Streamlining Detection of Fusion Genes in Colorectal Cancer: Having “Faith” in Precision Oncology in the (Tissue) “Agnostic” Era

Abstract

The FDA recently granted tissue-agnostic approval for the first-in-class TRK inhibitor larotrectinib for patients whose tumors harbor fusions in neurotrophic receptor tyrosine kinases. These fusion genes have a frequency of less than 1% in unselected patients with colorectal cancer. Using a multiomics approach and a clinically annotated cohort of patients with colorectal cancer, Cocco and colleagues showed that patients with sporadic, RAS/BRAF wild-type, mismatch repair–deficient colorectal cancer tumors with MLH1 promoter methylation present fusions in kinase genes in 42% of cases and suggested a diagnostic framework to improve the selection of patients eligible for gene fusion testing. See related article by Cocco et al., p. 1047

The Landscape of Actionable Gene Fusions in Colorectal Cancer

“…In this setting, the emerging role of genomic translocations has to be emphasized. Gene fusions represent an important piece of the puzzle of the tumor genomic landscape and are involved in the development of about 16% of all cancer types [12]. In fact, in some cases, they display a close correlation with a specific tumor subtype, thus representing a diagnostic marker (e.g., FLI1/EWS in Ewing Sarcoma), while in others they are endowed with a prognostic value, providing a risk stratification (e.g., the presence of gene fusions in embryonal rhabdomyosarcoma), or they could represent a potential therapeutic target (e.g., ALK and ROS1 in non-small cell lung cancer (NSCLC)) [13].…”

“…However, the low frequency of the singular novel genomic alterations and gene fusions is a limiting factor for their thorough study from a pathogenic and therapeutic perspective, hampering the investigation in dedicated clinical trials and the translation in the clinical practice setting [16]. In this light, the paradigm of cancer research is undergoing a deep change: from a tumor type-focused approach to a molecularly-directed agnostic one, exploring the role of biologic agents targeted to the driver genomic alteration irrespectively of the cancer histology [12]. Thanks to the recently-conducted basket trials, clinical studies in which patients affected by several tumor types harboring the same genomic aberration received a specific targeted treatment, the tyrosine kinase inhibitor (TKI) larotrectinib was granted accelerated approval by Food and Drug Administration (FDA) for cancers displaying NTRK pathogenic fusions while entrectinib, a TKI targeting NTRK , ALK and ROS1 fusions, was granted priority review by FDA [17,18].…”

Oncogenic fusion transcript analysis identified ADAP1‐NOC4L, potentially associated with metastatic colorectal cancer

“…In research practice, discovering chimeras involves two main aims and approaches: (1) Identifying targetable fusions associated with known therapeutic agents regardless of tumor type and (2) detailed molecular examination of a tumor to discover specific tumor alterations that require appropriately targeted treatments. 20 The critical issue in these two scenarios is the low frequency of discovered chimeras specially among solid tumors, which limits their pathogenetic and therapeutic relevance in trial studies and their applications in clinical settings. 21 It should be noted that in some cases the presence of these fusions defines certain subtypes of the tumor that may benefit from specific treatments and should not be ignored.…”

CircHMGCS1 is upregulated in colorectal cancer and promotes proliferation of colorectal cancer cells by targeting microRNA-503-5p

“…Currently, the incidence of CRC is still rising, and surgery is the only possible cure method for CRC. 1,2 However, the oncological outcome of CRC patients remains unsatisfactory. The 5-year survival rates markedly decline from about 90% in early-stage locally confined tumors to only about 5% in cases with metastatic disease, which is dependent on the tumor stage at a great extent.…”

“…9,10 Emerging evidence has elucidated that circRNAs participate in diverse signaling pathways, especially in the development of cancers. 2,11,12 CircHMGCS1, also called circ_0072391, is a critical enzyme in mevalonate pathway, which has been suggested as a promising cancer therapeutic target. 13,14 Besides, circHMGCS1 was dramatically overexpressed in hepatoblastoma cancer, while the depletion of circHMGCS1 could suppress cell growth in liver cancer cells, which indicates that circHMGCS1 takes a great role in hepatoblastoma progression.…”