Biallelic alteration and dysregulation of the hippo pathway in mucinous tubular and spindle cell carcinoma of the kidney

Rohit Mehra, Pankaj Vats, Marcin Cieslik, Xuhong Cao, Fengyun Su, Sudhanshu Shukla, Aaron M. Udager, Rui Wang, Jincheng Pan, Katayoon Kasaian, Robert Lonigro, Javed Siddiqui, Kumpati Premkumar, Ganesh Palapattu, Alon Weizer, Khaled S. Hafez, J. Stuart Wolf, Ankur R. Sangoi, Kiril Trpkov, Adeboye O. OsunkoyaMing Zhou, Giovanna A. Giannico, Jesse K. McKenney, Saravana M. Dhanasekaran, Arul M. Chinnaiyan

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1258-1266
Number of pages9
JournalCancer Discovery
Volume6
Issue number11
DOIs
StatePublished - Nov 1 2016

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Carcinoma
Kidney
Renal Cell Carcinoma
Genes
Exome
Mutation
Nuclear Proteins
Tumor Suppressor Genes
Transcriptome
Cytogenetics

ASJC Scopus subject areas

  • Oncology

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Biallelic alteration and dysregulation of the hippo pathway in mucinous tubular and spindle cell carcinoma of the kidney. / Mehra, Rohit; Vats, Pankaj; Cieslik, Marcin; Cao, Xuhong; Su, Fengyun; Shukla, Sudhanshu; Udager, Aaron M.; Wang, Rui; Pan, Jincheng; Kasaian, Katayoon; Lonigro, Robert; Siddiqui, Javed; Premkumar, Kumpati; Palapattu, Ganesh; Weizer, Alon; Hafez, Khaled S.; Wolf, J. Stuart; Sangoi, Ankur R.; Trpkov, Kiril; Osunkoya, Adeboye O.; Zhou, Ming; Giannico, Giovanna A.; McKenney, Jesse K.; Dhanasekaran, Saravana M.; Chinnaiyan, Arul M.

In: Cancer Discovery, Vol. 6, No. 11, 01.11.2016, p. 1258-1266.

Research output: Contribution to journalArticle

Mehra, R, Vats, P, Cieslik, M, Cao, X, Su, F, Shukla, S, Udager, AM, Wang, R, Pan, J, Kasaian, K, Lonigro, R, Siddiqui, J, Premkumar, K, Palapattu, G, Weizer, A, Hafez, KS, Wolf, JS, Sangoi, AR, Trpkov, K, Osunkoya, AO, Zhou, M, Giannico, GA, McKenney, JK, Dhanasekaran, SM & Chinnaiyan, AM 2016, 'Biallelic alteration and dysregulation of the hippo pathway in mucinous tubular and spindle cell carcinoma of the kidney', Cancer Discovery, vol. 6, no. 11, pp. 1258-1266. https://doi.org/10.1158/2159-8290.CD-16-0267
Mehra, Rohit ; Vats, Pankaj ; Cieslik, Marcin ; Cao, Xuhong ; Su, Fengyun ; Shukla, Sudhanshu ; Udager, Aaron M. ; Wang, Rui ; Pan, Jincheng ; Kasaian, Katayoon ; Lonigro, Robert ; Siddiqui, Javed ; Premkumar, Kumpati ; Palapattu, Ganesh ; Weizer, Alon ; Hafez, Khaled S. ; Wolf, J. Stuart ; Sangoi, Ankur R. ; Trpkov, Kiril ; Osunkoya, Adeboye O. ; Zhou, Ming ; Giannico, Giovanna A. ; McKenney, Jesse K. ; Dhanasekaran, Saravana M. ; Chinnaiyan, Arul M. / Biallelic alteration and dysregulation of the hippo pathway in mucinous tubular and spindle cell carcinoma of the kidney. In: Cancer Discovery. 2016 ; Vol. 6, No. 11. pp. 1258-1266.
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T1 - Biallelic alteration and dysregulation of the hippo pathway in mucinous tubular and spindle cell carcinoma of the kidney

AU - Mehra, Rohit

AU - Vats, Pankaj

AU - Cieslik, Marcin

AU - Cao, Xuhong

AU - Su, Fengyun

AU - Shukla, Sudhanshu

AU - Udager, Aaron M.

AU - Wang, Rui

AU - Pan, Jincheng

AU - Kasaian, Katayoon

AU - Lonigro, Robert

AU - Siddiqui, Javed

AU - Premkumar, Kumpati

AU - Palapattu, Ganesh

AU - Weizer, Alon

AU - Hafez, Khaled S.

AU - Wolf, J. Stuart

AU - Sangoi, Ankur R.

AU - Trpkov, Kiril

AU - Osunkoya, Adeboye O.

AU - Zhou, Ming

AU - Giannico, Giovanna A.

AU - McKenney, Jesse K.

AU - Dhanasekaran, Saravana M.

AU - Chinnaiyan, Arul M.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

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