包括的ゲノム・空間解析による尿膜管がんの分子基盤と起源の解明

がんは主要な死因の一つであり、この難治性疾患に対して研究や治療の面から貢献したいと考え腫瘍内科を志しました。臓器横断的な知識をベースとして、臨床試験の立案や希少がんの基礎研究など幅広い分野で活動できる点にも大きな魅力を感じています。

Integrated Genomic and Spatial Analyses Elucidate the Molecular Pathogenesis and Origins of Urachal Carcinoma

[Background]

Urachal carcinoma (UrC) is an aggressive malignancy that originates from a urachal remnant, an embryonic remnant of the urachus. Although located in the bladder, the pathological features of UrC resemble those of gastrointestinal cancers. However, the molecular basis of UrC and the mechanisms underlying its carcinogenesis remain poorly understood due to the rarity of the disease.

[Methods]

To elucidate the molecular mechanisms and cellular origin of cancer, we conducted a comprehensive analysis of 53 UrC and 39 urachal remnant samples, including those without UrC. Whole-exome sequencing (WES), RNA sequencing, spatial transcriptomics, and immunohistochemical analysis were performed. Specifically, epithelial cells from urachal remnants were isolated using laser microdissection (LMD) for subsequent WES.

[Results]

Mutations in the RTK/RAS/MAPK pathway were identified in approximately 60% of tumor cases, with a mutational profile distinct from colorectal and bladder cancers. Transcriptomic analysis clearly distinguished the pathological subtypes, but, importantly, cell clonality investigation demonstrated similarities among different subtypes, potentially implicating tumor plasticity arising from a common ancestry. Further, urachal remnants were revealed to lose its native urothelial characteristics and undergo metaplastic change, accompanied by the activation