Abstract
BackgroundProteogenomic characterization and integrative and comparative genomic analysis provide a functional context to annotate genomic abnormalities with prognostic value.MethodsHere, we analyzed the proteomes and performed whole exome and transcriptome sequencing and single nucleotide polymorphism array profiling for 2 sets of triplet samples comprised of normal colorectal tissue, primary CRC tissue, and synchronous matched liver metastatic tissue.ResultsWe identified 112 CNV-mRNA-protein correlated molecules, including up-regulated COL1A2 and BGN associated with prognosis, and four strongest hot spots (chromosomes X, 7, 16 and 1) driving global mRNA abundance variation in CRC liver metastasis. Two sites (DMRTB1R202H and PARP4V458I) were revealed to frequent mutate only in the liver metastatic cohort and displayed dysregulated protein abundance. Moreover, we confirmed that the mutated peptide number has potential prognosis value and somatic variants displayed increased protein abundance, including high MYH9 and CCT6A expression, with clinical significance.ConclusionsOur proteogenomic characterization and integrative and comparative genomic analysis provides a new paradigm for understanding human colon and rectal cancer liver metastasis.Trial registrationClinicalTrials, NCT02917707. Registered 28 September 2016, https://clinicaltrials.gov/ct2/show/NCT02917707.
Highlights
Proteogenomic characterization and integrative and comparative genomic analysis provide a functional context to annotate genomic abnormalities with prognostic value
Identification of peptides and proteins associated with Colorectal cancer (CRC) liver metastasis (CLM) Genomic features and proteomic analyses of CRC have been characterized; the primary genetic basis of CLM has not been fully elucidated, which is essential for discovering metastasis-specific molecular biomarkers and for devising a better therapeutic approach for this disease
MS)-based shotgun proteomics profiling of 2 sets of triplet samples comprised of para-tumor normal colorectal tissue (PN), primary CRC tissue (MT), and synchronous matched liver metastatic tissue (LM) (Fig. 1)
Summary
Proteogenomic characterization and integrative and comparative genomic analysis provide a functional context to annotate genomic abnormalities with prognostic value. It is important to illuminate the molecular basis of CRC liver metastasis (CLM) in hopes of developing new effective treatment modalities. The Cancer Genome Atlas (TCGA) has characterized the genomic features of many types of human cancers, including CRC [3,4,5] and The Clinical Proteomic Tumor Analysis Consortium has performed CRC-integrated proteomic analyses [6]. The primary genetic basis of CLM has not been fully elucidated. Understanding the genetic and proteogenomic differences between primary colon cancer and associated metastases to the liver is essential for discovering metastasis-specific molecular biomarkers and for devising a better therapeutic approach for this disease
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