Abstract
Drug-induced interstitial lung disease (DIILD) is a serious side effect of chemotherapy in cancer patients with an extremely high mortality rate. In this study, to identify genetic variants with greater risk of DIILD, we carried out whole genome sequencing (WGS) of germline DNA samples from 26 patients who developed DIILD, and conducted a case-control association study between these 26 cases and general Japanese population controls registered in the integrative Japanese Genome Variation Database (iJGVD) as a screening study. The associations of 42 single nucleotide variants (SNVs) showing P < 0.0001 were further validated using an independent cohort of 18 DIILD cases as a replication study. A further combined analysis of the screening and replication studies showed a possible association of two SNVs, rs35198919 in intron 1 of the chromosome 22 open reading frame 34 (C22orf34) and rs12625311 in intron 1 of the teashirt zinc finger homeobox 2 (TSHZ2), with DIILD (Pcombined = 1.87 × 10−5 and 5.16 × 10−5, respectively). Furthermore, in a subgroup analysis of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI)-induced interstitial lung disease (ILD), we observed seven candidate SNVs that were possibly associated with ILD (P < 0.00001). This is the first study to identify genetic markers for the risk of DIILD using WGS. Collectively, our novel findings indicate that these SNVs may be applicable for predicting the risk of DIILD in patients receiving chemotherapy.
Highlights
Drug-induced interstitial lung disease (DIILD) is a serious side effect of a wide range of drugs, including anticancer [1,2,3], antirheumatic [4,5,6], and cardiology drugs [7,8,9]
The development of predictive marker(s) for the risk of life-threatening toxicities related to cancer treatment, including ILD, based on germline mutation or variation is important in order to provide safe treatment regimens for patients with cancer
This study is the first whole genome sequencing (WGS) that attempts to identify common or rare genetic variants associated with DIILD in the Japanese population
Summary
Drug-induced interstitial lung disease (DIILD) is a serious side effect of a wide range of drugs, including anticancer [1,2,3], antirheumatic [4,5,6], and cardiology drugs [7,8,9]. While the incidence rate of DIILD is approximately 0.1%–10% for anticancer drugs, DIILD is potentially life-threatening and represents a serious clinical problem [10]. Genetic variants associated with drug-induced interstitial lung disease
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