Abstract
Patient-matched transcriptomic studies using tumour samples before and after treatment allow inter-patient heterogeneity to be controlled, but tend not to include an untreated comparison. Here, Illumina BeadArray technology was used to measure dynamic changes in gene expression from thirty-seven paired diagnostic core and surgically excised breast cancer biopsies obtained from women receiving no treatment prior to surgery, to determine the impact of sampling method and tumour heterogeneity. Despite a lack of treatment and perhaps surprisingly, consistent changes in gene expression were identified during the diagnosis-surgery interval (48 up, 2 down; Siggenes FDR 0.05) in a manner independent of both subtype and sampling-interval length. Instead, tumour sampling method was seen to directly impact gene expression, with similar effects additionally identified in six published breast cancer datasets. In contrast with previous findings, our data does not support the concept of a significant wounding or immune response following biopsy in the absence of treatment and instead implicates a hypoxic response following the surgical biopsy. Whilst sampling-related gene expression changes are evident in treated samples, they are secondary to those associated with response to treatment. Nonetheless, sampling method remains a potential confounding factor for neoadjuvant study design.
Highlights
In order to assess whether core biopsy and surgical excision sample pairs varied from one another, Pearson correlations were calculated between intra-tumour and inter-tumour samples (Fig. 1B)
Our study reports gene expression changes in the largest cohort of sequential samples from patients receiving no-intervening treatment yet assembled to demonstrate the molecular variation that occurs independent of treatment in the neoadjuvant and preoperative setting
Significant pairwise changes in gene expression were observed and a 50 gene signature identified comprised of genes associated with a number of cell growth, cell stress and cancer related signalling pathways, including ATF3, EGR1, FOS, FOSB and JUN, each of which have been previously implicated in prognostic discrimination and pathogenesis of breast cancer[39,40,41,42,43] as well as other cancers[44]
Summary
Previous work[26] that has utilised larger-scale assays (a panel of 147 cancer related genes) investigated molecular variation under conditions of no-intervening treatment (NIT) in 21 paired core needle biopsy (CB) and excision biopsy (EB) samples. Potential stimulation of tumour-associated macrophages (TAMs) in response to CB was reported, itself associated with poor prognosis in human breast cancer, raising concerns of taking multiple repeated biopsies from the same patient, underlining the importance of considering the full repertoire of genetic expression under conditions of no treatment. We present the largest dataset to-date of untreated patient-matched breast cancer samples to determine whether, and to what extent, sample pairs exhibit molecular heterogeneity independent of treatment, and what the implications of any variation are in terms of the interpretation of patient-matched gene expression profiling studies. We explore possible causes of consistent differential expression and whether these reflect a wounding or immune response to the first biopsy, a hypoxia- or stress-induced response following blood supply interruption[27] or the normal growth and evolution of tumours over time[28]
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