Unearthing novel fusions as therapeutic targets in solid tumors using targeted RNA sequencing

An, Sungbin; Koh, Hyun Hee; Chang, Eun Sol; Choi, Juyoung; Song, Ji-Young; Lee, Mi-Sook; Choi, Yoon–La

doi:10.3389/fonc.2022.892918

Cited by 4 publications

(2 citation statements)

References 30 publications

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“…Previously, such out-of-frame fusions have been shown to be stable, i.e., not rapidly degraded, but the specific function of the out-of-frame fragment remains unknown [192]. Fusions from this group are often assumed to be inactivating mutations [193], or are labeled passenger mutations or ignored altogether in analysis [135,194]. However, stable out-of-frame fusions with drastically distorted downstream amino acid sequences and passenger mutations possess the highest immunogenicity [190].…”

Section: Neoantigen Immunogenicitymentioning

confidence: 99%

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

Salokas

Dashi

Varjosalo

2023

Cancers

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Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients.

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Section: Neoantigen Immunogenicitymentioning

confidence: 99%

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

Salokas

Dashi

Varjosalo

2023

Cancers

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“…For instance, intergenic‐breakpoint ROS1 rearrangements theoretically should not be transcribed due to the lack of a promoter, but studies have showed some of them can unequivocally produce functional fusion transcripts [ 17 ]. Besides that, the functional implications of rare fusions identified at the genomic level are not easily predictable [ 18 , 19 ]. Therefore, validation of genomic fusions at transcriptional level was critical to optimize treatment strategy.…”

Section: Introductionmentioning

confidence: 99%

Novel insights into molecular patterns of ROS1 fusions in a large Chinese NSCLC cohort: a multicenter study

Zhou

Zhang

et al. 2023

Molecular Oncology

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ROS proto‐oncogene 1, receptor tyrosine kinase (ROS1) rearrangements are a crucial therapeutic target in non‐small cell lung cancer (NSCLC). However, there is limited comprehensive analysis of the molecular patterns of ROS1 fusions. This study aimed to address this gap by analyzing 135 ROS1 fusions from 134 Chinese NSCLC patients using next‐generation sequencing (NGS). The fusions were categorized into common and uncommon based on their incidence. Our study revealed, for the first time, a unique distribution preference of breakpoints within ROS1, with common fusions occurring in introns 31–33 and uncommon fusions occurring in introns 34 and 35. Additionally, we identified previously unknown breakpoints within intron 28 of ROS1. Furthermore, we identified a close association between the distribution patterns of fusion partners and breakpoints on ROS1, providing important insights into the molecular landscape of ROS1 fusions. We also confirmed the presence of inconsistent breakpoints in ROS1 fusions between DNA‐based next‐generation sequencing (DNA NGS) and RNA‐based NGS (RNA NGS) through rigorous validation methods. These inconsistencies were attributed to alternative splicing resulting in out‐of‐frame or exonic ROS1 fusions. These findings significantly contribute to our understanding of the molecular characteristics of ROS1 fusions, which have implications for panel design and the treatment of NSCLC patients with ROS1 rearrangements.

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Elacestrant plus alpelisib in an ESR1 and PIK3CA co-mutated and heavily pretreated metastatic breast cancer: the first case report for combination efficacy and safety

Tokat,

Bilgiç,

Aydın

et al. 2024

Ther Adv Med Oncol

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Breast cancer (BC) is the leading cause of cancer-related mortality among women, and hormone receptor (HR)-positive subtype makes up the majority of all cases. The standard of care in HR+/HER2− metastatic BC (MBC) is endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i). ESR1 mutations could impair the clinical efficacy of the ETs. Similarly, PIK3CA mutations may serve as a negative prognostic marker. Furthermore, MBC is challenging to treat despite new drug approvals. Our patient received multiple lines of ET ± CDK4/6i and chemotherapy but persistently progressed after each or stopped the treatment due to adverse events. Here we showed for the first time that an all-oral combination of elacestrant plus alpelisib was feasible, tolerable, and clinically active in an ESR1 and PIK3CA co-mutated and heavily pretreated patient. We achieved a remarkable response in the metastatic lesions with minor toxicity issues. This case highlights the importance of utilizing up-to-date therapeutic agents and reactive decision-making during personalized cancer treatment.

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Unearthing novel fusions as therapeutic targets in solid tumors using targeted RNA sequencing

Cited by 4 publications

References 30 publications

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

Novel insights into molecular patterns of ROS1 fusions in a large Chinese NSCLC cohort: a multicenter study

Elacestrant plus alpelisib in an ESR1 and PIK3CA co-mutated and heavily pretreated metastatic breast cancer: the first case report for combination efficacy and safety

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