Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways

被引：7

作者：

Kim, Eunji ^{[1
,2
]}

Han, Dong-Jin ^{[3
,4
,5
]}

Kim, Byoung Hyuck ^{[6
,7
,8
]}

Yoo, Jinseon ^{[3
]}

Kim, Hak Jae ^{[8
,9
,10
]}

Wu, Hong-Gyun ^{[8
,9
,10
]}

Kim, Kyung Su ^{[9
]}

Kim, Han-Soo ^{[11
]}

Han, Ilkyu ^{[11
]}

Moon, Kyung Chul ^{[12
]}

Park, Jeong Hwan ^{[12
,13
]}

Song, Sanghyuk ^{[14
]}

Kim, Tae-Min ^{[3
,4
,5
]}

Chang, Ji Hyun ^{[8
,9
]}

机构：

[1] Korea Inst Radiol & Med Sci, Dept Radiat Oncol, Seoul, South Korea

[2] Seoul Natl Univ, Grad Sch, Dept Adv Educ Clinician Scientists, Seoul, South Korea

[3] Catholic Univ Korea, Grad Sch, Dept Biomed & Hlth Sci, Seoul, South Korea

[4] Catholic Univ Korea, Coll Med, Dept Med Informat, Seoul, South Korea

[5] Catholic Univ Korea, Canc Res Inst, Coll Med, Seoul, South Korea

[6] Seoul Natl Univ, Dept Radiat Oncol, Seoul Metropolitan Govt, Boramae Med Ctr, Seoul, South Korea

[7] Armed Forces Med Res Inst, Div Biol Warfare Preparedness & Response, Daejeon, South Korea

[8] Seoul Natl Univ, Dept Radiat Oncol, Coll Med, Seoul, South Korea

[9] Seoul Natl Univ Hosp, Dept Radiat Oncol, Seoul, South Korea

[10] Seoul Natl Univ, Canc Res Inst, Coll Med, Seoul, South Korea

[11] Seoul Natl Univ, Dept Orthoped Surg, Coll Med, Seoul, South Korea

[12] Seoul Natl Univ, Dept Pathol, Coll Med, Seoul, South Korea

[13] Seoul Natl Univ, Dept Pathol, Seoul Metropolitan Govt, Boramae Med Ctr, Seoul, South Korea

[14] Sheikh Khalifa Specialty Hosp, Dept Radiat Oncol, Ras Al Khaymah, U Arab Emirates

来源：

MODERN PATHOLOGY | 2023年 / 36卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

germline mutation; radiation-induced sarcoma; second malignancy; somatic mutation; whole-genome sequencing; GERMLINE; PATTERNS; CANCERS;

D O I：

10.1016/j.modpat.2022.100004

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

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 al-terations 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-naive 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 iden-tified along with predisposing germline variants in the DNA-damageerepair 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.(c) 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

引用

页数：11

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