Genomic profiles of colorectal carcinoma with liver metastases and newly identified fusion genes. Issue 9 (30th July 2019)

• Record Type: Journal Article
• Authors: Oga, Takafumi; Yamashita, Yoshihiro; Soda, Manabu; Kojima, Shinya; Ueno, Toshihide; Kawazu, Masahito; Suzuki, Nobuaki; Nagano, Hiroaki; Hazama, Shoichi; Izumiya, Masashi; Koike, Kazuhiko; Mano, Hiroyuki
• Is Part Of: Cancer science. Volume 110:Issue 9(2019)
• Page Start: 2973
• Page End: 2981
• Publication Date: 2019-07-30
• Subjects: ADAP1 -- colorectal carcinoma -- exome sequencing -- gene fusion -- liver metastasis; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14127
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole‐exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage‐matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A‐to‐C nucleotide change in the context of "AAG" was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such "LM‐associated" genes were overrepresented for extracellular matrix‐receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1‐substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis. Abstract : Whole‐exome analysis of colon cancers revealed several hundreds of genes specific to LM; these LM‐associated genes were enriched for "Extracellular matrix (ECM)‐receptor interaction" and "Focal adhesion" pathways defined by the KEGG database. We also detected recurrent ADAP1 fusion genes that may contribute to the pathogenesis of colon cancers.