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



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.
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan.|Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Rohit
R
Mehra
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.|Michigan Center for Translational Pathology, Ann Arbor, Michigan.|Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.
Pankaj
P
Vats
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Marcin
M
Cieslik
Michigan Center for Translational Pathology, Ann Arbor, Michigan.|Howard Hughes Medical Institute, Ann Arbor, Michigan.
Xuhong
X
Cao
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Fengyun
F
Su
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Sudhanshu
S
Shukla
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.
Aaron M
AM
Udager
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Rui
R
Wang
Department of Urology, First Affiliated Hospital, Sun-Yat Sen University, Guangzhou, China.
Jincheng
J
Pan
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Katayoon
K
Kasaian
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Robert
R
Lonigro
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Javed
J
Siddiqui
Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.
Kumpati
K
Premkumar
Department of Urology, University of Michigan Health System, Ann Arbor, Michigan.
Ganesh
G
Palapattu
Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan.|Department of Urology, University of Michigan Health System, Ann Arbor, Michigan.
Alon
A
Weizer
Department of Urology, University of Michigan Health System, Ann Arbor, Michigan.
Khaled S
KS
Hafez
Department of Urology, University of Michigan Health System, Ann Arbor, Michigan.
J Stuart
JS
Wolf
El Camino Hospital, Department of Pathology, Mountain View, California.
Ankur R
AR
Sangoi
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
Kiril
K
Trpkov
Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia.
Adeboye O
AO
Osunkoya
Department of Pathology, New York University School of Medicine, New York, New York.
Ming
M
Zhou
Departments of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Giovanna
G
Giannico
Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, Ohio.
Jesse K
JK
McKenney
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.|Michigan Center for Translational Pathology, Ann Arbor, Michigan.
Saravana M
SM
Dhanasekaran
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan. arul@umich.edu.|Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan.|Michigan Center for Translational Pathology, Ann Arbor, Michigan.|Howard Hughes Medical Institute, Ann Arbor, Michigan.|Department of Urology, University of Michigan Health System, Ann Arbor, Michigan.
Arul M
AM
Chinnaiyan
D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D059472:Exome / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D000090683:Hippo Signaling Pathway; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D025581:Neurofibromin 2 / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D025581:Neurofibromin 2; C415864:SAV1 protein, human; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor