Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden.
Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden.
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DOI：
10.1038/ncomms4756
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发表时间：
2014-04-29
影响因子：
16.6
通讯作者：
Hamdy, F. C.
中科院分区：
文献类型：
--
作者：
Cazier, J. -B.;Rao, S. R.;McLean, C. M.;Walker, A. L.;Wright, B. J.;Jaeger, E. E. M.;Kartsonaki, C.;Marsden, L.;Yau, C.;Camps, C.;Kaisaki, P.;Taylor, J.;Catto, J. W.;Tomlinson, I. P. M.;Kiltie, A. E.;Hamdy, F. C.
膀胱癌是恶性肿瘤死亡的主要原因。分子标记物可能比现有的预后因素更准确地预测疾病进展和行为。在这里，我们使用全基因组测序，以确定体细胞突变和染色体的变化，在14个不同级别和阶段的膀胱癌。除了检测已知的膀胱癌驱动突变外，我们还报告了CDKN 1A和FAT 1中复发性蛋白失活突变的鉴定。前者与TP 53突变或MDM 2扩增并不相互排斥，表明CDKN 1A功能障碍不仅仅是p53通路失活的替代机制。我们发现较高的肿瘤分期/分级与较大的克隆多样性、体细胞突变的数量和拷贝数变化的负担之间存在强正相关。原则上，在早期或低级别肿瘤中鉴定具有更大多样性和/或突变负荷的亚克隆可以鉴定具有高侵袭性进展风险的病变。 膀胱癌是一种复杂的遗传性疾病，是恶性肿瘤导致死亡的常见原因。在这里，作者对14种膀胱癌进行了全基因组测序，以表征该疾病的基因组景观，并表明突变负荷与这些样本中的肿瘤进展相关。
Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 amplification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression. Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
23.4
作者：
Denzinger, Stefan;Fritsche, Hans-Martin;Burger, Maximilian
通讯作者：
Burger, Maximilian
影响因子：
7
作者：
Lunter, Gerton;Goodson, Martin
通讯作者：
Goodson, Martin
影响因子：
5.8
作者：
Cazier, Jean-Baptiste;Holmes, Chris C.;Broxholme, John
通讯作者：
Broxholme, John
影响因子：
48
作者：
Roth, Andrew;Khattra, Jaswinder;Shah, Sohrab P.
通讯作者：
Shah, Sohrab P.