The landscape of genetic alterations of UVB-induced skin tumors in DNA repair-deficient mice

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K08749
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Kobe University
• Principal Investigator: Kunisada Makoto 神戸大学, 医学研究科, 非常勤講師 (80566969)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: 紫外線皮膚発がん / 多段階発がん / Xpa-ノックアウトマウス / 炎症 / 次世代シーケンサー / 全エクソーム解析

Outline of Final Research Achievements

We performed whole-exome sequencing (WES) of squamous cell carcinoma (SCC) samples after repetitive ultraviolet B (UVB) exposure to investigate the differences in the landscape of somatic mutations between Xpa knockout and wild-type mice. Although the tumors that developed in mice harboured UV signature mutations in a similar set of cancer-related genes, the pattern of transcriptional strand asymmetry was largely different; UV signature mutations in Xpa knockout and wild-type mice preferentially occurred in transcribed and non transcribed strands, respectively, reflecting a deficiency in transcription-coupled nucleotide excision repair in Xpa knockout mice. Serial time point analyses of WES for a tumor induced by only a single UVB exposure showed pathogenic mutations in Kras, Fat1, and Kmt2c, which may be driver genes for the initiation and promotion of SCC in Xpa knockout mice.

Free Research Field

紫外線皮膚がん

Academic Significance and Societal Importance of the Research Achievements

紫外線発がんの仕組みについてはその始まりのDNA損傷という部分と最終的に皮膚腫瘍になった時点での遺伝子変異の種類などが分かっていたが、その途中の段階が全く明らかになっていなかった。大腸がんのような所謂多段階発がんのシステムが紫外線発がんでも同様に存在し、その途中経路、特に遺伝子変異の全容を把握することによって、発がんが生じる前に予防的介入等の目印として活用できる可能性が出来るため、今後の同様研究の礎となるような学術的意義および社会的意義があると考える。