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. 2017 Jul 25;117(3):367-375.
doi: 10.1038/bjc.2017.171. Epub 2017 Jun 15.

Tumour heterogeneity poses a significant challenge to cancer biomarker research

Karolina Cyll  1   2 , Elin Ersvær  1   2 , Ljiljana Vlatkovic  3 , Manohar Pradhan  1   2 , Wanja Kildal  1   2 , Marte Avranden Kjær  1   2 , Andreas Kleppe  1   2   4 , Tarjei S Hveem  1   2   4 , Birgitte Carlsen  5 , Silje Gill  6 , Sven Löffeler  6 , Erik Skaaheim Haug  6 , Håkon Wæhre  1   2 , Prasanna Sooriakumaran  7 , Håvard E Danielsen  1   2   4   8
Affiliations

Tumour heterogeneity poses a significant challenge to cancer biomarker research

Karolina Cyll et al. Br J Cancer. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Multi-sample analysis should be performed to support clinical treatment decisions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of included patients’ material from radical prostatectomy (RP) and active surveillance (AS) cohort and methods used in analysis of each cohort.
Figure 2
Figure 2
Visualisation of tumour heterogeneity in prostate cancer using Gleason grading, PTEN expression and DNA ploidy analysis. (A) Venn diagrams showing the distribution of heterogeneity of the investigated biomarkers in patients from the radical prostatectomy (RP) cohort, RP subgroup and active surveillance (AS) cohort. (B) A 3D reconstruction of a prostate gland from the RP subgroup using H&E stained tissue sections. The results from all three biomarkers were applied to the sampled regions.
Figure 3
Figure 3
Time to recurrence after radical prostatectomy stratified by: (A) worst DNA ploidy detected among all analysed samples for each patient (B) DNA ploidy from one sample with highest Gleason score (C) DNA ploidy from one randomly selected sample.
See this image and copyright information in PMC

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