Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature.
Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature.
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DOI：
10.3390/cancers13040754
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发表时间：
2021-02-11
期刊：
影响因子：
5.2
通讯作者：
Nik-Zainal S
中科院分区：
文献类型：
--
作者：
Davies HR;Broad KD;Onadim Z;Price EA;Zou X;Sheriff I;Karaa EK;Scheimberg I;Reddy MA;Sagoo MS;Ohnuma SI;Nik-Zainal S
视网膜母细胞瘤是一种儿童眼睛癌症，被认为是由RB1基因的两个拷贝的失活突变引起的。大多数RB1突变可以通过临床筛查检测到。然而，视网膜母细胞瘤病例中存在RB1突变未被检测到的情况。我们使用全基因组测序来研究一组散发性视网膜母细胞瘤的突变情况，包括先前未发现的RB1两个拷贝突变的病例。我们寻找癌症驱动基因的突变，并揭示了破坏RB1的各种结构重排。此外，我们研究了突变负荷和特定突变模式（突变特征），揭示了暴露于化疗的肿瘤中与治疗相关的突变特征。全基因组测序鉴定所有突变类型的RB1突变的能力对视网膜母细胞瘤患者的临床管理和其家庭的遗传咨询具有重要意义。视网膜母细胞瘤的发展被认为需要RB1基因的两个等位基因的病理遗传变化。然而，存在RB1突变无法检测的情况，这表明恶性肿瘤的替代途径。我们使用全基因组测序（WGS）和转录组学来研究来自20名患者的散发性视网膜母细胞瘤的情况，寻找RB1和其他驱动突变，并研究突变特征。在所有视网膜母细胞瘤中至少发现了一种RB1突变，包括除了先前通过临床筛查发现的突变之外的新突变。10个肿瘤进行结构重排，涉及RB1从相对简单到极其复杂的重排模式，包括一个肿瘤中的chromothripsis样模式。从一名患者获得的双侧肿瘤具有保守的生殖系，但不同的体细胞RB1突变，表明独立的进化。突变特征分析显示，在化疗暴露的肿瘤中，与细胞分裂相关的特征占主导地位，没有紫外线相关的DNA损伤和深刻的铂相关突变特征。大多数RB1突变可通过临床筛查识别。然而，通过WGS检测其他难以捉摸的重排的分辨率和能力的提高对临床管理和复发风险的建议具有重要影响。
Retinoblastoma, a childhood cancer of the eye, is thought to be caused by inactivating mutations of both copies of the RB1 gene. The majority of RB1 mutations can be detected by clinical screening. However, retinoblastoma cases exist where mutations in RB1 have not been detected. We used whole-genome sequencing to investigate the landscape of mutations in a cohort of sporadic retinoblastomas, including cases where mutations in both copies of RB1 had not been previously identified. We looked for mutations in cancer driver genes and revealed a wide variety of structural rearrangements disrupting RB1. In addition, we investigated mutation burden and specific mutation patterns (mutational signatures), uncovering a treatment-related mutational signature in a tumour exposed to chemotherapy. The power of whole-genome sequencing to identify RB1 mutations of all mutation types can have significant relevance to the clinical management of retinoblastoma patients and genetic counselling of their families. The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
20.3
作者：
Grossmann, Vera;Tiacci, Enrico;Falini, Brunangelo
通讯作者：
Falini, Brunangelo
影响因子：
8.8
作者：
Hooper, ML
通讯作者：
Hooper, ML
影响因子：
82.9
作者：
Davies H;Glodzik D;Morganella S;Yates LR;Staaf J;Zou X;Ramakrishna M;Martin S;Boyault S;Sieuwerts AM;Simpson PT;King TA;Raine K;Eyfjord JE;Kong G;Borg Å;Birney E;Stunnenberg HG;van de Vijver MJ;Børresen-Dale AL;Martens JW;Span PN;Lakhani SR;Vincent-Salomon A;Sotiriou C;Tutt A;Thompson AM;Van Laere S;Richardson AL;Viari A;Campbell PJ;Stratton MR;Nik-Zainal S
通讯作者：
Nik-Zainal S
DOI：
10.1073/pnas.86.14.5502
发表时间：
1989-07-01
影响因子：
11.1
作者：
HONG, FD;HUANG, HJS;LEE, WH
通讯作者：
LEE, WH