Abstract 5479: Somatic driver mutations among never smoking female lung cancer cases in China identify unique mutation pattern that may be associated with household coal burning

Globally, about 53% of lung cancer cases in women and 15% of lung cancer cases in men are not attributable to active tobacco use, making lung cancer in never smokers the seventh leading cause of cancer death. Experimental and epidemiological evidence suggest that lung cancer in never smokers has unique risk factors, clinical features, and histological distributions as compared to those lung cancer cases attributed to tobacco smoking. In general, lung cancer in never smokers presents predominately as adenocarcinoma and in females. The lung cancer rate among females in Xuanwei, China is among the highest in the world for nonsmoking females, and has been attributed to indoor air pollution from domestic fuel combustion, particularly from bituminous coal. To further explore the clinical and histological aspects of lung cancer in Xuanwei, we collected formalin-fixed paraffin embedded (FFPE) tissue samples from a series of 76 female lung cancer cases. The mean age of the patients was 47.7 years old (±9.2 years). Expert consensus review found 54 (71%) of the female lung cancer cases were adenocarcinomas (ADCs), 11 (14.5%) were squamous cell carcinomas (SCCs), 1 (1.3%) was an adenosquamous carcinoma (ADSC), 8 (10.5%) were large cell carcinomas, and 2 (2.7%) were other subtypes. We then used two multiplexed assays to detect in DNA from FFPE tissue more than 40 recurrent mutations in nine genes relevant to existing and emerging targeted lung cancer therapies among subjects who were confirmed never smoking female lung cancer cases (32 ADCs, 7 SCCs, 1 ADSC). These assays include amplification of DNA through Applied Biosystem9s SNaPshot technology to detect 38 different recurrent somatic point mutations in 8 driver genes (EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1, AKT1, and PTEN) and a PCR-based sizing assay that assesses for EGFR exon 19 deletions, EGFR exon 20 insertions, and HER2 exon 20 insertions. We detected 15 EGFR mutations [E20-6bp-ins. (n=1); EGFR_19-15bpDel (n=4); EGFR_G719A_2156G>C (n=2); EGFR_G719C_2155G>T (n=3); EGFR_G719S _2155G>T (n=1); EGFR_G719S_2155G>A (n=1); EGFR_L858R_2573T>G (n=2); EGFR L861Q_2582T>A (n=1)] in 12 ADCs and 2 SCCs. Six KRAS mutations, all of which were KRAS G12C_34G>T, were detected in 5 ADCs and 1 SCC. EGFR and KRAS mutations were mutually exclusive and no mutations were observed for BRAF, NRAS, PIK3CA, MEK1, HER2, AKT1, or PTEN. The high percentage of samples with KRAS mutations (15.0% overall; 15.6% ADCs; 14.3% SCCs) in our series is of interest, primarily because KRAS mutations are reportedly more rare in other populations from Asia (∼5%) and populations of never smokers from Asia (∼2%). Given that all subjects with KRAS mutations burned coal indoors for heating and cooking, our findings may provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5479. doi:1538-7445.AM2012-5479