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Differences in clinical characteristics and mutational pattern between synchronous and metachronous colorectal liver metastases.

ABSTRACT: Purpose:To investigate differences in clinical characteristics and mutational patterns between synchronous and metachronous colorectal liver metastases (CLMs). Patients and methods:From June 2008 to December 2014, patients with RAS wild-type CLMs treated at Zhongshan Hospital, Fudan University were included. DNA extracted from formalin-fixed paraffin-embedded tissue of primary tumors was sequenced with next-generation sequencing for single-nucleotide polymorphism of 96 genes according to custom panel. Mutations were compared between synchronous and metachronous liver metastases and correlated with clinical characteristics. Results:A total of 161 patients were included: 93 patients with synchronous CLM and 68 patients with metachronous CLM. Patients with metachronous CLM were obviously elder. For pathology of primary tumors, synchronous CLMs were larger in size, poorly differentiated, and more frequently local advanced and lymph node positive. For evaluation of liver metastases, synchronous CLM had more and larger metastatic lesions. The median number of mutations in synchronous CLMs was significantly higher than in metachronous group (22 vs. 18, p<0.001). EGFR rs2227983 is the most prevalent mutation in both groups and only a part of prevalent mutations is shared in both groups. Prevalent mutations were correlated with many clinical characteristics. EGFR rs2227983, RBMXL3 rs12399211, and PTCH1 rs357564 were prognostic for latency of metachronous CLM. Conclusion:Clinically, synchronous CLMs, compared with metachronous CLMs, were younger and showed heavier tumor burden for both primaries and liver metastases. Genetically, we identified different mutational patterns between synchronous and metachronous CLMs and several correlations between mutations and clinical characteristics. Further researches were needed to confirm these potential key mutations of CLMs.

SUBMITTER: Zheng P

PROVIDER: S-EPMC6118248 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Differences in clinical characteristics and mutational pattern between synchronous and metachronous colorectal liver metastases.

Zheng Peng P Ren Li L Feng Qingyang Q Zhu Dexiang D Chang Wenju W He Guodong G Ji Meiling M Jian Mi M Lin Qi Q Yi Tuo T Wei Ye Y Xu Jianmin J

Cancer management and research 20180827

<h4>Purpose</h4>To investigate differences in clinical characteristics and mutational patterns between synchronous and metachronous colorectal liver metastases (CLMs).<h4>Patients and methods</h4>From June 2008 to December 2014, patients with RAS wild-type CLMs treated at Zhongshan Hospital, Fudan University were included. DNA extracted from formalin-fixed paraffin-embedded tissue of primary tumors was sequenced with next-generation sequencing for single-nucleotide polymorphism of 96 genes accor ...[more]

PMID: 30214282

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Project description: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.

Dataset Information

Differences in clinical characteristics and mutational pattern between synchronous and metachronous colorectal liver metastases.

Publications

Differences in clinical characteristics and mutational pattern between synchronous and metachronous colorectal liver metastases.

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