PMID- 37445709
OWN - NLM
STAT- MEDLINE
DCOM- 20230717
LR  - 20230718
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 13
DP  - 2023 Jun 23
TI  - Rapid and Cost-Efficient Detection of RET Rearrangements in a Large Consecutive 
      Series of Lung Carcinomas.
LID - 10.3390/ijms241310530 [doi]
LID - 10530
AB  - RET-kinase-activating gene rearrangements occur in approximately 1-2% of 
      non-small-cell lung carcinomas (NSCLCs). Their reliable detection requires 
      next-generation sequencing (NGS), while conventional methods, such as 
      immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) or 
      variant-specific PCR, have significant limitations. We developed an assay that 
      compares the level of RNA transcripts corresponding to 5'- and 3'-end portions of 
      the RET gene; this test relies on the fact that RET translocations result in the 
      upregulation of the kinase domain of the gene and, therefore, the 5'/3'-end 
      expression imbalance. The present study included 16,106 consecutive NSCLC 
      patients, 14,449 (89.7%) of whom passed cDNA quality control. The 5'/3'-end 
      unbalanced RET expression was observed in 184 (1.3%) tumors, 169 of which had a 
      sufficient amount of material for the identification of translocation variants. 
      Variant-specific PCR revealed RET rearrangements in 155/169 (91.7%) tumors. RNA 
      quality was sufficient for RNA-based NGS in 10 cases, 8 of which carried 
      exceptionally rare or novel (HOOK1::RET and ZC3H7A::RET) RET translocations. We 
      also applied variant-specific PCR for eight common RET rearrangements in 4680 
      tumors, which emerged negative upon the 5'/3'-end unbalanced expression test; 33 
      (0.7%) of these NSCLCs showed RET fusion. While the combination of the analysis 
      of 5'/3'-end RET expression imbalance and variant-specific PCR allowed 
      identification of RET translocations in approximately 2% of consecutive NSCLCs, 
      this estimate approached 120/2361 (5.1%) in EGFR/KRAS/ALK/ROS1/BRAF/MET-negative 
      carcinomas. RET-rearranged tumors obtained from females, but not males, had a 
      decreased level of expression of thymidylate synthase (p < 0.00001), which is a 
      known predictive marker of the efficacy of pemetrexed. The results of our study 
      provide a viable alternative for RET testing in facilities that do not have 
      access to NGS due to cost or technical limitations.
FAU - Tiurin, Vladislav I
AU  - Tiurin VI
AUID- ORCID: 0000-0002-0157-5952
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Preobrazhenskaya, Elena V
AU  - Preobrazhenskaya EV
AUID- ORCID: 0000-0001-7800-013X
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
AD  - Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 
      194100 St.-Petersburg, Russia.
FAU - Mitiushkina, Natalia V
AU  - Mitiushkina NV
AUID- ORCID: 0000-0002-0179-3191
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Romanko, Aleksandr A
AU  - Romanko AA
AUID- ORCID: 0000-0002-6549-8378
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
AD  - Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 
      194100 St.-Petersburg, Russia.
FAU - Anuskina, Aleksandra A
AU  - Anuskina AA
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Mulkidjan, Rimma S
AU  - Mulkidjan RS
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Saitova, Evgeniya S
AU  - Saitova ES
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Krivosheyeva, Elena A
AU  - Krivosheyeva EA
AUID- ORCID: 0000-0001-8499-4409
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Kharitonova, Elena D
AU  - Kharitonova ED
AUID- ORCID: 0000-0001-7898-7405
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Shevyakov, Mikhail P
AU  - Shevyakov MP
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Tryakin, Ilya A
AU  - Tryakin IA
AUID- ORCID: 0009-0003-8995-8417
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Aleksakhina, Svetlana N
AU  - Aleksakhina SN
AUID- ORCID: 0000-0002-2149-7728
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Venina, Aigul R
AU  - Venina AR
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Sokolova, Tatiana N
AU  - Sokolova TN
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Martianov, Aleksandr S
AU  - Martianov AS
AUID- ORCID: 0000-0002-7690-8328
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
AD  - Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 
      194100 St.-Petersburg, Russia.
FAU - Shestakova, Anna D
AU  - Shestakova AD
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
FAU - Ivantsov, Alexandr O
AU  - Ivantsov AO
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
AD  - Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 
      194100 St.-Petersburg, Russia.
FAU - Iyevleva, Aglaya G
AU  - Iyevleva AG
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
AD  - Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 
      194100 St.-Petersburg, Russia.
FAU - Imyanitov, Evgeny N
AU  - Imyanitov EN
AUID- ORCID: 0000-0003-4529-7891
AD  - Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 
      St.-Petersburg, Russia.
AD  - Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 
      194100 St.-Petersburg, Russia.
LA  - eng
GR  - 17-75-30027/Russian Science Foundation/
PT  - Journal Article
DEP - 20230623
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 63231-63-0 (RNA)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - EC 2.7.10.1 (RET protein, human)
SB  - IM
MH  - Female
MH  - Humans
MH  - *Lung Neoplasms/pathology
MH  - *Carcinoma, Non-Small-Cell Lung/genetics/pathology
MH  - Protein-Tyrosine Kinases/metabolism
MH  - In Situ Hybridization, Fluorescence
MH  - Proto-Oncogene Proteins c-ret/genetics/metabolism
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Gene Rearrangement
MH  - Lung/pathology
MH  - *Carcinoma/genetics
MH  - RNA
MH  - Oncogene Proteins, Fusion/genetics
PMC - PMC10342123
OTO - NOTNLM
OT  - NGS
OT  - NSCLC
OT  - PCR
OT  - RET
OT  - fusion
OT  - pemetrexed
OT  - thymidylate synthase
OT  - tyrosine kinases
COIS- The authors declare no conflict of interest.
EDAT- 2023/07/14 13:06
MHDA- 2023/07/17 06:42
PMCR- 2023/06/23
CRDT- 2023/07/14 01:13
PHST- 2023/04/26 00:00 [received]
PHST- 2023/06/18 00:00 [revised]
PHST- 2023/06/20 00:00 [accepted]
PHST- 2023/07/17 06:42 [medline]
PHST- 2023/07/14 13:06 [pubmed]
PHST- 2023/07/14 01:13 [entrez]
PHST- 2023/06/23 00:00 [pmc-release]
AID - ijms241310530 [pii]
AID - ijms-24-10530 [pii]
AID - 10.3390/ijms241310530 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Jun 23;24(13):10530. doi: 10.3390/ijms241310530.