RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

Pietrantonio, Filippo; Nicolantonio, Federica Di; Schrock, Alexa B.; Lee, J.; Morano, Federica; Fucà, Giovanni; Nikolinakos, Petros; Drilon, Alexander; Hechtman, Jaclyn F.; Christiansen, Jason; Gowen, Kyle; Frampton, Garrett M.; Gasparini, Patrizia; Rossini, Daniele; Gigliotti, Chiara; Kim, S. T.; Prisciandaro, Michele; Hodgson, Jamie; Zaniboni, Alberto; Chiu, Vi K.; Milione, Massimo; Patel, Roopal; Miller, Vincent A.; Bardelli, Alberto; Novara, Luca; Wang, L.; Pupa, Serenella M.; Sozzi, Gabriella; Ross, Jeffrey S.; Bartolomeo, Maria Di; Bertotti, Andrea; Ali, Siraj M.; Trusolino, Livio; Falcone, Alfredo; Braud, Filippo de; Cremolini, Chiara

doi:10.1093/annonc/mdy090

Cited by 87 publications

(86 citation statements)

References 18 publications

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“…The most common fusions in CRC are CCDC6-RET and NCOA4-RET. More rare fusions involving TNIP1-, SNRNP70-, GEMIN5-and RRBP1 as N-terminal partners were also described (Table 1) [34,35]. In CRC, RET fusions were more frequent in old patients, right-sided, RAS/ BRAF wild-type, and MSI (microsatellite instable)-high tumors and were associated with negative prognosis.…”

Section: Ret Gene Fusions In Other Malignanciesmentioning

confidence: 96%

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RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

Santoro

Moccia

Federico

et al. 2020

Genes

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Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer.

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Section: Ret Gene Fusions In Other Malignanciesmentioning

confidence: 96%

“…RET fusions have been identified in <1% of colorectal carcinomas (CRC) [33,34,66]. The most common fusions in CRC are CCDC6-RET and NCOA4-RET.…”

Section: Ret Gene Fusions In Other Malignanciesmentioning

confidence: 99%

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

Santoro

Moccia

Federico

et al. 2020

Genes

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“…On the other hand, a robust biological rationale supported by preclinical in vitro findings seems to suggest a low EGFR-dependency of these rearranged tumors [47], confirmed also in small retrospective studies, in which the limited subset of patients with rearrangement-positive disease derived no benefit from anti-EGFR moAbs [54,55]. This observation should encourage clinicians to avoid EGFR inhibition and to adopt targeted approaches as soon as possible in the disease course of these patients.…”

Section: How To Deal With Very Rare Alterations? the Example Of Gementioning

confidence: 96%

“…Sharing some features with BRAF V600E mutation, ALK , ROS1 , NTRK , and RET rearrangements more frequently occur in elderly patients, right-sided tumors, RAS wild-type, and MSI-high cancers [54,55]. Furthermore, gene fusions confer a strong negative impact on survival, independent of other prognostic characteristics.…”

Section: How To Deal With Very Rare Alterations? the Example Of Gementioning

confidence: 99%

The Winding Roadmap of Biomarkers Toward Clinic: Lessons from Predictors of Resistance to Anti-EGFRs in Metastatic Colorectal Cancer

Antoniotti

Ongaro

Falcone

et al. 2018

IJMS

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In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors of resistance to anti-EGFR agents in preclinical and clinical retrospective series. Nevertheless, none of them have been implemented in clinical practice due to the lack of a formal prospective demonstration. Here, we propose a literature review of molecular alterations associated with resistance to anti-EGFRs, underlining the reasons why their roadmap from laboratories to clinics was prematurely halted.

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“…ALK, ROS1, NTRK and RET rearrangements have been described in CRC [109][110][111][112][113]. Although these genetic alterations are present in CRC at a quite low frequency (< 1%), they seem more frequent in CRC patients with microsatellite instability.…”

Section: Gene Fusionsmentioning

confidence: 99%

Colorectal cancer genomic biomarkers in the clinical management of patients with metastatic colorectal carcinoma

Rachiglio

Sacco

Forgione

et al. 2020

Exploration of Targeted Anti-Tumor Therapy

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Colorectal carcinoma (CRC) is an heterogeneous disease in which different genetic alterations play a role in its pathogenesis and progression and offer potential for therapeutic intervention. The research on predictive biomarkers in metastatic CRC (mCRC) mainly focused on the identification of biomarkers of response or resistance to anti-epidermal growth factor receptor monoclonal antibodies. In this respect, international guidelines suggest testing mCRC patients only for KRAS, NRAS and BRAF mutations and for microsatellite instability. However, the use of novel testing methods is raising relevant issue related to these biomarkers, such as the presence of sub-clonal RAS mutations or the clinical interpretation of rare no-V600 BRAF variants. In addition, a number of novel biomarkers is emerging from recent studies including amplification of ERBB2, mutations in ERBB2, MAP2K1 and NF1 and rearrangements of ALK, ROS1, NTRK and RET. Mutations in POLE and the levels of tumor mutation burden also appear as possible biomarkers of response to immunotherapy in CRC. Finally, the consensus molecular subtypes classification of CRC based on gene expression profiling has prognostic and predictive implications. Integration of all these information will be likely necessary in the next future in order to improve precision/personalized medicine in mCRC patients.

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RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

Abstract: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

Cited by 87 publications

References 18 publications

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

The Winding Roadmap of Biomarkers Toward Clinic: Lessons from Predictors of Resistance to Anti-EGFRs in Metastatic Colorectal Cancer

Colorectal cancer genomic biomarkers in the clinical management of patients with metastatic colorectal carcinoma

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