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

Cancer Discov. 2016 Nov;6(11):1258-1266. doi: 10.1158/2159-8290.CD-16-0267. Epub 2016 Sep 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Mucinous / genetics*
  • Adenocarcinoma, Mucinous / pathology
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Exome / genetics
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Middle Aged
  • Mutation
  • Neurofibromin 2 / biosynthesis
  • Neurofibromin 2 / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / biosynthesis
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics
  • Signal Transduction / genetics
  • Transcriptome / genetics*

Substances

  • Biomarkers, Tumor
  • Carrier Proteins
  • Cell Cycle Proteins
  • Neurofibromin 2
  • SAV1 protein, human
  • HIPK2 protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • PTPN14 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor