Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/BAF45A

Hima Anbunathan, Ruth Verstraten, Arun D. Singh, J. William Harbour, Anne M. Bowcock

Research output: Contribution to journalArticle

Abstract

Purpose: Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2, and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1, or EIF1AX. There are other characteristic chromosomal alterations, but their significance is not clear. Experimental Design: To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings. Results: We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of PHF10/BAF45a and one with a frameshift mutation with concomitant loss of the wild-type allele. Down-regulation of PHF10 in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for PHF10 as a novel tumor suppressor at Chr 6q27. Conclusions: Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for PHF10.

Original languageEnglish (US)
Pages (from-to)5156-5166
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number16
DOIs
StatePublished - Aug 15 2019

Fingerprint

Carcinogenesis
Mutation
Transcriptome
Genes
Neoplasms
Frameshift Mutation
Chromosomes, Human, Pair 3
Multigene Family
Tumor Cell Line
Cluster Analysis
Research Design
Down-Regulation
Alleles
Neoplasm Metastasis
Uveal melanoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/BAF45A. / Anbunathan, Hima; Verstraten, Ruth; Singh, Arun D.; William Harbour, J.; Bowcock, Anne M.

In: Clinical Cancer Research, Vol. 25, No. 16, 15.08.2019, p. 5156-5166.

Research output: Contribution to journalArticle

@article{56c16ca1eec4467b9a65442cadead46e,
title = "Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/BAF45A",
abstract = "Purpose: Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2, and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1, or EIF1AX. There are other characteristic chromosomal alterations, but their significance is not clear. Experimental Design: To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings. Results: We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of PHF10/BAF45a and one with a frameshift mutation with concomitant loss of the wild-type allele. Down-regulation of PHF10 in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for PHF10 as a novel tumor suppressor at Chr 6q27. Conclusions: Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for PHF10.",
author = "Hima Anbunathan and Ruth Verstraten and Singh, {Arun D.} and {William Harbour}, J. and Bowcock, {Anne M.}",
year = "2019",
month = "8",
day = "15",
doi = "10.1158/1078-0432.CCR-18-3052",
language = "English (US)",
volume = "25",
pages = "5156--5166",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

TY - JOUR

T1 - Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/BAF45A

AU - Anbunathan, Hima

AU - Verstraten, Ruth

AU - Singh, Arun D.

AU - William Harbour, J.

AU - Bowcock, Anne M.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - Purpose: Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2, and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1, or EIF1AX. There are other characteristic chromosomal alterations, but their significance is not clear. Experimental Design: To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings. Results: We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of PHF10/BAF45a and one with a frameshift mutation with concomitant loss of the wild-type allele. Down-regulation of PHF10 in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for PHF10 as a novel tumor suppressor at Chr 6q27. Conclusions: Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for PHF10.

AB - Purpose: Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2, and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1, or EIF1AX. There are other characteristic chromosomal alterations, but their significance is not clear. Experimental Design: To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings. Results: We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of PHF10/BAF45a and one with a frameshift mutation with concomitant loss of the wild-type allele. Down-regulation of PHF10 in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for PHF10 as a novel tumor suppressor at Chr 6q27. Conclusions: Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for PHF10.

UR - http://www.scopus.com/inward/record.url?scp=85070683197&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070683197&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-3052

DO - 10.1158/1078-0432.CCR-18-3052

M3 - Article

VL - 25

SP - 5156

EP - 5166

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 16

ER -