RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis

Abstract

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.

The RET fusion gene and its correlation with demographic and clinicopathological features of non-small cell lung cancer: a meta-analysis

“…The meta-analysis also suggested that non-smokers had an increased incidence RET fusion genes (4 times that of smokers), which accorded with most previous studies. 12,21 Interestingly, genotype-related sensitivity has also been proven in never smokers of other subgroups of lung cancer like EGFR mutated lung cancer and EML4-ALK-positive lung cancer, suggesting that lung cancer in non-smokers is likely to be an assemblage of molecularly defined subsets. 3,28,29 Risk factors for non-smokers in lung cancer have been described in several studies, including second-hand smoking, occupational exposure to carcinogens, hormonal element and cooking or heating fumes.…”

“…Other factors reported are infections, dietary factors et al 30,31 We also found a statistical difference between RET fusion genes and age, similar to Tsuta's result, demonstrating that RET fusion genes occurred preferentially in younger patients. 21 It has been suggested that familial susceptibility and Mendelian inheritance may result in the early onset of lung cancer, which may account for the early onset of the lung cancer in younger patients. 32,33 Moreover, the influence of different age-grouping criterion should be taken into consideration.…”

“…Finally, 9 studies including 6,899 patients were qualified for our meta-analysis. [10][11][12][20][21][22][23][24][25] Main features of 9 eligible studies were summarized in Table 1. The median age was reported in 7 studies and the average is 61.4.…”

“…11,16,20,21 So exploring the specific features of RET-positive patients may help to target people at high risk and narrow the scope of gene test. Heretofore, several studies have reported the distribution of the RET fusion gene in NSCLC patients, however, the results remain uncertain.…”

“…For example, Tsuta et al demonstrated that RET rearrangements were significantly more common in younger patients and tended to occur in non-smokers, while Cai et al revealed that there were no statistically significant difference in age, sex and smoking status. 21,22 Therefore, we performed a meta-analysis to quantify the association of RET fusion genes with demographic factors and clinicopathological characteristics of NSCLC, which may facilitate the selection of cases for the check of RET rearrangements and further treatment of RET inhibitors.…”