Jump to Main Contents
研究所ロゴ

Home > Organization > Divisions and Independent Research Units > Group for Development of Molecular diagnostics and Individualized Therapy > Division of Genome Biology > Research Projects

Research Projects

Genes for personalized therapy

We and others identified the RET fusion gene present in 1-2% of lung adenocarcinomas (18). LADCs with RET fusion lacked aberrations of other cancer-related genes, supporting the use of monotherapy with RET kinase inhibitor (10). A Nation-wide genome screening of lung cancer (LC-SCRUM) involving more than 200 hospitals in Japan, identified 34 RET fusion-positive cases among 1,536 screened ones. A total of 19 patients were enrolled into a phase II investigator-initiated clinical trial of a RET TKI, vandetanib. Seventeen cases eligible for efficacy analysis showed a promising result; overall response rate was 53% (90% CI, 31 to 74). This study demonstrates the significance of “seamless” medical science study, consisting basic, translational, clinical and regulatory science studies, to develop a new therapeutic way.

Translation of RET-fusion Discovery into Cancer Clinic

 

Low Tumor Mutation Burden in Oncogene Fusion (+) Lung Adenocarcinoma

Analysis of breakpoint junctions for oncogenic RET, ALK and ROS1 fusions revealed that DNA strand breaks formed at non-specific sites within this region trigger RET fusion. Two DNA-repair mechanisms, namely, DNA synthesis-dependent or -independent end-joining pathways were deduced to have contributed to the illegitimate joining of the DNA ends, in the generation of oncogenic fusions (12, 15).

Breakpoint Distribution for RET Oncogene Fusion in LADC and PTC

We identified multiple druggable oncogene fusions, including those involving the NRG1 (neuregulin, heregulin), ERBB4, BRAF and RET genes, in invasive mucinous adenocarcinoma (IMA), a malignant type of lung adenocarcinoma (14). These fusions also represent potentially clinically relevant targets for treatment of IMAs. NRG1 fusion induced NF-kB activity and promoted the IGF2 autocrine/paracrine circuit. Inhibition of ErbB2, PI3K, NF-kB, or IGF2 suppressed NRG1 fusion–induced cancer stem cell–like properties (9).

Druggable NRG1/Neuregulin Fusion in Invasive Mucinous Lung Adenocarcinoma

On the other hand, >30% of LADC and most of other types of lung cancers are negative for the oncogene aberrations above, therefore, other therapeutic targets are needed for precision lung cancer medicine. A comprehensive genetic alteration profiling studies of lung cancer genomes, including international ones (3, 18), revealed inactivation of chromatin-regulating genes, such as SMARCA4/BRG1 and CREBBP, in lung cancer cases negative for oncogene aberrations (10, 11, 16). We propose a synthetic lethal therapeutic method for chromatin regulator-deficient lung cancers based on inhibition of paralog proteins (13, 16). Recently, a synthetic lethality therapy for CREBBP-deficient small cell lung cancer was proposed; EP300 histone acetyltransferase (functional paralog for CREBBP) is a vulnerability of such cancer, and its functional suppression causes depletion of MYC oncogene product (5).

Novel Synthetic Lethality Therapy against CBP-deficient Cancer

Genes involved in DNA repair and/or chromatin remodeling are being analyzed to improve the efficiency of existing therapeutic methods. We established an assay tool for evaluating NHEJ activity against DSBs in chromosomal DNA in human H1299 dA3-1 cells (20).

DNA double strand break repair (NHEJ) assay in H1299 dA3-1 cells

Genes for personalized prevention

Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%), indicating Asian-specific risk factors for lung adenocarcinoma (6). Genetic factors underlying lung adenocarcinoma risk of Asians are being searched for by performing genome-wide association studies (GWASs), including several international collaborative studies, on SNPs (2, 7, 19). A genome-wide association study comprising a total of 6,029 individuals with lung adenocarcinoma (cases) and 13,535 controls identified four loci (17).

Frequent EGFR Mutation in Lung Adenocarcinoma in Japanese

Genetic Factors Responsible for Lung Adenocarcinoma Risk

GWAS of lung adenocarcinoma with EGFR mutation was performed as a multi-center collaborative study with a Japanese population consisting of 3,173 cases and 15,158 controls. Six loci, including HLA-DPB1, were discovered as risk loci for the disease (4). The result indicates that lung adenocarcinoma develops in vivo through interaction between somatic mutations and germline variations that modulate immune reaction.

Genetic Factors Responsible for EGFR Mutation (+) Lung Adenocarcinoma