Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer

被引：298

作者：

Makohon-Moore, Alvin P. ^{[1
,2
,10
]}

Zhang, Ming ^{[3
]}

Reiter, Johannes G. ^{[4
,5
]}

Bozic, Ivana ^{[5
,6
]}

Allen, Benjamin ^{[5
,7
,8
]}

Kundu, Deepanjan ^{[4
]}

Chatterjee, Krishnendu ^{[4
]}

Wong, Fay ^{[3
]}

Jiao, Yuchen ^{[3
]}

Kohutek, Zachary A. ^{[9
]}

Hong, Jungeui ^{[10
]}

Attiyeh, Marc ^{[10
]}

Javier, Breanna ^{[10
]}

Wood, Laura D. ^{[1
,2
]}

Hruban, Ralph H. ^{[1
,2
,11
]}

Nowak, Martin A. ^{[5
,6
,12
]}

Papadopoulos, Nickolas ^{[3
]}

Kinzler, Kenneth W. ^{[3
]}

Vogelstein, Bert ^{[1
,3
,13
]}

Iacobuzio-Donahue, Christine A. ^{[10
,14
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA

[2] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Ludwig Ctr, Baltimore, MD USA

[4] IST Austria, Klosterneuburg, Austria

[5] Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA

[6] Harvard Univ, Dept Math, Cambridge, MA 02138 USA

[7] Harvard Univ, Ctr Math Sci & Applicat, Cambridge, MA 02138 USA

[8] Emmanuel Coll, Dept Math, Boston, MA USA

[9] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA

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

[11] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[12] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA

[13] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD USA

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

来源：

NATURE GENETICS | 2017年 / 49卷 / 03期

基金：

美国国家卫生研究院; 奥地利科学基金会;

关键词：

INTRATUMOR HETEROGENEITY; GENOMIC INSTABILITY; ACQUIRED-RESISTANCE; TUMOR EVOLUTION; DIVERSITY; PATTERNS; MODEL; PROGRESSION; LANDSCAPE; CARCINOMA;

D O I：

10.1038/ng.3764

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The extent of heterogeneity among driver gene mutations present in naturally occurring metastases-that is, treatment-naive metastatic disease-is largely unknown. To address this issue, we carried out 60x whole-genome sequencing of 26 metastases from four patients with pancreatic cancer. We found that identical mutations in known driver genes were present in every metastatic lesion for each patient studied. Passenger gene mutations, which do not have known or predicted functional consequences, accounted for all intratumoral heterogeneity. Even with respect to these passenger mutations, our analysis suggests that the genetic similarity among the founding cells of metastases was higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of known driver gene mutations among metastases in the same patient has critical and encouraging implications for the success of future targeted therapies in advanced-stage disease.

引用

页码：358 / 366

页数：9

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