Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing.
Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing.
复制标题
DOI：
10.1038/s41436-020-0880-8
复制
发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Jones SJM
中科院分区：
文献类型：
--
作者：
Thibodeau ML;O'Neill K;Dixon K;Reisle C;Mungall KL;Krzywinski M;Shen Y;Lim HJ;Cheng D;Tse K;Wong T;Chuah E;Fok A;Sun S;Renouf D;Schaeffer DF;Cremin C;Chia S;Young S;Pandoh P;Pleasance S;Pleasance E;Mungall AJ;Moore R;Yip S;Karsan A;Laskin J;Marra MA;Schrader KA;Jones SJM
鉴于目前短读下一代测序的局限性，结构变异（SV）可能是遗传性癌症综合征的一个被低估的原因。在这里，我们研究了长读段测序在解析通过短读段基因组测序检测的癌症易感基因中的生殖系SV中的效用。使用Illumina基因组测序在具有配对肿瘤基因组和转录组测序的669名晚期癌症患者的队列中鉴定已知或疑似有害的生殖系SV。随后通过Oxford Nanopore长读取测序评估候选SV。纳米孔测序证实了8种简单的致病性或可能致病的SV，解决了另外3种变异，其影响无法通过短读测序完全阐明。染色体16p13上的复发性测序伪像和染色体5q35上的一个复杂重排随后被归类为可能是良性的，从而避免了进一步临床评估的需要。在一个复杂的致病性重排影响TSC 2的情况下，变异构型进一步解决。我们的研究结果表明，长读段测序可以提高种系SV的验证、分辨率和分类。这对结果的返回、级联携带者检测、癌症筛查和预防性干预具有重要意义。
Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing. Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing. Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2. Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.
登录
查看更多内容
影响因子：
11.5
作者：
Zhao, Eric Y.;Shen, Yaoqing;Jones, Steven J. M.
通讯作者：
Jones, Steven J. M.
影响因子：
64.8
作者：
Sudmant PH;Rausch T;Gardner EJ;Handsaker RE;Abyzov A;Huddleston J;Zhang Y;Ye K;Jun G;Fritz MH;Konkel MK;Malhotra A;Stütz AM;Shi X;Casale FP;Chen J;Hormozdiari F;Dayama G;Chen K;Malig M;Chaisson MJP;Walter K;Meiers S;Kashin S;Garrison E;Auton A;Lam HYK;Mu XJ;Alkan C;Antaki D;Bae T;Cerveira E;Chines P;Chong Z;Clarke L;Dal E;Ding L;Emery S;Fan X;Gujral M;Kahveci F;Kidd JM;Kong Y;Lameijer EW;McCarthy S;Flicek P;Gibbs RA;Marth G;Mason CE;Menelaou A;Muzny DM;Nelson BJ;Noor A;Parrish NF;Pendleton M;Quitadamo A;Raeder B;Schadt EE;Romanovitch M;Schlattl A;Sebra R;Shabalin AA;Untergasser A;Walker JA;Wang M;Yu F;Zhang C;Zhang J;Zheng-Bradley X;Zhou W;Zichner T;Sebat J;Batzer MA;McCarroll SA;1000 Genomes Project Consortium;Mills RE;Gerstein MB;Bashir A;Stegle O;Devine SE;Lee C;Eichler EE;Korbel JO
通讯作者：
Korbel JO
影响因子：
48
作者：
Sedlazeck FJ;Rescheneder P;Smolka M;Fang H;Nattestad M;von Haeseler A;Schatz MC
通讯作者：
Schatz MC
影响因子：
1.8
作者：
Wong HL;Yang KC;Shen Y;Zhao EY;Loree JM;Kennecke HF;Kalloger SE;Karasinska JM;Lim HJ;Mungall AJ;Feng X;Davies JM;Schrader K;Zhou C;Karsan A;Jones SJM;Laskin J;Marra MA;Schaeffer DF;Gorski SM;Renouf DJ
通讯作者：
Renouf DJ
影响因子：
2.7
作者：
Cheng DT;Prasad M;Chekaluk Y;Benayed R;Sadowska J;Zehir A;Syed A;Wang YE;Somar J;Li Y;Yelskaya Z;Wong D;Robson ME;Offit K;Berger MF;Nafa K;Ladanyi M;Zhang L
通讯作者：
Zhang L