Identification and Validation of Noncanonical RET Fusions in Non–Small-Cell Lung Cancer through DNA and RNA Sequencing

Xiang, Chan; Guo, Lianying; Zhao, Ruiying; Teng, Haohua; Wang, Yulu; Xiong, Liwen; Han, Yuchen

doi:10.1016/j.jmoldx.2021.12.004

Cited by 17 publications

(15 citation statements)

References 28 publications

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“…We intend to conduct further studies that include more clinical features of RET-rearranged patients and prognostic evaluations of different RET-fusion subtypes. Yes 19 [43] 2 [20] RET, rearranged during transfection; ADC, adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, break-apart displays low sensitivity in detecting non-canonical RET fusions (19). DNA-based NGS enables the detection of high-throughput genomic alterations and novel partners of gene rearrangement, but it fails to provide information on functional fusion transcripts (20). The main laboratory methods for RET rearrangements have not been systematically investigated and fully elucidated in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients

Feng¹,

Li²,

Wei³

et al. 2022

Transl Lung Cancer Res

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Background: Rearranged during transfection (RET) rearrangement has been identified as one of the crucial oncogenic drivers in non-small cell lung cancer (NSCLC). Recently, two highly selective RET inhibitors have been approved by the US Food and Drug Administration and demonstrated remarkable responses.However, the clinical characteristics, outcomes and optimal diagnostic method of RET-rearrangements are not well understood. This study sought to evaluate the prevalence and characteristics of RET rearrangement, identify an effective diagnostic method for it, and correlate its presence with outcomes.Methods: A total of 9,431 Chinese NSCLCs from two cancer centers who have undertaken targeted DNA-NGS were enrolled and 167 RET-positive cases were screened. Non-canonical RET rearrangements were confirmed by targeted RNA-NGS. If material was sufficient, positive cases were analyzed by fluorescence in situ hybridization (FISH) (n=30) and immunohistochemistry (IHC) (n=57). Clinicopathologic characteristics, molecular profiling and treatment outcomes of RET rearrangement were evaluated.Results: The prevalence of RET rearrangement was 1.52% (138/9,101) in unfiltered cases and 8.79%(29/330) in EGFR/KRAS/BRAF/ALK-negative cases. RET rearrangement was common in females, never smokers, and lung adenocarcinoma patients. Additionally, 40.3% of stage IV RET-rearranged NSCLC patients developed brain metastases. TP53 was the most common concurrent mutation, and 8 patients harbored concurrent driver oncogenic alterations, including EGFR (N=5), KRAS (N=2), and ALK (N=1).Non-canonical fusion partners were identified in 13.8% (23/167) of cases by DNA-based NGS, and RNAbased NGS identified 3 new partners (EPS8, GOLGA5, and TNIP1). The concordance of FISH and NGS was 83.3% (25/30), while the concordance of IHC and NGS was only 28.1% (16/57). Both IHC and FISH demonstrated lower sensitivity for NCOA4-/other-RET fusions. The CCDC6-RET subgroup had significantly ^ ORCID: 0000-0001-9588-4096. longer progression-free survival than the KIF5B-RET subgroup, both after chemotherapy (23 vs. 9.7 months; P=0.014).Conclusions: RET rearrangement occurs in 1.52% of Chinese NSCLCs and has identifiable clinicopathologic characteristics. RET IHC has a low sensitivity, disavowing its use in routine practice.While NGS and FISH has good performance in identifying RET rearrangement. Both IHC and FISH demonstrated lower sensitivity for NCOA4-/others-RET fusions. Clinical benefit with chemotherapy is different between CCDC6-RET and KIF5B-RET fusion patients, optimal treatment should be considered when selecting therapies for patients with RET-rearranged lung cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients

Feng¹,

Li²,

Wei³

et al. 2022

Transl Lung Cancer Res

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“…Moreover, although this FAM114A1 ‐ ALK rearrangement was predicted to produce an out‐of‐frame transcript, it was not sufficient to determine that this case had no functional ALK fusion. In our previous studies, we found that cases harbouring non‐productive/out‐of‐frame ALK / RET rearrangements always have canonical fusion transcripts at the RNA level [ 10 , 23 ]. On the other hand, it is a pity that this patient did not receive ALK‐targeted therapy, so we were unable to evaluate the efficacy of ALK‐TKI in this case.…”

Section: Discussionmentioning

confidence: 99%

Identification and therapeutic evaluation of ALK rearrangements in non‐small‐cell lung cancer

Zhao

Guo

Zhang

et al. 2022

The Journal of Pathology CR

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This study aimed to present a comprehensive assessment of anaplastic lymphoma kinase (ALK) rearrangements evaluated by DNA/RNA-based next-generation sequencing (NGS) and Ventana immunohistochemistry (IHC) in patients with non-small-cell lung cancer (NSCLC) and to evaluate the therapeutic outcomes of ALK tyrosine kinase inhibitor (TKI) treatment. We investigated ALK gene fusions in 14,894 patients with NSCLC using Ventana IHC and NGS, including 12,533 cases detected via DNA-based NGS and 2,361 cases using RNA-based NGS. The overall percentage agreement (OPA), positive percentage agreement (PPA), and negative percentage agreement (NPA) were calculated when comparing the results between NGS and IHC. The therapeutic responses to ALK-TKIs were also evaluated. In total, 3.50% (439/12,533) of specimens were NGS ALK-positive (NGS-p) in the DNAbased NGS cohort and 3.63% (455/12,533) were IHC ALK-positive (IHC-p). The OPA of NGS was 99.60%, whereas its PPA and NPA were 92.75 and 99.86%, respectively. In the adenocarcinoma (ADC) subcohort, the PPA was 95.69%. In the RNA-based NGS cohort, 2.20% (52/2,361) of specimens were NGS-p and 2.63% (62/2,361) were IHC-p. The OPA of NGS was 99.49%; its PPA and NPA were 82.26 and 99.96%, respectively. Thirteen patients with discordant results received ALK-TKI treatment. In the seven NGS-p/IHC-negative (IHC-n) patients, the overall response rate (ORR) was 85.4% (6/7) and the disease control rate (DCR) was 100%. In the six NGS-negative/IHC-p patients, the ORR was 66.7% (4/6) and the DCR was 100%. In summary, a high concordance of ALK gene fusion detected via NGS and IHC was observed in this study. DNA-based NGS had a higher OPA, PPA, and PPA in the ADC subcohort, whereas RNA-based NGS had a higher NPA. Overall, the results suggest that the combination of NGS and IHC can improve the accuracy of ALK fusion detection; hence, a result determination algorithm for clinical detection of ALK gene fusion was also proposed.

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“…The panel consists of 83 immunomodulatory genes ( Table S1 ). The prepared libraries were sequenced, and the sequencing data were processed as previously described [ 41 ]. Gene-level expression values were computed as transcripts per million (TPM) and normalized to Z-scores before clustering.…”

Section: Methodsmentioning

confidence: 99%

Immunologic Signatures across Molecular Subtypes and Potential Biomarkers for Sub-Stratification in Endometrial Cancer

Jiang

Cao

et al. 2023

IJMS

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Current molecular classification approaches for endometrial cancer (EC) often employ multiple testing platforms. Some subtypes still lack univocal prognostic significance, highlighting the need for risk sub-stratification. The tumor immune microenvironment (TIME) is associated with tumor progression and prognosis. We sought to investigate the feasibility of classifying EC via DNA sequencing and interrogate immunologic signatures and prognostic markers across and within subtypes, respectively. Formalin-fixed paraffin-embedding (FFPE) samples from 50 EC patients underwent targeted DNA and RNA sequencing, and multiplex immunofluorescence assay for TIME. DNA sequencing classified 10%, 20%, 52%, and 18% of patients into the subtype of POLE-mutant, microsatellite instability-high (MSI-H), TP53-wt, and TP53-mutant. POLE-mutant tumors expressed the highest T-effector and IFN-γ signature and the lowest innate anti-PD-1 resistance signature among subtypes. TP53-wt revealed a converse enrichment trend for these immunologic signatures. Survival analyses using the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) dataset identified associations of CCR5 (hazard ratio (HR) = 0.71, p = 0.035), TNFRSF14 (HR = 0.58, p = 0.028), and IL-10 (HR = 2.5, p = 0.012) with overall survival within MSI-H, TP53-mutant, and TP53-wt subtype, respectively. A TIME comparison between the sub-stratified subgroups of our cohort revealed upregulated tumor infiltration of immune cells in the low-risk subgroups. Our study demonstrates that targeted DNA sequencing is an effective one-stop strategy to classify EC. Immunomodulatory genes may serve as prognostic markers within subtypes.

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Identification and Validation of Noncanonical RET Fusions in Non–Small-Cell Lung Cancer through DNA and RNA Sequencing

Cited by 17 publications

References 28 publications

Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients

Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients

Identification and therapeutic evaluation of ALK rearrangements in non‐small‐cell lung cancer

Immunologic Signatures across Molecular Subtypes and Potential Biomarkers for Sub-Stratification in Endometrial Cancer

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