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.
N1 - Funding Information:
This work was supported in part by NCI grant R01CA161870 (to A.M. Bowcock and J.W. Harbour) and R01CA125970 (to J.W. Harbour). We thank Asif Chowdhury for technical assistance, Anita Rogic for help with the migration assays, and Dr. Jacqueline Frost for editorial comments. We acknowledge core grant NCI No. CA1667 to MD Anderson that supports validation of cancer cell lines.
Publisher Copyright:
© 2019 American Association for Cancer Research.
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.
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U2 - 10.1158/1078-0432.CCR-18-3052
DO - 10.1158/1078-0432.CCR-18-3052
M3 - Article
C2 - 31227497
AN - SCOPUS:85070683197
SN - 1078-0432
VL - 25
SP - 5156
EP - 5166
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -