ALK, ROS1, RET and NTRK1–3 Gene Fusions in Colorectal and Non-Colorectal Microsatellite-Unstable Cancers

Mulkidjan, Rimma S.; Saitova, Evgeniya S.; Preobrazhenskaya, Elena V.; Asadulaeva, Karimat A.; Bubnov, Mikhail G.; Otradnova, Ekaterina A.; Terina, Darya M.; Shulga, Sofia S.; Martynenko, Darya E.; Semina, Maria V.; Belogubova, Evgeniya V.; Tiurin, Vladislav I.; Amankwah, Priscilla S.; Martianov, Aleksandr S.; Imyanitov, Evgeny N.

doi:10.3390/ijms241713610

Cited by 8 publications

(9 citation statements)

References 31 publications

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“…While the incidence of NTRK activation in commonly occurring carcinomas affecting adults falls below 1:500-1:1000, NTRK1-3 translocations are detected at frequency of about 5% in pediatric tumors, sarcomas, and salivary gland carcinomas [53,54]. NTRK1-3 fusions are particularly common in microsatellite-unstable RAS/RAF mutation-negative colorectal carcinomas, while non-colorectal tumors with MSI rarely carry gene translocations [37]. Occasional instances of NTRK1-3 rearrangements were reported in KRAS mutation-negative pancreatic carcinomas and biliary tract cancers [55].…”

Section: Ntrk1-3 Rearrangementsmentioning

confidence: 99%

“…MSI is positioned as an agnostic target, however relevant clinical trials usually included only a few tumor types characterized by high or moderate frequency of MSI/MMR-D occurrence [29,30]. MSI is relatively common in colorectal, gastric, small bowel, and endometrial malignancies, occurs at low frequency in several other cancer types, e.g., biliary tract, pancreatic, or ovarian tumors, but is exceptionally rare in some of the most common oncological diseases, for example, breast or lung carcinomas [33][34][35][36][37]. The detection of MSI involves either the utilization of individually administered IHC or PCR tests, or the use of next-generation sequencing (NGS) panels consisting of several hundred genes [27].…”

Section: Microsatellite Instability (Msi)/mismatch Repair Deficiency ...mentioning

confidence: 99%

“…RET rearrangements are also common in colorectal tumors with microsatellite instability and Spitz melanomas. Occasional instances of RET rearrangements have been described in breast carcinomas, KRAS mutation-negative pancreatic cancers, and some other tumor types [37,59,60,[64][65][66]. Two RET inhibitors, selpercatinib and pralsetinib, are the standard treatment option for RET-driven thyroid carcinomas as well as for RET-rearranged non-small cell lung cancers [63,66].…”

Section: Ret Rearrangementsmentioning

confidence: 99%

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Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Aleksakhina,

Ivantsov,

Imyanitov

2024

IJMS

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Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

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Section: Ntrk1-3 Rearrangementsmentioning

confidence: 99%

Section: Microsatellite Instability (Msi)/mismatch Repair Deficiency ...mentioning

confidence: 99%

Section: Ret Rearrangementsmentioning

confidence: 99%

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Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Aleksakhina,

Ivantsov,

Imyanitov

2024

IJMS

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“…rearrangements such as ALK have MSI-H status, which provides more treatment options for future combination therapy (targeted therapy combined with immunotherapy for ALK)[33].According to the NCCN Oncology Clinical Practice Guidelines published in 2023, the two subtypes of pMMR/MSS and dMMR/MSI-H are o cially used as global classi cation criteria for the diagnosis and treatment of colon cancer, which means that mismatch repair gene/microsatellite status has o cially become selection…”

mentioning

confidence: 99%

An immune-related prognostic risk model for colorectal cancer was constructed based on next-generation sequencing

Zhang,

Chen,

Chen

et al. 2023

Preprint

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Objective Screening the immune-related genes of colorectal cancer based on clinical next generation sequencing and construction of an immune-related prognostic risk model, so as to provide an immediate indicator for evaluating the prognosis and efficacy of immunotherapy of CRC patients. Methodology: Univariate and multivariate Cox risk regression analysis was used to analyze the correlation between immune-related genes, clinicopathological features, and prognosis of CRC patients, and a prognostic risk model was established. Results A total of 57 mutant genes were detected in 150 CRC patients, of which SNV and Indel had the highest mutation frequency, (92.67% and 47.33%, respectively). The genes with the highest number of mutations were TP53 and APC. In all 150 CRC patients, 12 mutation genes were detected, including 6 drug-treatable genes: KRAS, PIK3CA, PTEN, BRAF, NRAS, and TP53.TP53 and PIK3CA were the genes with the most drug-treatable mutation sites, and KRAS, NRAS, and BRAS had the highest medication grade. The mutation rates of 36 CRC common detection genes in the NGS and TCGA clinical databases were very consistent, and they were enriched in negative regulation of cell proliferation, negative regulation of apoptosis, and kinase pathways such as PI3K-AKT signaling pathway. Through the correlation analysis of immune infiltration, 14 immune-related genes TP53, JAK1, MTHFR, EGFR, KDR, APC, KRAS, TSC2, PMS2, KIT, ALK, BRAF, CTNNB1, and FBXW7 were obtained. The Cox univariate analysis and Cox multivariate analysis showed that late clinical stage (stage), late T stage and ALK gene mutation increased the risk of death and were independent prognostic factors affecting the risk of death. A Cox proportional-hazards model was constructed : h(t,x)/h0(t) = EXP(0.835 clinical stage + 0.878T + 1.094ALK). Among the 112 clinical follow-up patients, the survival time of CRC patients with high-risk scores was significantly shorter than that of CRC patients with low-risk scores. In addition, the risk score of the MSI-L group was significantly higher than that of the MSS group in the 92 CRC patients data sets of the TCGA database. Conclusion ALK gene mutation may be related to immune and prognostic survival in CRC patients; the constructed prognostic risk model can be used to evaluate the prognosis and efficacy of immunotherapy in CRC patients.

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“…As regards CRC, biomarkers predictive of drug response for targeted agents (RAS wild-type for anti-EGFR and Microsatellite Instability-High (MSI-H) status for anti-programmed cell death 1 (anti-PD-1) monoclonal antibodies, NTRK gene fusions, BRAF V600E and KRAS G12C mutations) are employed only in the advanced stage [ 5 ]. The knowledge of the MSI-H status provides various clinical information.…”

mentioning

confidence: 99%

Clinical Updates for Gastrointestinal Malignancies

Laface,

Memeo

2023

JPM

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ALK, ROS1, RET and NTRK1–3 Gene Fusions in Colorectal and Non-Colorectal Microsatellite-Unstable Cancers

Cited by 8 publications

References 31 publications

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

An immune-related prognostic risk model for colorectal cancer was constructed based on next-generation sequencing

Clinical Updates for Gastrointestinal Malignancies

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