The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma

被引：257

作者：

Harms, Paul William ^{[1
,2
,3
]}

Vats, Pankaj ^{[1
,4
]}

Verhaegen, Monique Elise ^{[3
]}

Robinson, Dan R. ^{[1
]}

Wu, Yi-Mi ^{[1
,2
]}

Dhanasekaran, Saravana Mohan ^{[1
,2
]}

Palanisamy, Nallasivam ^{[1
,2
,5
]}

Siddiqui, Javed ^{[1
,2
]}

Cao, Xuhong ^{[1
,6
]}

Su, Fengyun ^{[1
]}

Wang, Rui ^{[1
,2
]}

Xiao, Hong ^{[1
,2
,5
]}

Kunju, Lakshmi P. ^{[1
,2
]}

Mehra, Rohit ^{[1
,2
,5
]}

Tomlins, Scott A. ^{[1
,2
,7
,8
]}

Fullen, Douglas Randall ^{[2
,3
]}

Bichakjian, Christopher Keram ^{[3
]}

Johnson, Timothy M. ^{[3
]}

Dlugosz, Andrzej Antoni ^{[3
,9
]}

Chinnaiyan, Arul M. ^{[1
,2
,6
,7
,8
]}

机构：

[1] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Sch Med, Dept Dermatol, Ann Arbor, MI 48109 USA

[4] Bharathidasan Univ, Dept Biomed Sci, Tiruchirappalli, Tamil Nadu, India

[5] Henry Ford Hlth Syst, Dept Urol, Detroit, MI USA

[6] Univ Michigan, Sch Med, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Sch Med, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA

[9] Univ Michigan, Med Ctr, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

来源：

CANCER RESEARCH | 2015年 / 75卷 / 18期

关键词：

OF-FUNCTION MUTATIONS; SOMATIC MUTATION; GENE; EXPRESSION; CANCER; DISCOVERY; TOPHAT;

D O I：

10.1158/0008-5472.CAN-15-0702

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the molecular pathogenesis of MCPyV-negativeMCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study, we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n = 16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 +/- 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 +/- 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways. (C) 2015 AACR.

引用

页码：3720 / 3727

页数：8

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