Open AccessGenomic profiles of colorectal carcinoma with liver metastases and newly identified fusion genes
Author(s) -
Oga Takafumi,
Yamashita Yoshihiro,
Soda Manabu,
Kojima Shinya,
Ueno Toshihide,
Kawazu Masahito,
Suzuki Nobuaki,
Nagano Hiroaki,
Hazama Shoichi,
Izumiya Masashi,
Koike Kazuhiko,
Mano Hiroyuki
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14127
Subject(s) - nonsynonymous substitution , metastasis , cancer research , colorectal cancer , context (archaeology) , biology , gene , fusion gene , somatic cell , germline mutation , mutation , medicine , genetics , cancer , genome , paleontology
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 ADAP 1 (Arf GAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF 6, an ADAP 1‐substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC . Additionally, recurrent ADAP 1 fusion genes were unexpectedly discovered. As these fusions activate small GTP ase, further experiments are warranted to examine their contribution to CRC carcinogenesis.