A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer

Abstract

Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of , and gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X-ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node-negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy. .

EIF3E–RSPO2 and PIEZO1–RSPO2 fusions in colorectal traditional serrated adenoma

“…In colorectal cancer, the reported prevalence of these fusions is similar. When the results of three previous studies were combined, PTPRK – RSPO3 and EIF3E – RSPO2 were detected in six (1.4%) and five (1.2%) lesions, respectively, among a total of 421 colorectal cancers . In contrast, EIF3E – RSPO2 is far less common than PTPRK – RSPO3 in TSAs, as shown in the present study .…”

“…In addition, we identified EIF3E – RSPO2 and PIEZO1 – RSPO2 fusions in three and one TSAs, respectively. Although EIF3E – RSPO2 has been reported as a recurrent genetic alteration in colorectal cancer, this fusion had not previously been found in any colorectal polyps. We formerly postulated the presence of a rare type of colorectal cancer precursor harbouring this fusion, because our previous studies involving a total of > 300 different types of colorectal polyp, including 129 TSAs, failed to identify EIF3E – RSPO2 in any of the lesions .…”

“…13,14 However, several other RSPO fusions have been detected in gastrointestinal neoplasms, including colorectal cancers, which raises the question of whether TSA is also a precursor of colorectal cancers harbouring RSPO fusions other than PTPRK-RSPO3. [18][19][20][21] In the present study, we analysed 99 TSAs to further characterise the spectrum of RSPO fusion genes.…”

RNA sequencing identifies a novel USP9X‐USP6 promoter swap gene fusion in a primary aneurysmal bone cyst

“…Recently, a novel USP9X‐ERAS promoter swap fusion was identified in a single colorectal cancer case, leading to high expression of ERAS, a RAS‐family member that enhances PI3K/AKT pathway activation . Overexpression was driven by the fusion of ERAS with the 5′UTR and promoter sequence of USP9X , which is highly expressed in colon .…”

“…34 Overexpression was driven by the fusion of ERAS with the 5 0 UTR and promoter sequence of USP9X, which is highly expressed in colon. 34 MPseq revealed that the novel promoter swap fusion was formed through a localized chromothripsis event on chromosome X including the region covered by USP9X and ERAS. 34 This case suggests that the ubiquitously expressed USP9X gene may be a recurrent translocation partner in other tumor types.…”