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Updated: May 3, 2026
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis
K Tsuta1, T Kohno2, A Yoshida1
1Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Background:
To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors.
Methods:
We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) were performed to detect RET gene rearrangement.
Results:
In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B-RET fusion genes, whereas 3 possessed CCDC6-RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001).
Conclusions:
The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected.
Insights
RET rearrangements occur in 1.2% of non-small cell lung cancers (NSCLC), primarily in adenocarcinomas (ADC) of younger, non-smoking patients. These genetic alterations can help identify individuals who may benefit from RET tyrosine kinase inhibitor therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) harbors various genetic alterations driving oncogenesis.
- RET rearrangements leading to oncogenic fusions are actionable targets for specific therapies.
Purpose of the Study:
- To characterize the clinicopathological features of NSCLC with RET rearrangements.
- To identify patient populations responsive to RET tyrosine kinase inhibitors.
Main Methods:
- Retrospective analysis of 1874 carcinoma patients, including 1620 adenocarcinomas (ADCs).
- Detection of RET gene rearrangements using fluorescence in situ hybridization (FISH) and/or reverse transcription-PCR (RT-PCR).
Main Results:
- RET rearrangements were identified in 1.2% (22/1874) of NSCLC cases, exclusively in ADCs.
- KIF5B-RET (19 cases) and CCDC6-RET (3 cases) fusions were observed.
- RET rearrangements were more frequent in younger patients and those without a smoking history.
- No significant association was found with gender, tumor stage, or survival.
- Cytoplasmic mucin was present in 54.5% of RET-rearranged ADCs; RET immunopositivity was observed in 71.4%.
Conclusions:
- RET rearrangements are a rare but targetable event in NSCLC, predominantly found in ADCs.
- Younger age and non-smoking status are associated with RET rearrangements.
- While specific histological patterns were not definitive, RET immunopositivity correlates with rearrangement status.
