YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines

Our plain-English summary of YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines, by Y.J. Kim, S.C. Lee, S.E. Kim, et al (Scientific Reports, 2020).

The study

• Authors: Y.J. Kim, S.C. Lee, S.E. Kim, S.H. Kim, S.K. Kim, C.S. Lee
• Journal: Scientific Reports
• Published: 2020;10(1):6209
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Recent experimental studies have demonstrated an essential role for the Hippo-Yes-associated protein (YAP) pathway in GNAQ/GNA11-induced tumorigenesis in uveal melanoma (UM). However, the association between YAP activity and clinical outcomes remains elusive. We investigated possible associations between YAP activity and clinicopathological features including survival outcomes in patients with UM using The Cancer Genome Atlas (TCGA) cohort and our local cohort. We estimated YAP activity by mRNA expression levels, Gene Set Variation Analysis (GSVA) for the TCGA cohort, and immunohistochemical YAP staining for the local cohort. In the TCGA cohort, most clinicopathological features including tumor stage, mitotic counts, mutation of genes, and tumor sizes did not significantly differ between low and high YAP activity groups. In the local cohort, YAP nuclear-positive staining was observed in 30 (42%) of 72 patients with primary UM. UM-specific survival was not significantly different between tumors with low and high YAP activities. Unlike mesothelioma cells harboring a mutation of negative regulators of YAP, the survival of multiple UM cell lines was not significantly reduced by YAP/TAZ depletion. Our results suggest that the effect of YAP on development, growth, and invasion of UM in actual patients is less than previously demonstrated in experimental studies.

In plain English

This study was about uveal melanoma, a cancer of the eye, not about asbestos. Mesothelioma appeared in its experiments only as two comparison cell lines; the discussion also mentioned data on mesothelioma patients. The authors examined whether the activity of a protein called YAP was linked to tumor features and survival. They used genetic data on 80 patients from The Cancer Genome Atlas and tumor tissue from 72 patients operated on at Severance Hospital, Seoul, in 2001 to 2012. In the local group, 30 of 72 tumors showed active (nuclear) YAP staining. Survival from uveal melanoma was not significantly different between low and high YAP groups by any of the three measures used. In the local group, the hazard ratio was 0.786 (95% confidence interval 0.369 to 1.675). In laboratory tests, reducing YAP and a related protein, TAZ, sharply lowered survival of two mesothelioma cell lines and a comparison line. It did not significantly lower survival of four uveal melanoma cell lines. The authors concluded that YAP's effects in patients were much less than experimental studies had shown. They noted that YAP mRNA levels may not reflect YAP activity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective analysis of two patient cohorts (a public genomic database cohort and a hospital cohort), plus laboratory cell-line experiments
• Who was studied: Patients with uveal melanoma. There were 80 from The Cancer Genome Atlas (TCGA) and a local cohort at Severance Hospital, Seoul, Republic of Korea, from January 2001 to December 2012. In the local cohort, 74 patients had resected primary tumors, and tissue was available for 72. The local cohort also included 16 liver metastasis specimens. The cell lines were four uveal melanoma lines (92.1, MP41, MP46, MP65), two mesothelioma lines (MSTO-211H, H2373) and RPE1 cells.
• Exposure: No asbestos or other environmental exposure was studied. The factor examined was YAP activity. In the TCGA cohort it was measured by YAP mRNA levels and a YAP gene-signature score. In the local cohort it was measured by immunohistochemical YAP staining. In the cell lines, YAP/TAZ was reduced using siRNA.
• Main results:
  • TCGA cohort: uveal melanoma-specific survival did not differ significantly between the low and high YAP mRNA expression groups (HR 1.173; 95% CI 0.483 to 2.850; P = 0.72).
  • TCGA cohort: uveal melanoma-specific survival did not differ between the low and high YAP signature groups (HR 1.272; 95% CI 0.523 to 3.093; P = 0.62).
  • Local cohort: of 72 primary tumors, 42 were YAP nuclear-negative and 30 were YAP nuclear-positive.
  • Local cohort: YAP nuclear-positive staining was not associated with poor uveal melanoma-specific survival (HR 0.786; 95% CI 0.369 to 1.675; P = 0.53).
  • Local cohort: metastases developed in 19 of 42 (45%) YAP nuclear-negative patients and 19 of 30 (63%) YAP nuclear-positive patients. No statistical test is reported for this comparison.
  • Of 16 liver metastasis tumors, 9 (56%) were YAP nuclear-positive. Staining patterns did not differ significantly between primary (n = 72) and metastatic (n = 16) tumors (P = 0.41).
  • Local cohort: the largest basal tumor diameter was reported as significantly smaller in the YAP nuclear-positive group (12.5 mm in the nuclear-negative group vs 10.9 mm in the nuclear-positive group; P = 0.038). Tumor thickness did not differ.
  • TCGA cohort: cancer stage, mitotic counts and gene mutation profiles did not differ between the low and high YAP activity groups.
  • TCGA cohort: the authors reported that epithelioid cell type was associated with high YAP activity.
  • At 144 hours after YAP/TAZ siRNA, relative survival was 0.02 (plus or minus 0.01) for RPE1 cells, 0.05 (plus or minus 0.02) for MSTO-211H mesothelioma cells and 0.28 (plus or minus 0.07) for H2373 mesothelioma cells. All three P values were less than 0.001.
  • The four uveal melanoma cell lines showed no significant reduction in survival at 72 hours after YAP/TAZ knockdown. Similar results were seen at 144 hours.
• The authors' conclusion: The authors concluded that YAP's effects on the development, growth and invasion of uveal melanoma in patients were much less than the effects seen in experimental studies. They also said YAP may contribute to the failure of anti-cancer therapies and that more studies are needed.
• Limitations the authors state:
  • The authors noted that YAP mRNA levels may not reflect YAP activity, so they also used a gene-signature score.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Mitotic Count, Mesothelioma.

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• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Targeting YAP in malignant pleural mesothelioma — W.Q. Zhang, Y.Y. Dai, et al. (2017)
• BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs — M. Carbone, L.K. Ferris, et al. (2012)
• Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma — R. Cunningham, S. Jia, et al. (2025)

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