Whole-genome sequencing analysis identifies a distinctive mutational spectrum in an arsenic-related lung tumor

Arsenic exposure is a significant cause of lung cancer in North America and worldwide. Arsenic-related tumors are structurally indistinguishable from those induced by other carcinogens. Because carcinogens, like tobacco, induce distinctive mutational signatures, we sought to characterize the mutational signature of an arsenic-related lung tumor from a never smoker with the use of whole-genome sequencing.

Tumor and lung tissues were obtained from a never smoker with lung squamous cell carcinoma (LUSC), without familiar history of lung cancer and chronically exposed to high levels of arsenic-contaminated drinking water. The Illumina HiSeq-2000 platform was used to sequence each genome at approximately 30-fold haploid coverage. The mutational signature was compared with those observed in previously characterized lung tumors.

The arsenic-related tumor exhibited alterations common in LUSC, such as the increased number of copies at 3q26 (SOX2 locus). However, the arsenic-related genome not only harbored a lower number of point mutations, but also had a remarkably high fraction of T>G/A>C mutations and low fraction of C>A/G>T transversions, which is uncharacteristic of LUSCs. Furthermore, at the gene level, we identified a rare G>C mutation in TP53, which is uncommon in lung tumors in general (<0.2%) but has been observed in other arsenic-related malignancies.

We generated the first whole-genome sequence of an LUSC from a never-smoker patient chronically exposed to arsenic, and identified a distinct mutational spectrum associated with arsenic exposure, providing novel evidence supporting the hypothesis that arsenic-induced lung tumors arise through molecular mechanisms that differ from those of the common lung cancer.