Development and validation of a whole-exome sequencing test for simultaneous detection of point mutations, indels and copy-number alterations for precision cancer care

被引：60

作者：

Rennert, Hanna ^{[1
,2
]}

Eng, Kenneth ^{[1
,3
]}

Zhang, Tuo ^{[1
,4
]}

Tan, Adrian ^{[1
,4
]}

Xiang, Jenny ^{[1
,4
]}

Romanel, Alessandro ^{[5
]}

Kim, Robert ^{[1
,2
]}

Tam, Wayne ^{[2
]}

Liu, Yen-Chun ^{[2
]}

Bhinder, Bhavneet ^{[1
]}

Cyrta, Joanna ^{[1
]}

Beltran, Himisha ^{[1
,6
]}

Robinson, Brian ^{[1
,2
]}

Mosquera, Juan Miguel ^{[1
,2
]}

Fernandes, Helen ^{[1
,2
]}

Demichelis, Francesca ^{[5
]}

Sboner, Andrea ^{[1
,2
,3
]}

Kluk, Michael ^{[1
,2
]}

Rubin, Mark A. ^{[1
,2
]}

Elemento, Olivier ^{[1
,3
]}

机构：

[1] Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York Presbyterian Hosp, New York, NY 10065 USA

[2] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA

[3] Weill Cornell Med, Inst Computat Biomed, New York, NY 10065 USA

[4] Weill Cornell Med, Genom Core Facil, New York, NY USA

[5] Univ Trento, Ctr Integrat Biol CIBIO, Trento, Italy

[6] Weill Cornell Med, Div Hematol & Med Oncol, Dept Med, New York, NY USA

来源：

NPJ GENOMIC MEDICINE | 2016年 / 1卷

关键词：

CTLA-4; BLOCKADE; MEDICINE; DISORDERS; GENOMICS; MELANOMA;

D O I：

10.1038/npjgenmed.2016.19

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We describe Exome Cancer Test v1.0 (EXaCT-1), the first New York State-Department of Health-approved whole-exome sequencing (WES)-based test for precision cancer care. EXaCT-1 uses HaloPlex (Agilent) target enrichment followed by next-generation sequencing (Illumina) of tumour and matched constitutional control DNA. We present a detailed clinical development and validation pipeline suitable for simultaneous detection of somatic point/indel mutations and copy-number alterations (CNAs). A computational framework for data analysis, reporting and sign-out is also presented. For the validation, we tested EXaCT-1 on 57 tumours covering five distinct clinically relevant mutations. Results demonstrated elevated and uniform coverage compatible with clinical testing as well as complete concordance in variant quality metrics between formalin-fixed paraffin embedded and fresh-frozen tumours. Extensive sensitivity studies identified limits of detection threshold for point/indel mutations and CNAs. Prospective analysis of 337 cancer cases revealed mutations in clinically relevant genes in 82% of tumours, demonstrating that EXaCT-1 is an accurate and sensitive method for identifying actionable mutations, with reasonable costs and time, greatly expanding its utility for advanced cancer care.

引用

页数：11