What did they find in these genome sequences? “Right off the bat, we were reassured to find trends in tumor mutational burden and specific oncogenic mutations between smokers and never-smokers that had previously been reported in other cohorts,” notes Moorthi. Indeed, they found a significantly higher tumor mutational burden in smokers compared to never-smokers, and they also noted trends in mutations in the notorious oncogenes KRAS and EGFR—tumors from smokers had significantly more mutations in KRAS, while tumors from never-smokers had significantly more EGFR mutations, particularly mutation types known as ‘insertions’ and ‘deletions.’ But Moorthi and team also found something which hadn’t been shown before: mutations in MGA, a tumor suppressor and member of the MYC transcription factor network (for more info, see here) were exclusively present in tumors from smokers. Cross-referencing their results with several larger-scale lung cancer genomics datasets confirmed that MGA mutations appear more frequently in smokers’ lung tumors than in never-smokers.
Equally as interesting as what Moorthi and Berger found was what they didn’t find. For example, when the team looked for mutational signatures (patterns that distinguish mutations arising from specific mutagens, like cigarette smoke), they noted that tumors from never-smokers showed little if any evidence of smoke exposure-associated mutational signatures, despite the fact that these patients still reported some ‘passive exposure’ to cigarette smoke. These findings support the notion that lung cancer in never-smokers is truly distinct from that of smokers, not simply a result of smoke exposure via means other than cigarettes.
When they turned their attention away from specific mutations and to larger-scale genomic alterations—including loss or duplication of whole genes, genomic regions, or even entire genomes—they found considerable diversity among tumors, but not in a way that systematically differed between smokers and never-smokers. “While other studies have used patterns of larger scale genomic lesions like chromosome arm copy number variants to group lung tumors from never-smokers, we find similar levels of variation in smokers’ tumors, suggesting that the processes that generate these lesions are characteristic of lung cancers in general and not related to smoking,” notes Moorthi.
Why should we care about studying all of these different mutations in smokers and never-smokers? “On the most basic level, looking at mutations can give us clues about the processes that contribute to tumorigenesis in each case,” notes Dr. Berger, “but also, mutations can determine the compatibility or effectiveness of specific therapies.” Moorthi agrees. “When we were looking at KRAS mutations, for example, we noticed that the G12C variant is significantly enriched in smokers compared to never-smokers—the few never-smokers who had mutations in KRAS instead preferentially showed the G12D variant. As G12C is currently the only druggable KRAS variant, it becomes important to understand the nuance in the way that KRAS is mutated in lung cancers from these two populations of patients.” Overall, while the team is still actively pursuing clues which explain why lung cancer in never-smokers seems to preferentially target women, they are excited to continue leveraging opportunities to collaborate with organizations like the Women’s Health Initiative to continue studying lung cancer in patient populations that all too often fly under the radar.