がんゲノム医学を基盤とした個別化医療

Personalized medicine based on cancer genomics

抄録

　がんは日本人の死因の第1位であり，保健衛生上重要な疾患である．その原因は体細胞ゲノム異常の蓄積であり，がんの発生や進展を駆動する遺伝子はドライバー遺伝子と呼ばれる．ドライバー遺伝子異常は分子標的薬のバイオマーカーであり，ゲノム情報は診断・治療・予防にとっても有用である．我々は本邦で罹患者数が多く，予後不良な消化器がんを中心として大規模かつ包括的なゲノム解析を行い，ドライバー遺伝子全体像を解明した．またFGFR2融合遺伝子を標的とした創薬開発や免疫療法に対するバイオマーカー同定など個別化医療の実装に貢献した．がんの進展や転移におけるクローン進化を解明し，治療抵抗性症例に対する血中遊離DNAによる経時的モニタリングを検討した．アルコール関連変異シグネチャーSBS16が日本人肝臓がんや食道がんに多く，びまん型胃がんにおいてはRHOA遺伝子変異を誘発する人種特徴的な発がん分子機構であることを解明し，個別化予防医療の可能性を示した．今後全ゲノム解析やエピゲノム情報を含めた包括的なゲノム・オミックス情報や腸内細菌叢など微小環境データとの統合，早期診断や予測医療などが次の展望として期待される．

Abstract

　Cancer is the leading cause of death in Japan and is a disease of public health importance. It is caused by the accumulation of somatic genome abnormalities, and the genes that drive cancer initiation and progression are called driver genes. Driver gene aberrations are biomarkers for molecularly targeted drugs, and genomic information is useful for diagnosis, treatment and prevention. We conducted a large-scale, comprehensive genomic analysis of gastrointestinal cancers, which affect a large number of people in Japan and have a poor prognosis, to elucidate the overall picture of their driver genes. We have also contributed to the implementation of personalized medicine, such as drug development targeting the FGFR2 fusion gene and biomarker identification for immunotherapy. Clonal evolution in cancer progression and metastasis was elucidated, and temporal monitoring using cell-free DNA for treatment-resistant cases was investigated. Mutational signature analysis revealed that alcohol-associated SBS16 is a characteristic oncogenic molecular mechanism that is common in Japanese liver and esophageal cancers and induces RHOA gene mutations in diffuse-type gastric cancer, indicating the potential of personalized preventive medicine. Comprehensive genomic and omics information including whole genome sequencing and epigenomic information, integration with microenvironmental data such as tissue microbiota, early diagnosis and predictive medicine are expected to be the next prospects.