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  • [Mod Pathol .] Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways

    [Mod Pathol .] Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways

    가톨릭의대, 서울의대 / 김은지, 김병혁, 한동진, 김태민*, 장지현*

  • 출처
    Mod Pathol .
  • 등재일
    2023 Jan
  • 저널이슈번호
    36(1):100004.
  • 내용

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    Abstract
    Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage-repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.

     

     

     

     

    Affiliations

    Eunji Kim 1, Dong-Jin Han 2, Byoung Hyuck Kim 3, Jinseon Yoo 4, Hak Jae Kim 5, Hong-Gyun Wu 5, Kyung Su Kim 6, Han-Soo Kim 7, Ilkyu Han 7, Kyung Chul Moon 8, Jeong Hwan Park 9, Sanghyuk Song 10, Tae-Min Kim 11, Ji Hyun Chang 12
    1Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea; Department of Advanced Education for Clinician Scientists, Graduate School, Seoul National University, Seoul, Republic of Korea.
    2Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea; Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
    3Department of Radiation Oncology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul, Republic of Korea; Division of Biological Warfare Preparedness and Response, Armed Forces Medical Research Institute, Daejeon, Republic of Korea; Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.
    4Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea.
    5Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
    6Department of Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea.
    7Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
    8Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
    9Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
    10Department of Radiation Oncology, Sheikh Khalifa Specialty Hospital, Ras Al Khaimah, United Arab Emirates.
    11Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea; Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: tmkim@catholic.ac.kr.
    12Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address: jh.chang@snu.ac.kr.

  • 키워드
    germline mutation; radiation-induced sarcoma; second malignancy; somatic mutation; whole-genome sequencing.
  • 연구소개
    방사선치료 이후 해당 자리에 발생한 육종 (Radiation-induced sarcoma, RIS)의 발생 원인 및 genomic footprint 에 대해서는 아직 알려진 바가 많지 않습니다. 본 논문은 RIS 환자의 조직 DNA로 Whole-genome sequencing을 진행한 결과를 보고한 논문입니다. 분석을 통해 cancer-related gene들이 다양한 형태의 genomic alteration을 보인다는 것을 밝혔고, RIS genome의 indel은 spontaneous sarcoma 에 비해 NHEJ genomic footprint를 보이는 특징이 있음을 보고하였습니다. 또한 RIS 의 경우 chromothripsis 가 빈번하게 관찰되었으며, DDR pathway 관련 predisposing germline variant 가 존재함을 밝혔습니다. 본 연구의 결과가 이후 RIS 진단 및 치료 발전의 기초가 되길 기대합니다.
  • 편집위원

    방사선-유도 육종(Radiation-induced sarcoma)은 방사선 치료에 의해 발생하는 합병증이다. 본 연구는 방사선-유도 육종의 전장 유전체 분석(Whole-Genome Sequencing)을 통해 방사선-유도 육종 특이적인 게놈의 변이를 확인한 연구로, 분석 결과 비동질성 말단 결합 경로(nonhomologous end joining pathway)와 종양 발생 간의 연관성을 밝혔다. 본 연구는 방사선-유도 육종의 진단 및 치료 전략 개발의 기반 연구로 활용될 수 있다는 점에 의의가 있다.

    2023-05-08 16:58:40

  • 편집위원2

    방사선에 유도되는 돌연변이에 대한 전체 지놈 시퀀싱에 대한 연구 결과 이며, 특히나, 유전체 정보가 부족한 sarcoma 환자에서의 유전체 프로파일 연구라서 흥미로움.

    2023-05-08 16:59:10

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