Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets

被引：866

作者：

Witkiewicz, Agnieszka K. ^{[1
,2
]}

McMillan, Elizabeth A. ^{[3
]}

Balaji, Uthra ^{[2
]}

Baek, GuemHee ^{[2
]}

Lin, Wan-Chi ^{[4
]}

Mansour, John

Mollaee, Mehri ^{[6
]}

Wagner, Kay-Uwe ^{[4
]}

Koduru, Prasad ^{[2
]}

Yopp, Adam ^{[5
]}

Choti, Michael A. ^{[5
]}

Yeo, Charles J. ^{[7
]}

McCue, Peter ^{[6
]}

White, Michael A. ^{[1
,3
]}

Knudsen, Erik S. ^{[1
,2
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Simmons Canc Ctr, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA

[4] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA

[6] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA

[7] Thomas Jefferson Univ, Dept Surg, Philadelphia, PA 19107 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

COPY-NUMBER ALTERATION; GENOMIC CHARACTERIZATION; DUCTAL ADENOCARCINOMA; SOMATIC MUTATION; TUMOR; CARCINOMA; PROGRESSION; SIGNATURES; DISCOVERY; MODELS;

D O I：

10.1038/ncomms7744

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.

引用

页数：11

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