Genomic profiles of colorectal carcinoma with liver metastases and newly identified fusion genes

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.

Characterization of genomic alterations in Chinese colorectal cancer patients with liver metastases

“…Just over half of all genomic alterations were detected in both paired primary tumor and metastasis samples in our cohort. However, when only focusing on recurrent driver genes, this proportion increased to a level that was similar to that seen in several small CRLM cohorts (approximately 70%) [ 7 , 8 , 30 , 31 ]. This change in proportion may be because systemic spread of colorectal cancer may occur while the tumor is clinically undetectable [ 31 ].…”

“…A large-scale integrated omics study in a Chinese CRC cohort demonstrated the ability of the phosphoproteome to distinguish metastasis and to predict drug response [6]. In research specifically focusing on CRLM, high similarities were observed between primary tumors and liver metastases (LMs), whereas ubiquitous private mutations in LMs suggested individual tumor heterogeneity and specific genetic biomarkers that were capable of predicting potential therapeutics for treating LMs [7][8][9]. However, these studies either handled primary tumors, LMs and other metastases identically or were restricted to quite small numbers of samples.…”

Molecular epidemiology and diagnostics of KRAS mutations in human cancer

“…It is equally interesting that in KRAS mutant colorectal cancers, simultaneous mutations of RYR2, MUC15, and FAT3 are frequent. On the other hand, mismatch repair deficiency is not associated with KRAS mutation in colorectal cancer [ 34 ]…”

Discovery of core gene families associated with liver metastasis in colorectal cancer and regulatory roles in tumor cell immune infiltration

“…Previous big data studies concerning CRC liver metastasis had achieved accomplishment in identifying altered transcriptome [29] , lncRNAs [30] , or fusion genes [31] that might be responsible for CRC liver metastasis. In all these studies, evidence that associate immune activities with CRC liver metastasis was scarce.…”