Introduction: Radon-222 (Rn) is a radioactive gas found in rocks and soil. It emits alpha particles that cause dsDNA breaks and increases potential for carcinogenesis. Rn is the 2nd leading cause of lung cancer in the US after smoking, with EPA estimates of >15000 deaths. A significant portion of land in US has high Rn soil levels; ‘action level' for indoor Rn mitigation is >4pci/L. Rhode Island (RI) contains several high Rn areas. We hypothesize that specific cellular and molecular mechanisms play a role in the neoplastic potential of Rn, detectable as signature genetic profiles. Our aim is to identify molecular patterns in patients (pts) from high Rn zones, by evaluating next generation sequencing (NGS) based assays in advanced lung cancer pts.

Methods: Using a commercially available NGS assay, we retrospectively analyzed genomic DNA alterations in 324 genes from FFPE specimens of 159 stage IV lung cancer pts treated at Lifespan Cancer Institute at Brown University from 2014- 2019. Based on EPA Rn maps, we identified counties in RI with high indoor Rn levels (>4 pci/L), and compared the gene mutation patterns with those residing in low Rn areas (<4 pci/L).

Results: Of the 159 pts (median age= 58), 35 (22%) belonged to high Rn and 124 (78%) to low Rn zones. Both groups had predominantly adenocarcinoma histology and high smoking prevalence (75-80%). Most prevalent genomic alterations in both cohorts were TP53, KRAS and CDKN2A mutations. In the high Rn group, we identified more frequent recurrent mutations in two DNA repair genes: ATM (11% in high Rn vs 1% in low Rn areas, p=0.00086) and CHEK2 (6% vs 0%, respectively, p=0.047). We then classified all detected genomic alterations into major pathways implicated in lung carcinogenesis; DNA repair, cell cycle, tyrosine kinase, and apoptosis. The only observed statistically significant difference in the frequency of mutations was for the DNA repair pathway (29% in high Rn vs 13% in low Rn, p=0.038).

Conclusion: To our knowledge, this is the first report of a novel and mechanistically unique insight into the pathobiology of Rn induced lung cancer. Our observations suggest that Rn induced dsDNA breaks may constitute an oncogenic hit in cells which are unable to efficiently repair them because of DNA repair pathway mutations (particularly ATM and CHEK2). We are further testing this “second hit” hypothesis in a larger nationwide dataset comparing NGS profiles of lung cancers from low and high Rn areas in the US.

Top 10 mutated genes in High and Low Radon groups (rank; frequency, %)

High RnLow RnP value
1. TP53 (63) 1. TP53 (70) 0.42 
2. KRAS (26) 2. KRAS (28) 0.83 
3. CDKN2A (23) 3. CDKN2A (24) 0.99 
4. RB1 (17) 4. RB1 (20) 0.81 
5. EGFR (14) 7. EGFR (10) 0.54 
6. CDKN2B (14) 6. CDKN2B (15) 0.99 
7. STK11 (11) 5. STK11 (19) 0.33 
8. RBM10 (11) -. RBM10 (3) 0.07 
-. SMARCA4 (3) 8. SMARCA4 (8) 0.46 
9. NF1 (11) 9. NF1 (7) 0.49 
10. ATM (11) -. ATM (1) 0.008 
-. MYC (6) 10. MYC (5) 0.99 
High RnLow RnP value
1. TP53 (63) 1. TP53 (70) 0.42 
2. KRAS (26) 2. KRAS (28) 0.83 
3. CDKN2A (23) 3. CDKN2A (24) 0.99 
4. RB1 (17) 4. RB1 (20) 0.81 
5. EGFR (14) 7. EGFR (10) 0.54 
6. CDKN2B (14) 6. CDKN2B (15) 0.99 
7. STK11 (11) 5. STK11 (19) 0.33 
8. RBM10 (11) -. RBM10 (3) 0.07 
-. SMARCA4 (3) 8. SMARCA4 (8) 0.46 
9. NF1 (11) 9. NF1 (7) 0.49 
10. ATM (11) -. ATM (1) 0.008 
-. MYC (6) 10. MYC (5) 0.99 

Citation Format: Hina Khan, Harish Saiganesh, Adam J. Olszewski, Christopher G. Azzoli, Howard Safran. Comparison of genomic alterations in lung cancer specimens from high and low radon zones: Search for a genomic fingerprint [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2338.