Association between lung cancer somatic mutations and occupational exposure in never-smokers

Abstract

Occupational exposure constitutes a common risk factor for lung cancer. We observed molecular alterations in 73% of never-smokers, 35% of men and 8% of women were exposed to at least one occupational carcinogen. We report herein associations between molecular patterns and occupational exposure.BioCAST was a cohort study of lung cancer in never-smokers that reported risk factor exposure and molecular patterns. Occupational exposure was assessed a validated 71-item questionnaire. Patients were categorised into groups that were unexposed and exposed to polycyclic aromatic hydrocarbons (PAH), asbestos, silica, diesel exhaust fumes (DEF), chrome and paints. Test results were recorded for and mutations, and alterations.Overall, 313 out of 384 patients included in BioCAST were analysed. Asbestos-exposed patients displayed a significantly lower rate of mutations (20% 44%, p=0.033), and a higher rate of mutations (18% 4%, p=0.084). alterations were not associated with any occupational carcinogens. The DEF-exposed patients were diagnosed with a mutation in 25% of all cases. Chrome-exposed patients exhibited enhanced and mutation frequency.Given its minimal effects in the subgroups, we conclude that occupational exposure slightly affects the molecular pattern of lung cancers in never-smokers. In particular, asbestos-exposed patients have a lower chance of mutations.

Asbestos-related lung cancers are rarely associated withALK,ROS1andRETrearrangements

“…Among 56 tumours, 32 were adenocarcinomas, 20 were squamous cell carcinomas and four were small cell carcinomas. Major differences in comparison with the study by PARIS et al [1] were that all patients were men and that nonsmokers only represented five (9%) patients in our cohort. Oncogenic chromosomal rearrangements were encountered in lung adenocarcinomas of four (7%) patients: two ALK-rearranged @ERSpublications ALK, ROS1 and RET rearrangements can also be diagnosed in asbestos-related lung cancers http://ow.ly/rFpb30hV5Wt tumours (with positive immunohistochemistry and FISH results) in a never-smoker and a 20-pack-year smoker, one ROS1-rearranged tumour in a 10-pack-year smoker (with positive immunohistochemistry and FISH results), and one RET-rearranged tumour in a 20-pack-year smoker ( positive FISH result).…”

“…Beyond chromosomal gains and losses, chromosomal alterations leading to gene fusions or amplifications that are of therapeutic relevance have been detected in few (ALK, 2p23 locus) to no studied (ROS1, 6q22.1 locus; RET, 10q11.21 locus; NTRK1, 1q23.1 locus; C-MET, 7q31.2 locus) in asbestos-related lung cancers. In the study by PARIS et al [1], none of the 21 asbestos-exposed patients had an ALK-rearranged cancer [1]. In our study, we have demonstrated that chromosomal alterations of theranostic relevance are rare but can be encountered among patients with asbestos-related lung cancers, among smokers and nonsmokers, opening potential access to targeted therapies for these patients.…”

“…The study by PARIS et al [1] of the frequencies of EGFR, ALK, KRAS, HER2, BRAF and PIK3 molecular alterations in never-smokers with lung cancer and occupational exposure to carcinogens including asbestos is very interesting in this manner. However, others biomarker that are also of therapeutic interest were not studied by PARIS et al [1], such as ROS1, RET, NTRK1 and MET. We have also just conducted a study focusing on oncogenic chromosomal rearrangements in a cohort of French patients with financially compensated asbestos-related lung cancers.…”

“…As an extension of this study and after approval by our institutional review board (CHRU Brest 2016.CE10), we collected formalin-fixed, paraffin-embedded tumour samples to perform additional molecular analyses in 56 patients (for 90 patients, no tumour sample was available at the time of our retrospective study). We performed not only ALK analyses, as reported by PARIS et al [1], using immunohistochemistry (5A4 clone; Clinisciences, Nanterre, France) and fluorescence in situ hybridisation (FISH) analyses (Vysis LSI ALK Dual Color Break Apart FISH probe; Abbott Molecular, Rungis, France) but also ROS1 analyses (immunohistochemistry with clone D4D6 (Cell Signaling Technology; Ozyme, Saint Quentin en Yvelines, France) and FISH with Vysis 6q22 ROS1 Break Apart FISH Probe Kit (Abbott Molecular)) as previously reported [3,4]. Using FISH, we also searched for RET and neurotrophic NTRK1 rearrangements ( probes ON RET (10q11) Break (Kreatech/Leica, Nanterre, France) and ZytoLight SPEC NTRK1 Dual Color Break Apart Probe (Zytovision GmbH, Bremerhaven, Germany)) as well as MET amplification (Vysis LSI D7S486 (7q31) SpectrumOrange/Vysis CEP 7 SpectrumGreen Probe, Abbott Molecular).…”

“…In our study, having considered only patients with financially compensated asbestos-related lung cancers constitutes a bias preventing any estimation of the frequency of chromosomal rearrangements among asbestos-related lung cancers. In a future work, it would be interesting (and may be feasible in the cohort of PARIS et al [1]) to analyse also ROS1, RET, NTRK1 and MET in a larger cohort of asbestos-exposed never-smokers to further study the relationship between asbestos exposure and chromosomal aberrations of theranostic interest.…”