Whole-exome sequencing identified recurrent and novel variants in benzene-induced leukemia

Abstract

Background: Genome-wide sequencing may extensively identify potential pathogenic variants, which helps to understand mechanisms of tumorigenesis, but such study has not been reported in benzene-induced leukemia (BIL).

Methods: We recruited 10 BIL patients and conducted the whole-exome sequencing on their peripheral blood samples. The obtained sequencing data were screened for potential pathogenic and novel variants, then the variants-located genes were clustered to identify cancer-related pathways. Shared or recurrent variants among the BIL cases were also identified and evaluated for their potential functional impact.

Results: We identified 48,802 variants in exons in total, 97.3% of which were single nucleotide variants. After filtering out variants with minor allele frequency ≥ 1%, we obtained 8667 potentially pathogenic variants, of which 174 were shared by all the BIL cases. The identified variants located in genes that could be significantly enriched into certain cancer-related pathways such as PI3K-AKT signaling pathway and Ras signaling pathway. We also identified 1010 novel variants with no record in the Genome Aggregation Database and in dbSNP, and one of them was shared by 90% cases. The recurrent and novel variant caused a missense mutation in SESN3.

Conclusions: We examined variations of the whole exome in BIL patients for the first time. The commonly shared variants implied a relation with BIL, and the recurrent and novel variant might be specifically related to BIL. The related variants may help unravel the carcinogenic mechanisms of BIL.

Keywords: Benzene; Exome; Genetic variant; High-throughput sequencing; Leukemia.

Fig. 1

Pathway enrichment of the genes where the identified variants with minor allele frequency < 1% located. Fold enrichment is calculated by dividing gene ratio (the number of genes enriched in the pathway divided by the total number of analyzed genes) with background ratio in KEGG database. P values were adjusted

Fig. 2

Classification of the functional impact of the commonly shared variants with minor allele frequency < 1%. Black bars represent single nucleotide variants, and gray bars represent small insertions and deletions

Fig. 3

Pathway enrichment of the genes where the newly identified variants located. Fold enrichment is calculated by dividing gene ratio (the number of genes enriched in the pathway divided by the total number of analyzed genes) with background ratio in KEGG database. P values were adjusted