Analysis of BRCAness as a Predictive Biomarker of Neoadjuvant Chemotherapy in Childhood, Adolescents, and Young Adults with Osteosarcomas
| Project/Area Number |
20K16904
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Keio University |
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Principal Investigator |
YAMAZAKI Fumito 慶應義塾大学, 医学部(信濃町), 助教 (70529354)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 骨肉腫 / BRCAness / 相同組み換え修復機能 / 化学療法感受性 |
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| Outline of Research at the Start |
遺伝性乳がん・卵巣がんの原因遺伝子であるBRCA1/2の機能喪失の際にみられるゲノム変化のパターンがBRCA1/2に異常がない腫瘍にもみられることがあり、BRCAnessと呼ばれている。BRCAnesを示す腫瘍がプラチナ製剤やPARP阻害剤といった特定の治療薬に対して高い効果が得られることが知られている。
思春期・若年成人の多種多様な肉腫のゲノム解析で骨肉腫がBRCAnessを示す傾向を見出したことから、小児の骨肉腫おいてBRCAnessを評価すると共に、その原因となりうる遺伝子異常を同定し、BRCAnessが化学療法の効果を予測する指標となりうるかを明らかにすることを目的として研究を行う。
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| Outline of Final Research Achievements |
Homologous recombination deficiency (HRD), mainly due to BRCA1/2 inactivation, causes many copy number alterations (CNAs) and structural variations (SVs) in breast and ovarian cancer genomes. Furthermore, similar genomic alterations are observed in BRCA1/2-intact cancers. This phenomenon is called “BRCAness.” Osteosarcoma (OS) exhibits a high number of CNAs and SVs. Thus, this study aimed to assess genomic alterations in OS from the viewpoint of HRD. Single nucleotide polymorphism array and whole-exome sequencing analyses were performed on 19 and 5 OSs, respectively, from childhood, adolescents, and young adults. The HRD-LOH (loss of heterozygosity) scores in OSs were as high as those reported in breast cancers, and the scores of good responders to neoadjuvant chemotherapy were higher than those of standard responders (20.8 vs. 14.9, P=0.023). The study results indicate that HRD underlies high genomic alterations in OS and the HRD-LOH score is a predictive biomarker for OS treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
小児・AYA世代骨肉腫症例でLOHスコアはBRCA1/2が不活化した乳がんと同等の高い水準にあり、相同組み換え修復機能の異常が腫瘍発症に寄与している可能性が示唆された。また、化学療法後の腫瘍壊死率が高い治療反応良好群でLOHスコアが高かったこと、およびLOHスコアが高値の例では限局例において予後良好な傾向があったことから、LOHスコアは治療開始時に評価可能な、化学療法感受性および予後を予測するためのバイオマーカーとなり得る可能性が示唆された。
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Report
(3 results)
Research Products
(1 results)
