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Cancer Discov. 2016 Nov;6(11):1258-1266. Epub 2016 Sep 7.

Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney.

Author information

1
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.
2
Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan.
3
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
4
Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.
5
Howard Hughes Medical Institute, Ann Arbor, Michigan.
6
Department of Urology, First Affiliated Hospital, Sun-Yat Sen University, Guangzhou, China.
7
Department of Urology, University of Michigan Health System, Ann Arbor, Michigan.
8
El Camino Hospital, Department of Pathology, Mountain View, California.
9
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
10
Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia.
11
Department of Pathology, New York University School of Medicine, New York, New York.
12
Departments of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
13
Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, Ohio.
14
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan. arul@umich.edu.

Abstract

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation.

SIGNIFICANCE:

MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258-66. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1197.

PMID:
27604489
PMCID:
PMC5096979
DOI:
10.1158/2159-8290.CD-16-0267
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

of Potential Conflicts of Interest: None

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