Molecular Characteristics of Radon Associated Lung Cancer Highlights MET Alterations

Abstract

Effective targeted treatment strategies resulted from molecular profiling of lung cancer with distinct prevalent mutation profiles in smokers and non-smokers. Although Rn is the second most important risk factor, data for Rn-dependent driver events are limited. Therefore, a Rn-exposed cohort of lung cancer patients was screened for oncogenic drivers and their survival and genetic profiles were compared with data of the average regional population. Genetic alterations were analysed in 20 Rn-exposed and 22 histologically matched non-Rn exposed LC patients using targeted Next generation sequencing (NGS) and Fluorescence In Situ Hybridization (FISH). Sufficient material and sample quality could be obtained in 14/27 non-exposed versus 17/22 Rn-exposed LC samples. Survival was analysed in comparison to a histologically and stage-matched regional non-exposed lung cancer cohort (n = 51) for hypothesis generating. Median overall survivals were 83.02 months in the Rn-exposed and 38.7 months in the non-exposed lung cancer cohort (p = 0.22). Genetic alterations of both patient cohorts were in high concordance, except for an increase in MET alterations and a decrease in TP53 mutations in the Rn-exposed patients in this small hypothesis generating study.

Keywords: genetic profile; lung cancer; radon exposure.

Figure 1

Fluorescence in-situ hybridization images showing ALK, ROS1 and RET signals of representative cases of (A) non-exposed LC group (n = 3) and (B) Rn-exposed group (n = 3). Yellow arrows highlight split signals (1F 1O 1G; insertion) or single red (in the case of ALK and ROS break apart probes) and single green signals (RET probe), both indicating insertion with deletion. (C) FISH images showing c-MET signal (green) and CEP17 signals (red) in two exemplary non-amplified cases. Images were taken using an Axioplan 2 (Zeis) microscope equipped with a 63× oil objective and a progress GRYPHAX SUBRA camera/software (Jenoptik). Scale bar = 50 µm.

Figure 2

Kaplan–Meier survival analysis-non-exposed (red dotted line) versus Rn-exposed subgroup (blue line). (A) overall survival (n = 51 vs. 19; median survival of 38.7 vs. 83.0 mths), (B) relapse free survival (n = 20 vs. 8; median survival of 16.13 vs. 32.82 mths) and (C) progression-free survival (n = 20 vs. 5; with median survival of 12.85 vs. 32 mths) of non-exposed and Rn-exposed groups.

Figure 3

Overall survival analysis stratified by summarized genetic alterations in patients of (A) Rn-exposed LC cohort and (B) non-exposed LC cohort. The red line represents MET alterations, and the black line, all other alterations (mainly TP53 and KRAS); the blue line depicts those without alterations.