Evolutionary history of human colitis-associated colorectal cancer.
Evolutionary history of human colitis-associated colorectal cancer.
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DOI：
10.1136/gutjnl-2018-316191
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发表时间：
2019-06
期刊：
影响因子：
24.5
通讯作者：
Graham TA
中科院分区：
文献类型：
--
作者：
Baker AM;Cross W;Curtius K;Al Bakir I;Choi CR;Davis HL;Temko D;Biswas S;Martinez P;Williams MJ;Lindsay JO;Feakins R;Vega R;Hayes SJ;Tomlinson IPM;McDonald SAC;Moorghen M;Silver A;East JE;Wright NA;Wang LM;Rodriguez-Justo M;Jansen M;Hart AL;Leedham SJ;Graham TA
IBD导致发生结直肠癌（CRC）的终生风险增加，结肠炎相关CRC（CA-CRC）与散发性CRC（S-CRC）在分子上不同。在这里，我们已经解剖了CA-CRC的进化历史，使用多区域测序。对来自12名CA-CRC患者的新鲜冷冻的癌、邻近非癌粘膜和血液的多个区域进行外显子组测序（n=55个外显子组），并且用正交方法验证关键变体。使用单核苷酸多态性阵列和低通全基因组测序对存档的非异型增生粘膜（n=9）、低度异型增生（LGD; n=30）、高度异型增生（HGD; n=13）、混合型LGD/HGD（n=7）和CA-CRC（n=19）进行全基因组拷贝数分析。系统发生树进行了重建，进化分析用于揭示导致CA-CRC的事件的时间顺序。10/12例肿瘤微卫星稳定，中位突变负荷为3.0个单核苷酸改变（SNA）/Mb，比S-CRC（2.5个SNA/Mb）高约20%，与衰老相关突变过程升高一致。非异型增生粘膜有相当大的突变负荷（中位数47 SNA），包括与邻近CA-CRC共享的突变，表明癌前突变场。CA-CRC通常接近三倍体（40%）或接近四倍体（20%），系统发育分析显示，拷贝数改变（CNA）开始在非异型增生的肠道中积累，但LGD/HGD转换通常涉及间断的“灾难性”CNA增加。进化的基因组分析揭示了癌前克隆携带广泛的SNA和CNA，在HGD时进展为癌症涉及CNA的急剧增加。癌变区域的检测对于监测来说是一个令人鼓舞的前景，但是间断性的演变可能会限制早期检测的窗口。
IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase. Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
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作者：
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通讯作者：
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影响因子：
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Shihab, Hashem A.;Gough, Julian;Cooper, David N.;Stenson, Peter D.;Barker, Gary L. A.;Edwards, Keith J.;Day, Ian N. M.;Gaunt, Tom R.
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Gaunt, Tom R.
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通讯作者：
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影响因子：
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作者：
Hao, XP;Frayling, IM;Tomlinson, IPM
通讯作者：
Tomlinson, IPM