Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing

M B Mogensen,P Jess,E V Hogdall,O Østrup,B Vainer,K Osterlind,F C Nielsen,P J Heiberg Engel,M Rossing,L N Jørgensen,H J Nielsen,J Eriksen,P Ibsen,P N Larsen,M Grauslund

doi:10.1186/s12885-018-4639-4

Abstract

BackgroundColorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.MethodsFresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as ‘damaging’ or ‘potentially damaging’ by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.ResultsShared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.ConclusionThe examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Highlights

Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection
The present study compared the genomic profiles of paired primary tumours and synchronous liver metastases from CRC patients and found from 50 to 96% concordance between the primary tumour and the metastasis in the investigated patients, i.e. these data are not in support of the view of genomic entities
The example of the patient with two closely located primary right-sided tumours having completely different genomic profiles emphasises the importance of mutational analysis of all primary tumours of a patient and of the metastasis if it is relevant for the treatment strategy

Summary

Introduction

Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The treatment of disseminated CRC has improved significantly during the last decade, including systemic as well as surgical treatment This progress has enabled the cure of metastatic disease in cases where the metastases are resectable at diagnosis or after neoadjuvant chemotherapy [2]. A resected primary tumour offers an accessible archetypal cancer tissue for the formulation of a genomic-guided treatment composition. The success of such a policy depends on whether the metastases display major differences in their genomic and proteomic profiles compared to those of the primary tumours [3, 4]

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Discussion

Conclusion