Exploration of biomarkers for the choice of chemotherapy in colorectal cancer patients

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07204
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: Kindai University
• Principal Investigator: FUJITA Yoshihiko 近畿大学, 医学部, 講師 (80192730)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 進行性大腸がん / irinotecan / oxaliplatin / bevacizumab / CGH アレイ法 / 遺伝子コピー数増加

Outline of Final Research Achievements

Among patients of metastatic colorectal cancer (mCRC) with copy number gain (CNG) at chromosome 8q24.1-q24.2 (~ 40% of the patients), response rate and prognosis factors (OS and PFS) were better for those treated with irinotecan(iri)-based than those with oxaliplatin(ox)-based combination chemotherapy. Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either iri- or ox-based chemotherapy in combination with bevacizumab for treatment of mCRC patients. Myc-knocked down Colo320 cells (with a CNG at 8q24.1-24.2) reduced sensitivity to SN38, but Myc-overexpressed DLD1 cells (without CNG at 8q24.1-24.2) did not, suggesting that Myc is not indispensable factor for iri sensitivity. Fam84B-overexpressed DLD1 cells increase sensitivity to SN38, suggesting that this gene that resides in the 8q24.1-24.2 region could be a critical factor to choose ox- or iri-based chemotherapy in combination with bevacizumab for treatment of mCRC patients.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

これまで大腸がん患者へのベバシズマブの併用療法としてFOLFOX療法またはFOLFIRI療法のどちらを選択するか決まった指針がなかった。今回の結果から、がん部DNAにおける8q24.1-q24.2染色体領域に遺伝子増幅がある患者は全体の約40%を占め、そのような患者ならばFOLFOX療法よりFOLFIRI療法を採用するのが良いことが示された。また、この染色体上におけるMYC、FAM84B遺伝子が薬剤感受性に関与することから、効果予測バイオマーカーの特定のみならず大腸がん患者の分子標的治療への道が拓けた。これらのことは臨床的にはたいへん意義深いことである。