Exome and transcriptome sequencing identifies loss of PDLIM2 in metastatic colorectal cancers

Abstract

Bo Young Oh,1,* Jeonghee Cho,2,* Hye Kyung Hong,3 Joon Seol Bae,4 Woong-Yang Park,4–6 Je-Gun Joung,4 Yong Beom Cho3,5 1Department of Surgery, College of Medicine, Ewha Womans University, Seoul, 2Department of Nanobiomedical Science, Dankook University, Cheonan, 3Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 4Samsung Genome Institute, Samsung Medical Center, 5Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, 6Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea *These authors contributed equally to this work Background: Understanding the genomic determinants associated with metastasis in colorectal cancers (CRCs) provides crucial clues for improving patient care. Patients and methods: In this study, we performed whole-exome sequencing as well as RNA sequencing analyses on five pairs of primary and liver metastasized samples from CRC patients together with blood/normal control samples for each pair. Results: We identified genomic deletions in the region of 8p21-23 (q value <0.01) from analysis of recurrent regions with copy number variations in both primary and matched metastatic lesions. Consistent with this result, we found significantly decreased expression levels of all 12 genes (ADAMDEC1, C8orf80, CLDN23, EPHX2, GFRA2, NEFL, NEFM, PDLIM2, PTK2B, SCARA5, SLC18A1 and STMN4) located within this region (adjusted P<0.01). Notably, the mRNA levels of PDLIM2, a key regulator of well-known cancer-associated genes including the proto-oncogene c-MYC, an early response gene IER3, and regulators of apoptosis such as BCL2, FAS, and FASLG, were highly downregulated in tumors compared to normal tissues. Conclusion: Taken together, our findings uncovered various genomic alterations potentially leading to metastasis in CRC and provide important insights into the development of potential therapeutic targets for preventing metastatic progression of CRC. Keywords: colorectal cancers, liver metastasis, whole-exome sequencing, RNA sequencing, copy number variation

Keywords

• Colorectal Cancers
• Liver Metastasis
• Whole-Exome Sequencing
• RNA Sequencing
• Copy Number Variation