Whole genome sequencing to identify predictive markers for the risk of drug-induced interstitial lung disease

Autoři: Chihiro Udagawa aff001;  Hidehito Horinouchi aff002;  Kouya Shiraishi aff003;  Takashi Kohno aff003;  Takuji Okusaka aff004;  Hideki Ueno aff004;  Kenji Tamura aff005;  Yuichiro Ohe aff002;  Hitoshi Zembutsu aff001
Působiště autorů: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan aff001;  Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan aff002;  Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan aff003;  Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan aff004;  Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan aff005;  Project for Development of Liquid Biopsy Diagnosis, Japanese Foundation for Cancer Research, Research Institute, Tokyo, Japan aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0223371


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.

Klíčová slova:

Cancer treatment – Genome analysis – Human genetics – Introns – Lung and intrathoracic tumors – Oxygen – Replication studies – Genetic screens


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