Lalonde E, Ishkanian A, Sykes J, Fraser M, Ross-Adams H, Erho N . Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014; 15(13):1521-1532. DOI: 10.1016/S1470-2045(14)71021-6. View

Hompland T, Hole K, Ragnum H, Aarnes E, Vlatkovic L, Lie A . Combined MR Imaging of Oxygen Consumption and Supply Reveals Tumor Hypoxia and Aggressiveness in Prostate Cancer Patients. Cancer Res. 2018; 78(16):4774-4785. DOI: 10.1158/0008-5472.CAN-17-3806. View

Ragnum H, Vlatkovic L, Lie A, Axcrona K, Julin C, Frikstad K . The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. Br J Cancer. 2014; 112(2):382-90. PMC: 4453458. DOI: 10.1038/bjc.2014.604. View

Pintilie M, Iakovlev V, Fyles A, Hedley D, Milosevic M, Hill R . Heterogeneity and power in clinical biomarker studies. J Clin Oncol. 2009; 27(9):1517-21. DOI: 10.1200/JCO.2008.18.7393. View

Andreoiu M, Cheng L . Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum Pathol. 2010; 41(6):781-93. DOI: 10.1016/j.humpath.2010.02.011. View

Berglund E, Maaskola J, Schultz N, Friedrich S, Marklund M, Bergenstrahle J . Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity. Nat Commun. 2018; 9(1):2419. PMC: 6010471. DOI: 10.1038/s41467-018-04724-5. View

Boutros P, Fraser M, Harding N, De Borja R, Trudel D, Lalonde E . Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat Genet. 2015; 47(7):736-45. DOI: 10.1038/ng.3315. View

10.

Carm K, Hoff A, Bakken A, Axcrona U, Axcrona K, Lothe R . Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer. Sci Rep. 2019; 9(1):13579. PMC: 6753093. DOI: 10.1038/s41598-019-49964-7. View

11.

Cooper C, Eeles R, Wedge D, Van Loo P, Gundem G, Alexandrov L . Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat Genet. 2015; 47(4):367-372. PMC: 4380509. DOI: 10.1038/ng.3221. View

12.

Linch M, Goh G, Hiley C, Shanmugabavan Y, McGranahan N, Rowan A . Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol. 2017; 28(10):2472-2480. PMC: 5815564. DOI: 10.1093/annonc/mdx355. View

13.

Lindberg J, Klevebring D, Liu W, Neiman M, Xu J, Wiklund P . Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins. Eur Urol. 2012; 63(2):347-53. DOI: 10.1016/j.eururo.2012.03.050. View

14.

Lovf M, Zhao S, Axcrona U, Johannessen B, Bakken A, Carm K . Multifocal Primary Prostate Cancer Exhibits High Degree of Genomic Heterogeneity. Eur Urol. 2018; 75(3):498-505. DOI: 10.1016/j.eururo.2018.08.009. View

15.

Wei L, Wang J, Lampert E, Schlanger S, DePriest A, Hu Q . Intratumoral and Intertumoral Genomic Heterogeneity of Multifocal Localized Prostate Cancer Impacts Molecular Classifications and Genomic Prognosticators. Eur Urol. 2016; 71(2):183-192. PMC: 5906059. DOI: 10.1016/j.eururo.2016.07.008. View

16.

Yun J, Lee S, Ryu D, Park S, Park W, Joung J . Biomarkers Associated with Tumor Heterogeneity in Prostate Cancer. Transl Oncol. 2018; 12(1):43-48. PMC: 6161410. DOI: 10.1016/j.tranon.2018.09.003. View

17.

Padhani A, Barentsz J, Villeirs G, Rosenkrantz A, Margolis D, Turkbey B . PI-RADS Steering Committee: The PI-RADS Multiparametric MRI and MRI-directed Biopsy Pathway. Radiology. 2019; 292(2):464-474. PMC: 6677282. DOI: 10.1148/radiol.2019182946. View

18.

Ukimura O, Gill I . Targeted prostate biopsies for a histogram of the index lesion. Curr Opin Urol. 2013; 23(2):118-22. DOI: 10.1097/MOU.0b013e32835d4dc8. View

19.

Raleigh J, Chou S, Arteel G, Horsman M . Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res. 1999; 151(5):580-9. View

20.

DAmico A, Whittington R, Malkowicz S, Schultz D, Blank K, Broderick G . Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998; 280(11):969-74. DOI: 10.1001/jama.280.11.969. View