内容紹介
Summary
Recently, the interest in cancer genomic medicine has increased, owing to the powerful and cost-effective technology of next-generation sequencing(NGS), which allows rapid identification of a large number of gene mutations. TP53 mutations are frequently found in solid cancers, especially in esophageal squamous cell carcinoma(ESCC), wherein the frequency of TP53 mutation is considered to be 90% or more. However, there is no clinical targeted therapy as yet utilizing TP53. Here, we aimed to characterize TP53 mutations associated with ESCC, in order to assess its feasibility as a therapeutic target. We extracted DNA and RNA from specimens of ESCC patients and analyzed them using NGS, which revealed different TP53 mutations. Based on previous reports, it is considered that different TP53 mutations lead to different functions of the protein, and subsequently account for varied prognosis in squamous cell carcinoma of the head and neck. We also performed cell viability assay using ESCC cell lines with different TP53 mutations and 2 kinds of p53-targeted drug and found differences in the growth inhibition of the cell lines. Although individual treatment can be determined depending on the type of TP53 mutation, it would be necessary to further examine the interaction of TP53 with other genes to determine its therapeutic efficacy as a target.
要旨
近年,がんゲノム医療への関心が高まっており,多数の遺伝子変異が同定可能な次世代シーケンサー(next-generation sequencing: NGS)の高速化,低コスト化により遺伝子解析技術が実臨床に導入されつつある。固形癌においてTP53変異は高頻度に認められ,とくに食道扁平上皮癌(esophageal squamous cell carcinoma: ESCC)においては,その頻度は90%以上ともいわれている。しかしながら臨床導入されている標的治療は存在しない。われわれは,ESCC患者の検体よりDNA,RNAを抽出しNGSを用いて解析を行ったところ,mRNA発現量の異なるTP53変異が認められた。頭頸部扁平上皮癌においてTP53変異の詳細により予後が異なることが報告されており,ESCCにおいても機能,ひいてはその表現型である患者予後が異なる可能性が考えられる。さらにTP53変異の異なるESCC細胞株と2種類のp53標的治療薬を用いて細胞毒性試験を行ったところ,増殖抑制効果に違いが認められた。遺伝子相互作用ならびに患者背景などを考慮したTP53標的治療の開発が期待される。
目次
Recently, the interest in cancer genomic medicine has increased, owing to the powerful and cost-effective technology of next-generation sequencing(NGS), which allows rapid identification of a large number of gene mutations. TP53 mutations are frequently found in solid cancers, especially in esophageal squamous cell carcinoma(ESCC), wherein the frequency of TP53 mutation is considered to be 90% or more. However, there is no clinical targeted therapy as yet utilizing TP53. Here, we aimed to characterize TP53 mutations associated with ESCC, in order to assess its feasibility as a therapeutic target. We extracted DNA and RNA from specimens of ESCC patients and analyzed them using NGS, which revealed different TP53 mutations. Based on previous reports, it is considered that different TP53 mutations lead to different functions of the protein, and subsequently account for varied prognosis in squamous cell carcinoma of the head and neck. We also performed cell viability assay using ESCC cell lines with different TP53 mutations and 2 kinds of p53-targeted drug and found differences in the growth inhibition of the cell lines. Although individual treatment can be determined depending on the type of TP53 mutation, it would be necessary to further examine the interaction of TP53 with other genes to determine its therapeutic efficacy as a target.
要旨
近年,がんゲノム医療への関心が高まっており,多数の遺伝子変異が同定可能な次世代シーケンサー(next-generation sequencing: NGS)の高速化,低コスト化により遺伝子解析技術が実臨床に導入されつつある。固形癌においてTP53変異は高頻度に認められ,とくに食道扁平上皮癌(esophageal squamous cell carcinoma: ESCC)においては,その頻度は90%以上ともいわれている。しかしながら臨床導入されている標的治療は存在しない。われわれは,ESCC患者の検体よりDNA,RNAを抽出しNGSを用いて解析を行ったところ,mRNA発現量の異なるTP53変異が認められた。頭頸部扁平上皮癌においてTP53変異の詳細により予後が異なることが報告されており,ESCCにおいても機能,ひいてはその表現型である患者予後が異なる可能性が考えられる。さらにTP53変異の異なるESCC細胞株と2種類のp53標的治療薬を用いて細胞毒性試験を行ったところ,増殖抑制効果に違いが認められた。遺伝子相互作用ならびに患者背景などを考慮したTP53標的治療の開発が期待される。