Home LiteratureArticle Details
PMID: 28618431 Published · ppublish English Journal Article

Tumour heterogeneity poses a significant challenge to cancer biomarker research.

British journal of cancer ·Vol. 117 ·No. 3 ·2017-07-25 ·Pages 367-375

Cyll K, Ersvær E, Vlatkovic L, Pradhan M, Kildal W, Avranden Kjær M, Kleppe A, Hveem TS, Carlsen B, Gill S, Löffeler S, Haug ES, Wæhre H, Sooriakumaran P, Danielsen HE

Abstract

The high degree of genomic diversity in cancer represents a challenge for identifying objective prognostic markers. We aimed to examine the extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model. We assessed Gleason Score (GS), DNA ploidy status and phosphatase and tensin homologue (PTEN) expression in radical prostatectomy specimens (RP) from 304 patients followed for a median of 10 years (interquartile range 6-12). GS was assessed for every tumour-containing block and DNA ploidy for a median of four samples for each RP. In a subgroup of 40 patients we assessed DNA ploidy and PTEN status in every tumour-containing block. In 102 patients assigned to active surveillance (AS), GS and DNA ploidy were studied in needle biopsies. Extensive heterogeneity was observed for GS (89% of the patients) and DNA ploidy (40% of the patients) in the cohort, and DNA ploidy (60% of the patients) and PTEN expression (75% of the patients) in the subgroup. DNA ploidy was a significant prognostic marker when heterogeneity was taken into consideration. In the AS cohort we found heterogeneity in GS (24%) and in DNA ploidy (25%) specimens. Multi-sample analysis should be performed to support clinical treatment decisions.

MeSH Terms
Aged Biomarkers, Tumor Biopsy, Needle DNA, Neoplasm/analysis Genetic Heterogeneity Humans Male Middle Aged Neoplasm Grading Neoplasm Recurrence, Local/genetics PTEN Phosphohydrolase/analysis Ploidies Prostate/pathology Prostatectomy Prostatic Neoplasms/chemistry,genetics,pathology,therapy Tumor Burden Watchful Waiting
Chemicals
Biomarkers, Tumor DNA, Neoplasm PTEN Phosphohydrolase PTEN protein, human
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Cyll Karolina
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway.
Ersvær Elin
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway.
Vlatkovic Ljiljana
Department of Pathology, Oslo University Hospital, Oslo, NO-0424, Norway.
Pradhan Manohar
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway.
Kildal Wanja
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway.
Avranden Kjær Marte
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway.
Kleppe Andreas
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway. | Department of Informatics, University of Oslo, Oslo, NO-0316, Norway.
Hveem Tarjei S
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway. | Department of Informatics, University of Oslo, Oslo, NO-0316, Norway.
Carlsen Birgitte
Department of Pathology, Vestfold Hospital Trust, NO-3103 Tønsberg, Norway.
Gill Silje
Department of Urology, Vestfold Hospital Trust, Tønsberg, NO-3103, Norway.
Löffeler Sven
Department of Urology, Vestfold Hospital Trust, Tønsberg, NO-3103, Norway.
Haug Erik Skaaheim
Department of Urology, Vestfold Hospital Trust, Tønsberg, NO-3103, Norway.
Wæhre Håkon
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway.
Sooriakumaran Prasanna
Surgical Intervention Trials Unit, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
Danielsen Håvard E
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo NO-0424, Norway. | Centre for Cancer Biomedicine, University of Oslo, Oslo, NO-0424, Norway. | Department of Informatics, University of Oslo, Oslo, NO-0316, Norway. | Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, UK.
References (36)
36 references, click to expand
  1. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System.
    Am J Surg Pathol. 2016 Feb;40(2):244-52 PMID: 26492179
  2. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer.
    Br J Cancer. 2013 Jun 25;108(12 ):2582-9 PMID: 23695019
  3. Gleason score and lethal prostate cancer: does 3 + 4 = 4 + 3?
    J Clin Oncol. 2009 Jul 20;27(21):3459-64 PMID: 19433685
  4. PTEN: a new guardian of the genome.
    Oncogene. 2008 Sep 18;27(41):5443-53 PMID: 18794879
  5. Combined value of validated clinical and genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort.
    Eur Urol. 2015 Feb;67(2):326-33 PMID: 24998118
  6. BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer.
    Cancer Cell. 2017 Jan 9;31(1):79-93 PMID: 28073006
  7. Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials.
    J Natl Cancer Inst. 2007 Jul 4;99(13):998-1003 PMID: 17596575
  8. Utilization of a Genomic Classifier for Prediction of Metastasis Following Salvage Radiation Therapy after Radical Prostatectomy.
    Eur Urol. 2016 Oct;70(4):588-596 PMID: 26806658
  9. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
    Nat Med. 2016 Jan;22(1):105-13 PMID: 26618723
  10. Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy.
    Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):848-53 PMID: 23755923
  11. Prostate cancer.
    Lancet. 2016 Jan 2;387(10013):70-82 PMID: 26074382
  12. Evaluation of tumor heterogeneity of prostate carcinoma by flow- and image DNA cytometry and histopathological grading.
    Anal Cell Pathol. 2000;20(1):49-62 PMID: 11007438
  13. Heterogeneity of prostate cancer in radical prostatectomy specimens.
    Urology. 1994 Jan;43(1):60-6; discussion 66-7 PMID: 8284886
  14. Discovery and saturation analysis of cancer genes across 21 tumour types.
    Nature. 2014 Jan 23;505(7484):495-501 PMID: 24390350
  15. Tracking the clonal origin of lethal prostate cancer.
    J Clin Invest. 2013 Nov;123(11):4918-22 PMID: 24135135
  16. International variation in prostate cancer incidence and mortality rates.
    Eur Urol. 2012 Jun;61(6):1079-92 PMID: 22424666
  17. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  18. The causes and consequences of genetic heterogeneity in cancer evolution.
    Nature. 2013 Sep 19;501(7467):338-45 PMID: 24048066
  19. DNA heterogeneity in prostatic adenocarcinoma. A DNA flow cytometric mapping study with whole organ sections of prostate.
    Cancer. 1993 May 1;71(9):2797-802 PMID: 8467459
  20. Gene based prediction of clinically localized prostate cancer progression after radical prostatectomy.
    J Urol. 2010 Oct;184(4):1521-8 PMID: 20723930
  21. An update of the Gleason grading system.
    J Urol. 2010 Feb;183(2):433-40 PMID: 20006878
  22. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.
    Nat Genet. 2015 Apr;47(4):367-372 PMID: 25730763
  23. Comparison of contemporary methods for estimating prostate tumour volume in pathological specimens.
    BJU Int. 2014 Mar;113 Suppl 2:29-34 PMID: 24053510
  24. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications.
    Hum Pathol. 2010 Jun;41(6):781-93 PMID: 20466122
  25. DNA ploidy measured on archived pretreatment biopsy material may correlate with prostate-specific antigen recurrence after prostate brachytherapy.
    Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):829-34 PMID: 23688814
  26. Tumor focality in prostate cancer: implications for focal therapy.
    Nat Rev Clin Oncol. 2011 Jan;8(1):48-55 PMID: 21116296
  27. Cancer chromosomal instability: therapeutic and diagnostic challenges.
    EMBO Rep. 2012 Jun 01;13(6):528-38 PMID: 22595889
  28. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate.
    Eur Urol. 2015 Apr;67(4):795-802 PMID: 25454616
  29. Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate.
    Cancer. 2004 Jun 1;100(11):2362-6 PMID: 15160339
  30. Intratumoral and Intertumoral Genomic Heterogeneity of Multifocal Localized Prostate Cancer Impacts Molecular Classifications and Genomic Prognosticators.
    Eur Urol. 2017 Feb;71(2):183-192 PMID: 27451135
  31. Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications.
    Eur Urol. 2015 Apr;67(4):729-37 PMID: 24836153
  32. Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer.
    Urol Oncol. 2015 Feb;33(2):85-94 PMID: 24768356
  33. Spatial genomic heterogeneity within localized, multifocal prostate cancer.
    Nat Genet. 2015 Jul;47(7):736-45 PMID: 26005866
  34. Conventional assessment of needle biopsy specimens is more useful than digital image analysis of proliferation and DNA ploidy in prediction of positive surgical margins at radical prostatectomy.
    Urology. 2006 Jul;68(1):94-8 PMID: 16844452
  35. Significance of abnormal diploid DNA histograms in localized prostate cancer and adjacent benign prostatic tissue.
    Cancer. 1993 Sep 1;72(5):1692-700 PMID: 7688657
  36. Revisiting tumour aneuploidy - the place of ploidy assessment in the molecular era.
    Nat Rev Clin Oncol. 2016 May;13(5):291-304 PMID: 26598944
Article Info
Journal
British journal of cancer
Abbr.
Br J Cancer
ISSN
1532-1827
DOI
10.1038/bjc.2017.171
Published
2017-07-25
Epub
2017-00-15
Pages
367-375
Language
English
Region
England
NLM ID
0370635
PMCID
PMC5537489
Subset
IM
External Links
PubMed source DOI: 10.1038/bjc.2017.171 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2