Identification of novel ALK rearrangements in neonates with fetal lung interstitial tumor

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K09637
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Yamagata University
• Principal Investigator: Onoda Tadashi 山形大学, 医学部, 非常勤講師 (10582562)
• Co-Investigator(Kenkyū-buntansha): 浅尾 裕信 山形大学, 医学部, 教授 (80250744)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: ALK転座 / 新生児間質性肺腫瘍 / FLIT / ALK関連腫瘍 / A2M-ALK / FISH / 5'RACE / 全ゲノムシークエンス

Outline of Final Research Achievements

Fetal lung interstitial tumor (FLIT) is a recently reported type of congenital lung lesion comprising solid and cystic components. FLIT is extremely rare and its gene expression profile has not been fully understood. In this study, we report a novel chromosomal rearrangement resulting in alfa-2-macroglobulin (A2M) and anaplastic lymphoma kinase (ALK) gene fusion in neonates with FLIT. The tumor cells contained a t(2;12)(p23;p13). Break apart FISH demonstrated chromosomal rearrangement at ALK 2p23. Using 5'-RACE or WGS, we further identified a novel transcript fusing exon 22 of A2M to exon 19 of ALK. The corresponding chimeric gene was subsequently confirmed by sequencing, including the genomic break point between intron 22 and 18 of A2M and ALK, respectively. Discovery of A2M as a novel ALK fusion partner, together with the involvement of ALK, provides new insights into the pathogenesis of FLIT, and suggests the potential for new therapeutic strategies based on ALK inhibitors.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

新生児肺腫瘍 Fetal Lung Interstitial Tumor (FLIT) は, 2010年に新たに報告された稀な新生児間質性肺腫瘍である. 治療法に一定の見解はなく, 発症機序, 疾患特異的遺伝子は未解明であった. 本研究では, FLITがALK 2p23転座, 特にA2M-ALK転座を有するALK関連腫瘍の一つである可能性が示唆された. ALK転座の同定と新規腫瘍関連分子としてのA2Mの発見はALKとともにFLITの病態解明に大きく寄与するとともに, 分子標的薬の応用による治療成績の向上が見込まれることから, 稀な腫瘍の治療方法の拡大につながり, 学術的な意義は極めて高い.