Reliability of Whole-Exome Sequencing for Assessing Intratumor Genetic Heterogeneity

被引：77

作者：

Shi, Weiwei ^{[1
]}

Ng, Charlotte K. Y. ^{[2
,3
,4
]}

Lim, Raymond S. ^{[2
]}

Jiang, Tingting ^{[1
]}

Kumar, Sushant ^{[5
,6
]}

Li, Xiaotong ^{[1
,6
]}

Wali, Vikram B. ^{[1
]}

Piscuoglio, Salvatore ^{[2
,3
]}

Gerstein, Mark B. ^{[5
,6
,7
]}

Chagpar, Anees B. ^{[8
,9
]}

Weigelt, Britta ^{[2
]}

Pusztai, Lajos ^{[1
,9
]}

Reis-Filho, Jorge S. ^{[2
,10
]}

Hatzis, Christos ^{[1
,9
]}

机构：

[1] Yale Univ, Dept Med, Yale Sch Med, New Haven, CT 06520 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[3] Univ Hosp Basel, Inst Pathol, Basel, Switzerland

[4] Univ Basel, Dept Biomed, Basel, Switzerland

[5] Yale Univ, Mol Biophys & Biochem, New Haven, CT USA

[6] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA

[7] Yale Univ, Comp Sci, New Haven, CT USA

[8] Yale Univ, Yale Sch Med, Dept Surg, New Haven, CT USA

[9] Yale Canc Ctr, New Haven, CT 06510 USA

[10] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

来源：

CELL REPORTS | 2018年 / 25卷 / 06期

基金：

瑞士国家科学基金会;

关键词：

PRIMARY BREAST-CANCER; MUTATIONAL PROCESSES; COPY NUMBER; SOMATIC MUTATION; CLONAL EVOLUTION; TUMOR; DNA; SAMPLES; DIVERSITY; ARTIFACTS;

D O I：

10.1016/j.celrep.2018.10.046

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Multi-region sequencing is used to detect intratumor genetic heterogeneity (ITGH) in tumors. To assess whether genuine ITGH can be distinguished from sequencing artifacts, we performed whole-exome sequencing (WES) on three anatomically distinct regions of the same tumor with technical replicates to estimate technical noise. Somatic variants were detected with three different WES pipelines and subsequently validated by high-depth amplicon sequencing. The cancer-only pipeline was unreliable, with about 69% of the identified somatic variants being false positive. Even withmatched normal DNA for which 82% of the somatic variants were detected reliably, only 36%-78% were found consistently in technical replicate pairs. Overall, 34%-80% of the discordant somatic variants, which could be interpreted as ITGH, were found to constitute technical noise. Excluding mutations affecting low-mappability regions or occurring in certain mutational contexts was found to reduce artifacts, yet detection of subclonal mutations by WES in the absence of orthogonal validation remains unreliable.

引用

页码：1446 / 1457

页数：12

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